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UNIVERSITY OF ILLINOIS
DEPARTMENT OF CHEMISTRY AND CHEMICAL ENGINEERING
ORGANIC SEMINARS
1955-1956
iM
SEMINAR TOPICS
CHEMISTRY 435 I SEMESTER 1955-56
Nitration With Cyanohydrin Nitrates
S. J. Strycker, September 23 1
Some Rearrangement Reactions of Organic Phosphites
J. C. Little, September 23 4
The Biosynthesis of Cholesterol
R. G. Schultz, September 30 7
The Chemistry of Pyrrocoline
Donald S. Matteson, September JO 11
Acetylenic Ethers
Albert J . Lauck, October 7 15
Cylic Diarsines
A. J. Reedy, October 7 19
The Tropolone Benzoic Acid Rearrangement
L. M. Werbel, October 14 23
Reduction of Aromatic Systems With Dissolved Metals
B. M. Vittimberga, October 14 26
Theoretical Aspects of Nuclear Magnetic Resonance
E. W. Cantrall, October 21 30
Nuclear Magnetic Resonance: Applications to Organic
Chemistry
Louis R. Haefele, October 21 34
Organic Fluorine Compounds
R. J. Crawford, October 28 ♦. 37
Organic Reactions Effected by Ionizing Radiation
Part One: Non Aqueous Systems
R. A. Scherrer, October 28 40
Organic Reactions Effected by Ionizing Radiations
Part Two: Aqueous Systems
W. DeJarlais, November 4 43
Transannular Reactions and Interactions
Kenneth Conrow, November 4 47
Stereochemistry of Reserpine and Deserpidine
Ralph J . Leary , November 11 50
The Ivanoff Reagent
Norman Shachat, November 18 , 55
--2
Steric Effects in Unimolecular Olefin -Forming
Elimination Reactions
Joe A. Adamcik, November 18 58
A New Route to Tertiary a-Keto Alcohols
H. S. Killam, December 2 62
Acid Hydrolysis of Reissert Compounds
J . S . Dix, December 2 65
Mechanisms for the Hydrolysis of Organic Phosphates
John F. Zack, Jr., December 9 71
Epoxyethers
Willis E. Cupery, December 9 Jh
Reductions With Formic Acid
C. W. Schimelpfenig, December 9 78
Quaterenes
G. W. Griffin, December 1 6 8l
New Cyclobutane Derivatives: Preparation and Reactions
J . H. Rassweiler, December 16 85
Isomerization of 5-Aminotetrazoles
M. E. Peterson, January 6 88
Structure Determination by Raman Spectroscopy
W. A. Remers, January 6 91
Anodic Synthesis of Long Chain Unsaturated Fatty Acids
Thet San, January 6 95
Polyacetylenic Compounds From Plants of the Compositae
Family
Philip N. James, January 13 99
Kinetic Conformational Analysis of Cyclohexane
Derivatives
Carol K. Sauers, January 13 103
NITRATION WITH CYANOHYDRIN NITRATES
Reported by S. J. Strycker September 23, 1955
The nitrate esters of ketone cyanohydrins, I, are unique
reagents for effecting nitration under alkaline conditions.1"3
Previous nitration attempts involving the use of nitrate esters
have either led to poor yields of the nitrate,4"7 except in the
case of certain active methylene compounds,8'9 or to alkyla-
tion.10'11 This type of compound, heretofore unknown, fulfills
the structural requirements found to be necessary from a
preliminary study on the nitration of amines:12 (l) the nitrate
ester should possess no a-hydrogen atoms; (2) it should contain
bulky groups around the a-carbon atom to hinder bimolecular
displacement reactions; and, (3) it should contain an electro-
negative group to weaken the oxygen -nitrogen bond.
(CH3)2C-OH + KN03 (CH3CO)20> (CH3)2C-ON02
CN CN
I
Both primary and secondary amines are converted to the
corresponding nitramines in excellent yields by the use of I.
(CH3)2C-ON02 + 2R2NH > R2NN02 + R2N-C-(CH3)2
CN CN
Primary amines require a solvent such as acetonitrile or
tetrahydrofuran but the secondary amines serve as their own
solvent. Aromatic amines and aliphatic amines with branching
on the a-carbon atom are unaffected by nitrate esters.
The unique reactivity of I appears to be due to three
factors:
(1) the tertiary nature of the nitrate ester reduces the
possibility of a simple alkylation reaction;
(2) the presence of the electronegative nitrile group
weakens the oxygen-nitrogen bond, thereby favoring attack
at the nitro group; and
(3) the cyanohydrin structure is easily decomposed upon
attack by a nucleophilic reagent.
Several active methylene compounds have been nitrated
effectively by means of I.2 The solvent used was of necessity
non-hydroxylic since it was found that metal alkoxides readily
destroyed the nitrate ester.3 Typical conditions are the use
of a threefold excess of sodiomalonic ester in tetrahydrofuran
with sodium hydride as the base.
Na[CH(C02C2H5)2] + I » CH(C02C2H5 )2 + NaCN + (CH3)2CO
N02
-2-
The fact that an excess of sodium hydride degraded the
nitromalonic ester to ethyl nitroacetate led to the discovery
that a general synthesis of a-nitroesters could be realized
by means of this reagent. Thisjnethod is more general and more
efficient than previous ones.
13-15
The proposed mechanism is:
0N02
i
(CH3)2C-CN + B%
0 CH3
6' W + i r£~
B N.^..Oi^/C--..CN
0,.
a
CH:
£ BN02 + (CH3)2C0 + CN'
RCH(C02C2H5 )z
or
R-CHC02C2H5
COCH3
2NaH
->
RCHC02C2H5
N02
Metal alkoxides react with I to produce a nitrate ester
plus the corresponding ester of a-hydroxyisobutyric acid.3
Although the yields are low the reaction is a general one.
2NaOR + I
H+
H20
RONOj
(CH3)2C-C00R
OH
An intramolecular denitration step initiated by the strongly
nucleophilic imide ion is proposed.
(CH3)2-C-0N02
I T
R0-C=N"
+ c
— — > (CH3)2ct)0R + [NH2N02]
H*° OH
N20 + H20
Nitrous oxide was identified by means of an infrared spectro-
meter. The predominance of attack at the nitrile instead of
at the nitro group by the alkoxide ion is attributed to the
unique structural features of I and to the fact that the
alkoxide ion is a more powerful nucleophile than either amines
or active methylene anions.16
BIBLIOGRAPHY
1. W. D. Emmons and J. P. Freeman, J. Am. Chem. Soc, 77,
^387 (1955).
2. W. D. Emmons and J. P. Freeman, ibid., 77 , 4391 (1955).
3. W. D. Emmons and J. P. Freeman, ibid. , 77, 4673 (1955)*
4. H. J. Backer, Sammlung Chem. und Chem. Tech. Vortrage,
18, 365 (1912).
5. E. Bamberger, Ber., ££, 2321 (1920).
6. H. Wieland, P. Garbsch and J. J. Chavan, Ann., 46l, 295
(1928).
7. R. L. Shriner and E. A. Parker, J. Am. Chem. Soc, 55,
766 (1933).
-3-
8. W. Wislicenus and A. Endres, Ber., 3£, 1755 (1902).
9. W. Wislicenus and H. Wren, ibid., j5§7 502 (1905).
10. E. S. Lane, J. Chem. Soc . , 1172 (1955).
11. D. T. Gibson and A. K. Macbeth, ibid., 438 (1921).
12. W. D. Emmons, K. S. McCallum and J. p. Freeman, J. Org.
Chem., 12, 1472 (1954). b
13. W. Steinkopf and A. Supan, Ber., 43, 3248 (1910).
14. J. Schmidt and K. Widmann, ibid., 42. 1893 (1909).
5# ?; P^?S,/^,BC Hass and K- s- Warren, J. Am. Chem. Soc,
Xi» ^07o (1949).
16. G. S. Hammond, ibid., 77, 334 (1955).
-4-
SOME REARRANGEMENT REACTIONS OP ORGANIC PHOSPHITES
Reported by J. C. Little September 23, 1955
Michaelis1 and Arbusov1 have reported the reaction of
trivalent phosphorus compounds having at least one ester
grouping with compounds possessing a polarized covalent bond
to form pentavalent phosphorus derivatives. The path of the
reaction could conceivably involve two successive nucleophilic
attacks, first by the phosphorus on the positive center and
then by the resulting anion on the ester grouping1 :
VP.-"
I.
OR ^+<£
+ R!X
II.
A i, OR A J)
>P^ + X" v \p
B^ \R" B^ ^R1
+ RX
III.
i IV.
V.
Several articles have been published recently describing
preparations which utilize the Michaelis-Arbusov reaction.
Table I lists a few of these applications and will serve to
illustrate the versatility of the reaction.
Tab
le I.
R»
X
A
_B_
Yield
Ref.
,iVCCl3
XTh-(CHa)5
CI
EtO
EtO
9*%
2
I
EtO
EtO
61
3
n-Bu yo
OTs
EtO
EtO
82
4
(CH3)2NC-
CI
EtO
EtO
92
5
EtS
CI
n-Pr
n-Pr
95
6
RCOCH2CH2
MeEt
2NI
EtO
EtO
72
7
R
Et
Et
Na
Et
n-Pr
Et
A reaction closely related to the Michaelis-Arbusov re-
action involves the treatment of phosphites with carbonyl
compounds. Prior to 19 54, there had been reports that a-halo
aldehydes, ketones, and esters underwent the normal Michaelis-
Arbusov reaction with trialkyl phosphites8. However, Perkow9
and later Allen and Johnson10 showed that the product was a
vinyl phosphate rather than the usual phosphonate:
(RO)2POR
0 X
i> i
+ R"C-CH-R" «
VI* R= Alkyl. VII.
+ (R0)2P-0C=CHR"' + R'X
i
R"
VIII. IX.
11
No readily acceptable reaction path has been proposed9
but if we consider an initial nucleophilic attack by the
phosphorus electrons, we have three alternatives: attack at
the oxygen10, carbonyl carbon10, or at the a-carbon9.
Initial attack on the carbonyl oxygen is not without
analogy. The action of zinc on a-halo12 and a-acetoxy13 ketones
possibly proceeds through attack on the carbonyl oxygen13, if
we allow the phosphorus to play the same role as the zinc and
assume an additional nucleophilic attack on the ester group by
the resulting anion, we have:
r*.
OAC
Zn: — >0
6
T^r
X.
Zn-tf
=CN + OAc
XI.
R'O
^P:
VI.
c — c —
VII.
j>p-cf i
XII.
/
0-
4 _>P-0-C=C + R'X
VIII.
IX
Initial attack on the carbonyl carbon might be favored
since this is the "normal" point of nucleophilic attack. In
this case formation of the intermediate XIV followed by a
1,2-shift by the phosphorus from carbon to oxygen is con-
ceivable:
R
i
0
.P:
VI.
P x
i
VII.
-*
R
i
0
X
9
Ip— c— c
I I I
XIII.
X*
0
i \- t
XIV. -
VIII
and
IX
This approach draws support from observations made with a
similar reaction with dialkyl hydrogen phosphites. Abramov11'14
demonstrated the formation of hydroxyalkyl phosphonates similar
to XIV from aldehydes and ketones using a basic catalyst. A
striking parallel is to be found in the condensation of
chloral with a series of dialkyl hydrogen phosphites in the
absence of base15. The products in this case were 0,0-dialkyl-
l-hydroxyl-2,2,2-trichloroethyl phosphonates XVII whose
structures were confirmed by physical data16. Mild treatment
with alkali yielded the vinyl phosphates XVIII. These struct-
ures were confirmed independently by two groups16' 17.
(R0)2P0H + CI3CCHO
XV. XVI.
(R0)2P-CH0HCC13 Na0H> (R0)2P-0CH=CC12
-HC1
XVII.
XVIII.
The third alternative attack by the phosphorus electrons
at the a-carbon atom can be compared to the original Michaelis-
Arbusov reaction described above. The observation by perkow9
that the chloroacetaldehydes react in the order: CI3CCHO >
C12CHCH0 > C1CH2CH0 seems somewhat contradictory, however.
Additional investigations have undoubtedly been already
undertaken, and the final result should help clarify some of
the confusion concerning the course of these reactions,
particularly in the patent literature18.
-6-
BIBLIOGRAPHY
1. (a) A. Michaelis et al., Berichte 30, 1003 (1897); H>
1048 (1898). (b) A. E. Arbusov, Dissertation, Kazan
(1905); Berichte ^8, 1171 (1905); J. russ. physik-chem.
Ges. 42, 395 (1910J. (c) A. N. Pudovik, Dok. Akad.
Nauk TSSSR) 84, 519 (1952).
2. See I. S. Bengelsdorf and L. B. Barron, J.A.C.S., 77 »
2869 (1955).
3. J. P. Parikh and A. Burger, J.A.C.S., TJ_, 2386 (1955).
4. T. C. Myers, S. Preis and E. V. Jensen, J.A.C.S., £6,
4172 (1954).
5. T. Reetz, D. H. Chadwick, E. E. Hardy and S. Kaufman,
J.A.C.S., 71, 3813 (1955).
6. D. C. Morrison, J.A.C.S., 77, l8l (1955).
7. T. C. Myers, R. G. Harvey and E. V, Jensen, J.A.C.S., TJ_,
3101 (1955).
8. See J. F. Allen and 0. H. Johnson, J.A.C.S., H, 2871
(1955) for various references.
9. W. Perkow et al., Naturwissenschaften 32, 353 (1952);
Berichte 8£, 755 (1954); 88, 662 (1955 )T
10. J. F. Allen and 0. H. Johnson, loc. clt .
11. V. S. Abramov et al., Zhur. Obsch. Khim. USSR 22, 647
(1952).
12. C. K. Ingold and C. W. Shoppee, J. Chem. Soc, 1928, 401.
13. R. B. Woodward et al., J.A.C.S., 14, 4225 (1952"5T"
14. V. S. Abramov et al., Dok. Akad. Nauk (SSSR) 73, 487
(1950); Zhur. Obsch. Khim. USSR 2J5, 257, 1013~Tl953);
24, 123, 315 (1954); 25, 1141 (1955).
15. W. F. Barthel, P. A. Giang and S. A. Hall, J.A.C.S., 76,
4186 (1954). ~~
16. W. Lorenz, A. Henglein and G. Schrader, J.A.C.S., 77,
2554 (1955); W. Lorenz, U. S. Pat. 2,701,225 (195477
17. W. F. Barthel, B. H. Alexander, P. A. Giang and S. A. Hall,
J.A.C.S., 21, 2424 (1955).
18. w. E. Craig and W. F. Hester, U. S. Pat. 2,485,573 (1949);
E. K. Fields, U. S. Pat. 2,579,810 (1951); R. H. Wiley,
U. S. Pat. 2,478,441 (1949). See also references 8 and 15.
19. G. M. Kosolapoff, "Organophosphorus Compounds", John Wiley
and Sons, New York, 1950.
20. C. K. Ingold, "Structure and Mechanism in Organic
Chemistry", Cornell University Press, Ithaca, New York,
1953.
-7-
THE BIOSYNTHESIS OF CHOLESTEROL
Reported by R. G. Schultz September 50, 1955
In 1934 Robinson1 proposed that cholesterol (I) was
formed by the cyclization of squalene; in 1935 Bryant2
postulated carotene as a precursor; in 1938 Reichstein3
suggested that nine moles of a triose condensed to form
cholesterol.
It was noted as early as 1926 that the feeding of
squalene (II) increased the production of cholesterol in rats
by as much as 100$4 • Squalene was known primarily as a con-
stituent of shark livers, but it has since been found in rat
liver and human fatty tissue5.
It was shown using methyl C14 and carboxyl C14 labeled
acetate that acetic acid was a precursor of cholesterol6.
Labeled sterols were produced by several methods. Cholesterol
was synthesized by feeding rats labeled acetate and then
isolating the sterol from the liver6. Ergosterol was
synthesized by incubating yeast preparations with labeled
acetate7.
Bloch8 determined the ratio of methyl carbons to
carboxyl carbons of acetate in cholesterol to be 15/12 (calc.
1.25* found 1.27). The isooctyl side chain of cholesterol
was removed by well known reactions and the tetracyclic pro-
duct subjected to Kuhn-Roth degradation to form two moles of
acetic acid. From further degradations it was shown that
carbons 18 and 19 and probably carbon 17 were from the methyl
and that carbon 10 was from the carboxyl of acetate. Further
systematic degradation was carried out on cholesterol. The
arrangement of the isooctyl side chain was determined by
Bloch9. Cornforth10 degraded rings A and B of cholesterol
and determined that carbons 1,3*5 and lg came from methyl and
carbons 2,4,6 and 10 from carboxyl of acetate.
The proposal on the cyclization of squalene was re-
examined. Labeled squalene was degraded and the source of
each carbon atom determined.11 The distribution of carbons
in squalene (II) is shown.
o o o
xxxxxxooooovo
00 o'o cr o x x'x X X X
II
x 5= from carboxyl of acetate
o = from methyl of acetate
\ \ \
000
In addition to the scheme of Robinson1, A below, Woodward
and Bloch12 proposed an alternate method of cyclization, B
below. The schemes differ in the source of carbon at C-7,8,
12 and 13 in cholesterol. To check the validity of their
proposal, Bloch degraded cholesterol synthesized from methyl
labeled acetate.13 Carbon 7 was removed as C02 and shown to
possess 75-80$ of the activity as calculated from the Woodward
and Bloch scheme .
-8-
X XX 80^\
X
li
x i2\x o xx ^x x ^o \x ^tf
i 13 I N3 I II I \Q
<3 ? o o^ .o ^x^ 0 ov .o
o o
\ .^ \«
•X
1
X X
II i
^X 0 o
1
CX .0
xx
x ^o \x
v^o
1 II 1
X xx
I * '
%8 X °
^X-O \
1 II
1 °
o> o
o
v^x N
X^7
/ N
O 0
O /O X
>X^ \X^7
6
A B
x = carbon from carboxyl of acetate
o = carbon from methyl of acetate
Search was now begun for other intermediates in the
biosynthetic pathway. Isovaleric acid14 and acetoacetate15
were found to be more efficient than acetate in cholesterol
format ion « p-Hydroxyisovaleric acid16, £-hydroxy-£-methyl-
glutaric acid1T and £,£-dimethylacrylic acid18 were isolated
as intermediates in the rat. The latter three compounds are
all active in cholesterol biosynthesis.18 Using acids labeled
only at the ^-carbon, radioactivity should be found only at
carbons 4, 8, 10, 14, 20 and 25 and should be 4.5 times as
great as the overall average for the molecule. Degradations
determined18 tttat the activity at carbons 10 and 25 had on
the average 3.85 times the average activity. Similar
labeling experiments on the gem dimethyl carbons of the five
carbon acids are in agreement with the above data, but when
the carboxyl carbon is labeled, complete randomization
occurs.19 This might be explained by decarboxylation and
random recarboxylation. Work is currently in progress with
C14 labeled fame sol to see whether this is an intermediate
in the squalene synthesis.19
In the conversion of squalene to cholesterol the only
intermediate isolated has been lanosterol (III). Bloch19
has studied sterol synthesis in rat intestinal tissue for
short time periods. After ten minutes and sixty minutes of
synthesis before sacrificing the animal the relative
activities of the fractions were measured. The results
appear in Table I.
$> Total Activity
10 min. 6o min.
Unsaponif iable fraction 13
Squalene 6o.5 1
Lanosterol 20 1.8
Cholesterol 6.3 83
Table I, Sterol Synthesis in the Intestine19
It can be seen that squalene and lanosterol fulfill the re-
quirements as intermediates. Bloch19 proposed isoeuphol (IV),
as yet unisolated, in the sequence squalene —» lanosterol. The
overall biosynthetic pathway for cholesterol is summarized
-9-
below:
OH
iH2ox
CH3COOH— » CK3COCH2COOH— ;ch3-c-ch2cooh
CH2COOH
A
± C02
CHCOOH
ll
H3C-C-CH2COOH
i co2
CH3?H
V\ CH
+TT n CH3
C-CH2COOH " 2 n vC=CHCOOH
^ CH^
^
.\ .^
ho ^Jk f\/*
II
HO
©
NK
f~
[fame sol (?)]
iYy^2"Y
18
ho iVvV^-
4 1 e
lvC=Cv migration
2 Tox id at ions
3.decarboxyla- HO'
tions
V\
^
III
-10-
BIBLIOGRAPHY
1. R. Robinson, J. Soc . Chem. Ind., ^, 1062 (1934).
2. W. M. D. Bryant, Chem, and Ind., 1935, 907, 1082; C.A.,
10, 1064 1t 18269.
3. T. Reichstein, Helv. Chim. Acta, 20, 978 (1937).
4. H. J. Channon, Biochem. J., 20, 400 (1926); £1, 738
(1937); R. G. Langdon and K. Bloch, J. Biol. Chem.,
200. 135 (1953).
5. E. Calandra and Pt Cattanet, Rev. soc. Argentina Biol.
£4, 275 (1948); C. A., 4£, 8494d; R. G. Langdon and
K. Bloch, J. Biol. Chem., 200, 129 (1953).
6. K. Bloch and D. Rittenberg, J. Biol. Chem., 14^, 625
(1942)5 D. Rittenberg and K. Bloch, ibid., lo"oT 417
(1945); K. Bloch, E, Borek and D. Rittenberg, ibid., 162,
441 (1946),
7. I. S. MacLean and D. Hoffert, Biochem. J., 20, 343 (1926);
E. Schwenk, G. J. Alexander, T. H. Stoudt and C. A. Pish,
Arch, Biochem. Biophys,, *£, 274 (1955).
8. H. N. Little and K. Bloch, J. Biol. Chem,, l8£, 33
(1950).
9. J, Wuersch, R, L. Huang and K, Bloch, ibid., 1?5, 439
(1952).
10. J. W. Cornforth, G, D. Hunter and G, Popjak, Biochem* J.,
£4, 590, 597 (1953).
11. J. W, Cornforth and G. Popjak, ibid., ^8, 403 (1954).
12. R, B. Woodward and K. Bloch, J, Am. Chem. Soc, 75,
2023 (1953).
13. K. Bloch, Helv. Chim, Acta, J56, l6ll (1953).
14. I. Zabin and K. Bloch, J, Biol. Chem., 185, 131 (1950);
R. C. Ottke, E. L. Tatum, I. Zabin and K. Bloch, ibid.,
189, 429 (1951); I. Zabin and K. Bloch, ibid., 192,
2o7 (195D.
15. G. L. Curran, ibid., lgl, 775 (1951); R. W. Chen,
D. D. Chapman and I. L. Chaikoff, ibid., 205, 383 {1953);
M. Blecher and S. Gurin, ibid., 209, 953 7*1954);
R. 0. Brady, et.al., ibid.. 19?, 137 (1951).
16. J. L. Rabinowitz, J. Am. Chem. Soc., XL, 1295 (1955).
17. J. L. Rabinowitz and S, Gurin, J. Biol, Chem., 208,
307 (1954).
18. K. Bloch, L. C. Clark and I. Harary, ibid., 211, 687
(1954).
19. K. Bloch, Seventh Summer Seminar in the Chemistry of
Natural Products, University of New Brunswick, 1955.
-11-
THE CHEMISTRY OP PYRROCOLINE
Reported by Donald S. Matte son September 30, 1955
Substituted pyrrocolines have been prepared from a-alkyl-
pyridines and a-haloketones(l)1'2 '3 . Pyrrocoline(Il) is best
prepared by decarboxylation of 2-pyrrocolinecarboxylic acid,
which is obtained from ethyl bromopyruvate and a-picoline4.
rs
CH2Ri
V-
N
C0R2
XCHR3
0
V
4
3
N /
Rx and R3 = H or CH3
II
R2 = alkyl, aryl or -COOEt
Acid catalyzed condensation of ace tonylace tone with
3-substituted indoles leads to benzopyrrocolines (III)5.
+ (CH3CGCH2)2
/^
III
Molecular orbital calculations for pyrrocoline indicate
a high electron density on carbon atoms 1 and 3> the higher
density being on 3 6, By a similar calculation, the resonance
energy Is about 62 kcal./mole.16
Although the calculated electron density on the nitrogen
atom is lower for pyrrocoline than for pyrrole, pyrrocoline
is a base of moderate strength5' 7. Salt formation is some-
times slow; Vfo aqueous hydrochloric acid will not extract
benzopyrrocolines from ether, but ether will not extract
benzopyrrocolines from a Vf> hydrochloric acid solution. The
transformation is easily observed, since pyrrocolines are
fluorescent but their salts are not. This behavior has been
clarified by ultraviolet spectra, which indicate that the
salts are mixtures of pyridinium compounds (IV) and (V)T,8,1S.
H ^H
R. .R
V
VII
-12-
On alkylation with alkyl iodides, an alkyl group enters
the 3-position first, followed by the 1-position2. On
prolonged treatment, another alkyl group enters the 1- or
3-position to give a mixture of quaternary salts (VI ) and
(VII)2'7.
Hydrogenation over platinum or copper chromite catalysts
converts pyrrocolines to their 5>6,7>8-tetrahydro derivatives;
hydrogen with Raney nickel catalyst gives octahydro deriv-
atives9. Zinc and acid do not attack the pyrrocoline
nucleus9. Oxidation of pyrrocolines with hydrogen peroxide,
useful in structure work, gives picolinic acid N-oxide10.
Pyrrocoline has no acidic hydrogen. Pyrrole can be
ethylated with ethanol and sodium ethoxide at 200°, a re-
action in which the anion may be an intermediate; 2 -phenyl -
pyrrocoline is not ethylated under these conditions9.
Attempts to prepare Grignard reagents analogous to the indole
Grignard reagent have failed11.
Several studies of electrophilic substitution in the
pyrrocoline series have been made 2 '3,11,:L2>i3>i4 # The re_
actions are often similar to those encountered with indole
and pyrrole. Most of the work has been done on 2-methyl- or
2-phenylpyrrocoline, which are easier to make than pyrrocoline
itself.
Pyrrocolines are acetylated in excellent yield by heating
with acetic anhydride and sodium acetate3'12. The acetyl
group enters the 3-position, or if this is blocked, the
1-position. Diacetylation occurs only in moderate yield on
prolonged heating. Acetylation is reversible; 3-acetyl-2-
phenylpyrrocoline is hydrolyzed by hydrochloric acid at
room temperature1
Iodination also causes cleavage of the
acetyl group; the hydriodic acid generated is a sufficient
catalyst, and l,3-di-iodo-2-phenylpyrrocoline is the product
unless sodium acetate is added to prevent hydrolysis11.
Rossiter and Saxton2 claimed an 8$ yield of 3-formyl-2-
methylpyrrocoline (VIII) from the reaction of 2-methyl-
pyrrocoline with N-methylformanilide and phosphorus oxy-
chloride. Holland and Nayler12 attempted to duplicate this,
but obtained only 1,3-diformylpyrrocoline . They12 prepared
2-methylpyrrocolinecarbonyl chloride (IX) by the reaction
of 2-methylpyrrocoline with phosgene, and reduced it to the
aldehyde by the procedure of McFadyen and Stevens. An
attempted Rosenmund reduction gave di-2-methyl-3-pyrrocolinyl
ketone (X).
l.H2NNH2
CH3 2.0SO3C1
v
V
N /
v_ch3 S2-^
VIII
5.Na2C03 ^^/\/
CHO C0C1
IX
ICzO
X
-13-
Pyrrocoline aldehydes and ketones show a lack of re-
activity similar to pyrrole aldehydes and ketones. They do nc
not give a positive Tollens test, and most do not form
semicarbazones.2 Oximes and 2,4-dinitrophenylhydrazones
have been prepared, but only one carbonyl group of 1,3-di-
acylpyrrocolines will react with these reagents.12 Re-
duction of these carbonyl groups with lithium aluminum hydride
leads to alkylpyrrocolines, and is a better preparative methoc
than Wolff-Kishner or Clemmensen reduction.9 Also analogous
to the pyrrole series, 2-methylpyrrocolinecarboxylic acid
is weaker than acetic acid and is easily decarboxylated.
Reactive aldehydes and ketones will add reversibly to
pyrrocolines. Acetone and 2,3-dimethylpyrrocoline form an
addition product (XI) in the presence of perchloric acid.2
Ehrlich's reagent, p-dimethylaminobenzaldehyde, adds to
pyrrocolines having a free 1- or 3-position to form blue
dyes.7 A Mannicli base (XII ) has been prepared from form-
aldehyde, dimethylamine and 2,3-dimethylpyrrocoline. Reverse
aldol condensation occurs upon addition of water to the
magnesium alcoholate formed from 2-acetyl-2-phenylpyrrocoline
and ethylmagnesium bromide, the only products being methyl
ethyl ketone and 2-phenylpyrrocoline.11
CH2N(CH3)2
CH3
XI
XII
Pyrrocolines are nitrosated by nitrous acid,13 and
couple with diazoniurn salts,12 both in good yield.
In contrast to all the substitution reactions mentioned
above, in which the 3-position is attacked in preference
to the 1-position, treatment of 2-methylpyrrocoline with
nitric and sulfuric acids gives l-nitro-2-methylpyrrocoline
(XIII) in 62$ yield, with a 1.5$ yield of the 3-isomer.14
Under the same conditions, 2-phenylpyrrocoline is nitrated
at the para position in the benzene ring (XIV); excess nitric
acid attacks the 1-position in the pyrrocoline ring.14
W*
XIV
-14-
An additional example of anomalous electrophilic sub-
stitution is the reaction of 2-phenylpyrrocoline with acetyl
chloride and aluminum chloride, which leads to a mixture of
2-(£-acetylphenyl)-pyrrocoline and l,3-diacetyl-2-phenyl-
pyrrocoline.3
BIBLIOGRAPHY
1. A. E. Tschitschibabin, Ber. 6g, 1607 (1927).
2. E. D. Rossiter and J, E. Saxton, J.C.S., 3o54 (1953).
3. E. T. Borrows, D. 0. Holland and J. Kenyon, J.C.S.,
1069 (1946).
4. E. T. Borrows and D. 0. Holland, J.C.S., 672 (1947).
5. R. Robinson and J. E. Saxton, J.C.S., 3136 (1950).
6. H. C. Longuet-Higgins and C. A. Coulson, Trans. Faraday
Soc, 42, 87 (1947),
7. D. 0. Holland and J. H. C. Nayler, J.C.S., 1657 (1955).
8. J. E. Saxton, J.C.S., 3239 (1951).
9. E. T* Borrows, D. 0. Holland and J. Kenyon, J.C»S.,
IO83 (1946).
10. 0. Diels and R. Meyer, Ann. 513, 129 (1934).
11. E. T. Borrows and D. 0. Holland, J.C.S., 6£0 (1947).
12. D. 0. Holland and J. H. C. Nayler, J.C.S., 1504 (1955).
13. E. T. Borrows, D. 0. Holland and J. Kenyon, J.C.S.,
1075 (1946).
14. E. T. Borrows, D. 0. Holland and J. Kenyon, J.C.S.,
1077 (1946).
15. R. Robinson and J. E. Saxton, J.C.S., 976 (1952).
16. Unpublished calculation.
-15-
ACETYLENIC ETHERS
Reported by Albert J, Lauctc
October 7, 1955
Introduction: Acetylenic ethers, compounds in which the triple
bond carbon is attached directly to oxygen, possess a rather
unique structure. These ethers are derivatives of the
"yne-ol" system which is related to the aldoketenes.
-C=C-OH
1
-CH=C=0
Acetylenic ethers might be expected to show considerable
reactivity since such carbonyl derivatives as ketene acetals
are unusually reactive and enol ethers possess an active
double-bond and are easily hydrolyzed by acids. The
structurally similar acetylenic halides might be compared since
in both cases the carbon-carbon triple-bond is attached directly
to an atom containing unshared pairs of electrons.
Acetylenic ethers have been mentioned1 in the early
literature and also been postulated2 as intermediates in
organic reactions. The first isolation was made by Slimmer3
when he prepared phenoxyacetylene which he described as an
unstable oil which became a black, viscous mass in a few hours.
It was not until 19^0 when Jacobs and his coworkers4 became
interested in these compounds that a systematic investigation
was begun.
Preparations :
1
Br
i
RC=CH0R»
Powdered KOH
->
RC=C0R
R=H, R'=Me, Et', Pr, iso-Pr, Bu, 0
R=Me, Et, C5H11, R'=Et , R=Bu, R ' =0
This method3'4^, e, 7, e, 9, 10 involves the preparation of
the p-bromo- or P-chlorovinyl ether. These vinyl ethers
P?J?n??iZe readily and or'ly the trans isomer reacts smoothly
with the powdered potassium hydroxide to form the desired
product ,
2. cichsCh
OR
OR
TETfc* NaC£C0R
HOH
-> HC=C0R + NaOH
R=Me, Et, Bu
This recently developed method11'12 affords a 60$ yield
from the commercially available a-chloroacetals and is practical
on a large scale. The use of the bromoacetals offers no
™Ia" J?e# Tf16 reaction d°es not proceed with higher homologs.
n? «£E VS alkoxyacetylenes are extremely pyrophoric. The use
ot sodamide as a dehydrohalogenation agent has also been
successful with p-halovinyl ethers and a,p-dihaloethyl ethers.11
3. #0C=CH + HOBr
KOH solution
jZfoC=CBr
-16-
Bromophenoxyacetj^lene was prepared13 after several
attempts. The reaction mixture polymerized very readily,
times explosively.
some-
Phenoxyacetylene polymerizes3'4 ,14 at room temperature
and must be stored at -7°, while the alkoxyacetylenes are stable
at 0° for several weeks and are safe to handle. These low
boiling ethers show some anesthetic properties but are toxic.5
Reactions: Acetylenic ethers show the usual addition reactions
of the triple bond and form metallic acetylide ethers.
1. RC=C0Et
OH
RCK=C-0Et
-> RCH2C02Et
Water adds to the triple -bond when catalyzed by mineral
acids to yield esters.5'9 >10>15 The inverse addition product
was not found. The rate of hydrolysis of the acetylenic ethers
is faster than the corresponding vinyl ethers and slower than
the ketene acetals. The reaction is first order with respect
to the ether and hydrogen fon concentration.15
2. RC=C-0-CH2CH3 12° > CH2=CH2 + JrC=C-0H
0
II
RCH2C-NHR'
<■
R'NH2
Jrch=c=o
RC=C0Et
RCH-C02Et
C=CR
Ethyl and butyl ethoxyacetylene have been reported9 to
evolve ethylene when heated at 120°. The product isolated was
a 6-acetylenic ester or if an amine was present an amide was
formed .
5- CH=C0Et itrm^ B™sc5
CH-
CH3
DEt LCJkk™-> CH3-C-C=C0Et
i
r+
0
l3 I!
-C=CH-CH <-L
CH3
CH3
CH3-C-CH=CHOEt
OH
OH
H2
Pd • BaS04
10$
H2S04
Ni/
CH3 ,?
^C=C-C-0Et
CH3
Acetylenic ethers as Grignard reagents react with aldehydes
and ketones. 5,11,:L6 The reaction provides an alternative to
the Reformatsky reaction for the synthesis of ^-unsaturated
acids or a, 6-un saturated aldehydes when an intermediate hydro-
genation stage is employed. The reactions have been applied
to the systhesis of vitamin A aldehyde17, terpene analogs18 and
-17-
a total systhesis of cortisone.19
4. 2RC00H + HC-COEt ^ (RCO)20 + CH3COOEt
This method9'11'20 seems to be the mildest yet devised
for converting a carboxylic acid into its anhydride. The re-
action has also been applied to a sulfonic acid11 and diethyl
phosphate.21
R
5. RCOOH + R'NH2 + CH=COEt - ) RC-NHR' + CH3C02Et
In the presence of ethoxy- or methoxyacetylene an acid
and an amine condense very smoothly to yield an amide. The re-
action has also been applied to syntheses of peptides.22
6. CH2-NH2 Np.n CH2-NH
I + EtOC=CR iiH^ | XC-CH2R + EtOH
CH2-NH2 CHa-N^
Ethoxyacetylene reacts with 1,2-diaminoethane to form the
2-substituted imidazoline. Ethoxypropyne reacts smoothly only
when mercuric oxide is used as a catalyst.
BIBLIOGRAPHY
1. A. Sabanejeff and P. Dworkowitsh, Ann*, 216, 279 (l883)j
J. U. Nef, ibid*, 298, 337 (1897); J; W* Lawrie, Am* Chem.
J., 36, 487 (1906); v. Grignard and H* Perrichon, Ann.,
465,~84 (1928).
2* H* S* Rhine smith, Abstracts of Papers 9^th Meeting of ACS,
Division of Organic Chemistry, p. 11 (1937).
3* M. Slimmer, Ber., 36, 289 (1903).
4* T. L* Jacobs, R* Cramer and P* T. Weiss, J. Am. Chem. Soc,
62, 1849 (19^0)*
5» T* L* Jacobs, R* Cramer and J. E. Hanson, ibid. , 64, 223
(1942).
6* A. E. Favorkii and M. N. Shchukina, J. Gen. Chem. Russia,
15, 394 (1945); C.A., 40, 4347 (19^6).
7. M. N. Shchukina, ibid., 18, 1350 (19^8); C.A., 43, 2158
(1949)*
8. D* A* Dorp, J* F. Arens and 0. Stephenson, Rec Trav* chim*,
70, 289 (1951).
9. Miss J. Ficini, Bull. soc. chim., [5], 21, 1367 (195*0*
10* J. F* Arens, Rec. Trav. chim., 74, 271 (1955)*
11. G. Eglinton, E* R. H. Jones, B* L* Shaw and M* C* Whiting,
«t* Chem; Soc, i860 (1951!).
12* W* S. Johnson, "Organic Synthesis", John Wiley and Sons,
inc*, New York, N* Yi, 195^, Vol. Jh , p. 46*
13. T. L. Jacobs and W. J. Whitcher, J. Am. Chem. Soc, 64,
2635 (1942). ~
-18-
14. P. Tut tie, Jr. and T. L. Jacobs, Abstracts of Papers
104th Meeting of ACS, 13M, (1942).
15. T. L, Jacobs and S. Searies, Jr., J. Am. Chem. Soc, 66,
666 (1944). "~~
16. I. Hellbron, E. R. H. Jones, M. Julia and B. C. L. Weedon,
J. Chem. Soc, 1822 (1949).
17. D. A. Dorp and J. F. Arens, Nature, l6o, 189 (1947).
18. G. R. Clemo and B. K. Davison, J. Chem. Soc, 447 (1951).
19. L. H. Sarett, G. E. Arth, R. M. Lukes, R. E. Beyler,
G. I. Poos, W. E. Johns and J. M. Constantin, J. Am. Chem.
Soc, 74, 4974 (1952).
20. J. F. Arens and P. Modderman, Nederland. Akad. Wetenschap,
55, 1165 (1950); C.A., 4J5, 6152 (1951).
21. J. F. Arens and T. Doornbos, Rec. Trav. chim., 74, 79
(1955).
22. J. F. Arens, ibid., 74, 769 (1955).
-19-
CYLIC DIARSINES
Reported by A. J. Reedy
SYNDESES
October 7, 1955
(1,2,3,4)
/\
AsCl
RMgX>
V^
AsCl2
AsR;
C2H*Brs
_\
kA
\x XA3R2
^-^
R
i
As
\
vAs/
I
R
(5)
^
rYT
02H
AQ-0
As-0
V02H
C2H4Br2
>>•
PC1;
-HC1
(6)
•V
Me Me
\ /
As _^
^^As
Me Me
<?
2Br'
^
m.p.
Vac"*
/VASW>
2Br" |
C2H4Br2 N^Nas^
/
v \N
-20-
(7)
CI
I
As
V^s
ASC12
JL AS *
F.C.
^
0NHNH;
/
"V
ci
i
AS
i1
VNu/V
CI
Na2C03
REACTIONS
(8) *
Me
As*
/i
Me
Br2
Pd ^
Me
. /
-As
Sas^^
• \
Me
HoO
2U2
(5)
(6)
o-xytLylenedibromide
i Me
2Br
Me
. ^
0
As*,
V^)As/
Me ^0
(8)
C2H4Br2
(1 mole)
125°-6 hr.
Me
1
AS
2Br~ Me
Me,
Vac
"ZT
^
V^As^V
Br
(9)
HBr
^
-21-
Br
A
I
Br
MeMgBr
Me
I
As
I
Me
STEREOCHEMISTRY
Me 2
t
* As —
V
v^as".
f
Me2
Fi°: . 1
v
2Br'
Fig. 2
The horizontal plane in Fig. 2 corresponds to the plane of
Fig. 1 comprised cf the two As-CH2- groups (substituents
omitted). The benzene ring of the o-xylylene group tilts
above; or below this plane. This results in geometric
isomerism.6
C7H7
AvV\
1
C7H7
(id
/>
r^XV
C7H7
As
(Ila)
-^As
/
C7H7
\X><
AS
C7H7
(lib)
AV\.
V
X
As
■?
(lie)
The triangular pyramidal structure of trivalent arsenic causes
II to fold about the As-As axis, resulting in isomers Ila and
lib. The other possible isomer, lie, could not exist. e,1°
-22-
Nj
Me
/Vx
AaoAA
'AS'
i
Me
(III)
Me
Me
\
As
Me
s7^»
As
Me
/
(III) exhibits optical activity.8 The asymmetry of the
molecule is due to the folding about the As-As axis.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
BIBLIOGRAPHY
L. Kalb, Ann., 423, 72 (1921).
J. Chatt and F. G. Mann, J. Chem. Soc . , 1939, 6l0.
F. G. Mann and F. C. Baker, J. Chem. Soc, 1952, 4142.
A. J. Quick and Roger Adams, J. A. C
N. P. McCleland and J. B. Whitworth,
2753.
R. H. Jones and F. G. Mann, J. Chem. Soc, 1955* 405.
Kalb, Ann., 42J), 39 (1921).
Mann ,
S., 4T7~B05 (1922).
J. Chem. Soc, 1927,
L.
R.
R.
H.
H.
Chem.
Chem.
Soc, 1955, 411.
Soc, 1955, 401.
H. Jones and F. G. mtuin, o»
H. Jones and F. G. Mann, J.
Gilman, ORGANIC CHEMISTRY I,
S. Elins, Studies in the Synthesis of Some Arsenic
Analogs of Fluorescein. Ph.D. Thesis, University of Illinois,
(1949). ~~
431 (1938).
-23-
THE TROPOLONE BENZOIC ACID REARRANGEMENT
Reported by L. M. Werbel
October 14, 1955
Perhaps the most important reaction of the tropolone
system is its alkaline rearrangement to a benzenoid system.
This is most valuable as a tool in structure proof of those
natural products containing the ring system, and may also be
significant in biogenesis of these materials.
Numerous mechanisms have been advanced to explain this
phenomenon. The more noteworthy of these follow.
Mech. 1
1 >2 >7 y 8
— involving Ci attack.
0
?~\
B
0
4
<s
X
SJ5
BC-
B-c=o
v-
+ X
e
/S
Mech. 1A3'4 — a modification involving the Faworskii type
norcaradienone intermediate .
0
,c
X
B-C=0
\.
.X
B
\ r
— > /i V *
'/
^_
+ X
G
%./
Mech. II5 — involving C2 attack and displacement of carbonyl
oxygen .
B
e
0
I
X
r
.B
->
L
This is advanced to explain elimination of the stronger base,
OCH3 fe-, in molecules such as 3,5,7-tribromo- or trichloro-
tropolone methyl ether, by providing a situation where
elimination of X is not a product determining factor.
-24-
Mech. IIA6 — C2 attack without oxygen rearrangement.
0
X
\>
/
!
vV
Me
X.
0.
;\
r*
x
(+) C
■,<
©-V--';v
pferv
Y i?
B-C=0
Me
Poering and Denney9 using labelling studies have recently
demonstrated that Ci of the carbonyl group becomes the carbon
of the carboxylic acid in the rearrangement product. This now
excludes all mechanistic hypotheses wherein a carbon other
than that of the carbonyl function emerges from the ring to
become the carboxyl group. Mechanisms such as II can no
longer be considered.
They propose a modification of Mech. IA including
assignp/.-.-it of a separate transition state to the elimination
step thus making the hypothesis compatible with the character-
istic ''in sensitivity to base strength of leaving substituent" .
B
CO
X
B
c=o
0
e
y
B
B
e x
^
s
>
Unfortunately an ideal pair of compounds with which to
test this double transition state mechanism is not available.
BIBLIOGRAPHY
1. R. D. Haworth and P. R. Jeffries, J, Chem. Soc, 1951, 2067.
2. Nozoe, Kitahara and Masamune, Proc . Japan Acad, 27, 649
(1951).
3. W, von E. Doering and L, H. Knox, Jc Am. Chem. Soc, 73.
8^3 (19:51).
-25-
4. R. 3. Loft fie Id, J. Am. Chem. Soc . , 72, 633 (1950).
5. W. von E. Doering and L. H. Knox, J. Am. Chem. Soc, 74,
5683 (1952). J~'
6. p. Akroyd, R. D. Haworth and P. R. Jeffries, J. Chem. Soc,
7. J. W. Cook, R. A. Raphael and A. I. Scott, J. Chem. Soc,
1952, 4416.
8. A. W. Johnson, J. Chem. Soc, 1954, 1331.
9* 461 VO? E* ?oering and D# B# Denney> J. Am. Chem. Soc, 77*
-26-
REDUCTION OF AROMATIC SYSTEMS WITH DISSOLVED
METALS
Reported by B. M. Vittimberga October 14, 1955
Alkali metals are readily dissolved by ammonia and lower
primary amines. Such systems of dissolved metals are very
powerful reducing agents for homogeneous phase reductions.
Reductions by these systems are thought to proceed by the
addition of electrons resulting from the ionization of metal
atoms.2
Unsaturated hydrocarbons are reduced by alkali metals to
yield initially organo-metallic compounds which are either
stable or ammonolysed in the presence of liquid ammonia de-
pending on the acidity of the hydrocarbon involved.3
Diphenyl ethers are cleaved by sodium in liquid ammonia
to form derivatives of benzene and sodium phenoxide ,4,s
The proposed mechanism is:
Ar-O-Ar + 2Na+ + 2e~ » Are" + Ar-Oe~ + 2Na+
Are" + NH3 + Na+ > ArH + NH2" + Na+
The type of substitution on the aromatic rings greatly
influences the position of electron attack. Accordingly,
the ring which is most negative will be the one that is
attached to the oxygen after cleavage.
In 1944 , Birch6 showed that If available hydrogen were
present in these reducing systems, different reducing
properties were observed. Reaction of aromatic systems with
sodium and alcohol in liquid ammonia caused reduction to take
place at the aromatic nucleus to form a dihydroaromatic
derivative.
Many aromatic systems have been reduced6'7, successfully
in this manner. A typical reaction is that of m-xylene.
CH3
-27-
A probable mechanism for this reaction is:e
CH:
v
+ e
CH-
AD alternative reaction_path in some cases may involve the
formation of the di-anion Ar= which can then add two protons
from the alcohol to give the stable hydrogenated product.
Vinyl carbinol type compounds have been found9 to be
reduced to hydrocarbons by sodium and alcohol in liquid
ammonia.
Application of these methods for synthetic purposes has
recently become more extensive. io*n»ia Another synthesis of
carvone is:10
C02Et
OCH;
CH3MgI
CH
(i
OCH-
OH
vCHr
Na
C2H50
(>:)NH:
OCH:
V
\\
CH-
,C-H
CH-
Na
4
CaH5OH
(NH3)
OCH3
dil.
HC1
*x
&
C-H
/ \
CH3 CH3
/v
0
's
XC-H
CH3 CH3
NaOC2Hs n
C2H5OOCH7
CHOH
I
0
//
Vs
l.Na(C2Hr5OH)
CH3I
2. OH*
i
^C-H
CH3 CH3
C-H
CH3 CH3
Although the Birch reaction has been used successfully
with many aromatic compounds, in some cases the yields have
been very low, as for example in the following conversion:
-28-
—> < > — <; />— 0CH'
^ -CCH
Recently13'14 it was determined that if lithium was used
instead of sodium and if the alcohol was added last much
higher yields were realized in most instances.
The enhanced yields obtained with lithium appear to be
due to the following factors:13
(1) The higher concentration of lithium due to its
greater solubility.
(2) The slower rate of reaction of lithium with alcohols
(3) The higher normal reduction potential of lithium.
(4) The greater tendency for lithium to react to form
addition compounds. 15>16>17
Further work on these reactions has shown that lithium
in low molecular weight amines will selectively reduce
aromatic hydrocarbons to monoolefins.
Naphthalene is converted mainly to 9^10-octalin.
^v% /V
%
I
-*
V
The amine most commonly used in this reduction is ethylamine.
Other amines which are equally satisfactory are methyl- and
n -propylamine s .
The mechanism for this reduction is postulated as being
a rapid 1,4 -addition of lithium. The organ o -metal lie compound
so produced then reacts with the solvent to form a 1,4-dihydro
product. In the basic medium this product rearranges to the
more stable conjugated diene system. 1,4-Addition of lithium
then reoccurs. Only very small quantities of the completely
hydrogenated products are formed since 1,2-addition is slow
in comparison .
BIBLIOGRAPHY
1. P. Lebeau and M. Picon, Comp. rend., 152, 70 (1914).
2. C. A. Kraus, Chem. Rev., 8, 251 (1931TT"
3. C. B. Wooster and J. F. Ryan, J. Am. Chem. Soc . , 54,
2419 (1932). **-
4. P. A. Sartoretto and F. J. Sowa, ibid. , J59, 603, (1937).
5. A. L. Kranzfelder, J. J. Verbanc and F. J. Sowa, ibid.,
52, 1488 (1937).
-29-
6. A. J. Birch, J. Chem. Soc, 430 (1944).
7. A. J. Birch, A. R. Murray and H. Smith, ibid,, 1945 (1951).
8. A. J. Birch, ibid., 1551 (1950).
9. A. J. Birch, ibid., 809 (1945).
10. A. J. Birch and S. M. Mukherji, ibid., 2531 (1949).
11. A. J. Birch, ibid., 367 (1950).
12. A. J. Birch, J. A. K. Quartey and H. Smith, ibid., 1768
(1952).
13. A. L. Wilds and N. A. Nelson, J. Am. Chem. Soc, 75*
5360 (1953).
14. A. L. Wilds and N. A. Nelson, ibid., 7£, 5366 (1953).
15. R. A. Benkeser, R. E. Robinson, D. M. Sauve and
0. H. Thomas, ibid., 77, 3230 (1955).
16. R. A. Benkeser, C. Arnold, Jr., R. F. Lambert and
0. H. Thomas, Abstracts 128th Meeting Am. Chem. Soc,
70-0 (1955).
17. R. A. Benkeser, G. Schroll and D. M. Sauve, Abstracts
127th Meeting Am. Chem. Soc, 21N (1955).
-30-
TR30RETICAL ASPECTS OP NUCLEAR MAGNETIC RESONANCE
Reported by E. W« Cant rail
October 21, 1955
In 1952, Felix Bloch and E. M. Purcell were awarded the
Nobel Prize in Physics for their discovery of nuclear magnetic
resonance, a phenomenon1,2,3,4,5,6 which occurs when a sub-
stance containing magnetic nuclei is placed under the influence
of two mutually perpendicular magnetic fields, one a
stationary field and the other oscillating. The strength of
the first and the frequency of the latter are matched in such
a way that these microscopic magnets are caused to precess
about their axes of rotation. The frequency at which
precession occurs is termed the Larmor frequency, and the
substance is said to be in a state of resonance.
Consideration of a simple case may serve to clarify
what is meant by precession and resonance frequency and how
these phenomena are brought about. In Figure 1 below, a series
of arrows is used to represent microscopic protonic magnets,
i.e., the protons found in some source of hydrogen atoms, such
as water. Just as current passing through a loop of wire
produces a magnetic field about the wire, the spin of the
proton produces a magnetic moment, /J , in the direction of the
axis of rotation. Let the
head of the arrow be the
north pole of the
nuclear magnets and
the top of the stationary
magnet be its south pole. 1
When the substance is 7, S /f\
put under the influence
of this field of
strength H0> there x*
is immediate space y Hx
quantization which
limits the alignment
of these microscopic
magnets to two
orientations; i.e.,
parallel and anti-
parallel to the
direction of the Figure 1.
stationary field.
The number of
orientations possible depends upon the spin of the nucleus and
will, for the general case, be (21 +1), where I is the
nuclear spin, when the oscillating field, Hi, (acting in the
direction of the X-axis) is turned on, those magnets with
their arrows pointed downward experience a torque, (- //pH0sin9) .
The energy required to completely turn an arrow which has its
direction opposed to that of the stationary field is
represented by
t t t J A? ilj
N
Hr
/^180°
W
u
Mp HoSinedQ
(1)
-31-
Bloch and Puree 11 have shown that the energy required to effec
this transformation may also be expressed in terms of the
fundamental energy equation
E - hi/
where h is Planck's constant and i^ls the frequency of the
oscillating field when the substance is in a state of
resonance .
Equating (1) and (2):
H - i
no - p
for the proton (3)
Ho = I
h-y
A*.
for the general {k)
case
Associated with the precessing nucleus is an alternating
magnetic flux, alternating in the present example across the
XZ-plane. This magnetic flux may be detected by the voltage
it induces in a coil of wire wrapped about the sample and at
right angles to that of the alternating magnet.
t
Precession
s >£ Axis of
"dotation
H,
Spinning
Nucleus
N
Figure 2.
\
i .xp
Neither electrical fields, external or internal, nor
motion of the nucleus itself produces any detectable effects on
the nuclear magnetic moment. However, the Drincipal cause of
line broadening is dipole-dipole interaction exemplified in
the case of ice in which one proton exerts on its nearest
SttrtSS; * f^6ld °f several Sauss> the oscillating component
of which is in resonance with its neighbor's precession.
Molecular motion in most liquids prohibits dipole-dipole
interactions; consequently, most fluid substances give sharp
and intense resonance lines. =>"cup
-32-
That Identical nuclei in the same applied field but In
chemically different molecules do not precess at exactly the
same frequency was first discovered by Knight7. The magnetic
field at the atomic nucleus varies from the applied field as
a result of diamagnetic snielding effects of the electron
cloud about the nucleus. The atom's electron configuration
differs slightly, depending upon what it Is bonded to. The
net result is a displacement of the resonance line termed
"chemical shift'1. It is this phenomenon which has been most
useful to organic chemists. If we assume6'8 that H=H0 + HT nc%
where H = field at the nucleus, H0 = external applied
field, and HLoc = local shielding field; then by" holding iS
constant, the external field strength may be varied according
to the shielding field, i.e., when the shielding field is
large, a larger external field must be applied In order to
penetrate it. Chemical shifts are measured in terms of
J = HR " H° x 105
HR
where HR is the strength of the external field required to
cause resonance in some reference sample, usually water.
A sample tube containing the nuclei to be studied is
placed in the field of the permanent magnet9 ,10,11'1s . There
is a net alignment of the microscopic nuclear magnets in
this field which is disturbed by the application of a second
magnetic field, aweak radio-frequency field applied via the
R-F transmitter. The precession of the nuclear magnets
effected by the second field induces a small but detectable
voltage in the receiver coil, which is picked up by the R-F
receiver, is amplified, and then recorded on a graph. It is
to be noted that the receiver coil is perpendicular to the
transmitter coil to prevent signals from the driving field
being picked up.
In the latest type of NMR equipment11, the sample is
rapidly spun between the poles of the stationary magnet to
minimize field gradients. This treatment provides considerably
better resolution than was formerly available. Also high
resolution spectrometers now require only a 0.01 ml. sample.
Complete reviews of the literature concerning NMR and
Its applications are available13'14 and include the litera
through 1954.
rature
BIBLIOGRAPHY
1. Darrow, K. K., Bell System Tech. J., 32, 74-99 (1953).
2. Purcell, E. M., Am. J. Phys., 22, 1-8 (1954).
3. Purcell, E. M., Science, 118, 4^1-36 (1953).
4. Bloch, F., ibid., Il8, 425-31 (1953).
5. Bloch, F., Am. Scientist, 4j, 48-62 (1955).
6. Obermayer, A. S., MIT Seminars, Fall 1953, pp. 179-86.
-33-
7. Knight, W. D., Phys. Rev., 76, 1259-60 (1949).
8. Gutowsky, H. S., McCall, D. W., McGarvey, B. R., and
L. H. Meyer, J. Chem. Phys., 19, 1328 (1951).
Varian Associates, Palo Alto, Calif., publication no. 42.
Varian Associates, Palo Alto, Calif., publication no. 76.
Varian Associates, Palo Alto, Calif., publication no. 142.
12. Rogers, Emery, Industrial Laboratories, 6(9), September
1955.
13. Gutowsky, H. S., Ann. Rev. of Phys. Chem., 5, 333-56
(1954). -*'
14. Shoolery, J. N., and H. E. Weaver, ibid., 6, 433-56
(1955). ~
9.
10.
11.
-54-
NUCLEAR MAGNETIC RESONANCE: APPLICATIONS TO ORGANIC CHEMISTR*
Reported by Louis R. Haefele October 21, 1955
The usefulness of nuclear magnetic resonance to organic
chemistry depends primarily upon the so-called "chemical
shift", whereby the applied magnetic field is altered, due to
a shielding effect of the electrons surrounding an atom. This
causes a shift in the frequency of the resonance for the
nucleus. The "chemical shift", then, is dependent upon the
electron density about the atom and therefore upon the electro-
negativity of the group to which it is attached. Gut ow sky
has compiled a chart of "chemical shifts" for the proton
resonance of twenty-five common functional groups as determinec"
by a study of over one hundred compounds.
N.M.R. is probably most useful for work involving
hydrogen, which has excellent magnetic properties2. This is
fortunate, since it is often difficult to apply such things as
infrared and x-ray techniques in the case of hydrogen, due, in
the former case to the complexity of many spectra, and in the
latter to the difficulty of locating the hydrogen atom.
A number of applications of this method involve the
quantitative determination of the number of non -equivalent
hydrogens present in a molecule. This can be done easily and
accurately by means of graphical integration to find the area
under each of the proton peaks in the spectrum. For example,
the spectrum of toluene consists of two distinct peaks3, one
corresponding to the resonance of the hydrogens attached
directly to the aromatic nucleus and the other, to those of
the methyl group. The areas under these peaks are found to be
in a ratio of 5:3, corresponding to five aromatic hydrogens
and three for the methyl group.
Arnold4 has studied the N.M.R. spectra of the first five
primary alcohols. Three peaks were obtained in each case
(except methanol which had only two), corresponding to proton
resonance frequencies for OH,CK2, and R groups. The results
are summarized in Table I which gives the ratio of the areas
under the respective peaks, taking the hydroxy 1 area as
unity in each case.
Table I
Alcohol Calculated Ratio Observed Ratio
(R/CH2/OH ) (R/CH2/OH )
CH3OH 5/1 2.7/1
C2H5OH 5/2/1 3/2.1/1
C3H7OH 5/2/1 5/1.8/1
C4H9OH 7/2/1 7.1/1.9/1
CsHnOH 9/2/1 9.2/1.7/1
It is interesting to note that ethanol has been studied
under higher resolution and with a carefully purified
sample (5), and it is found that the hydroxyl peak is
actually a triplet. This is attributed to spin-spin inter-
actions of the proton with the hydrogens of the adjacent
methylene group.
-55-
A more practical application of N.M.R. is found in the
estimation of the composition of gasolines3. For an average
premium gasoline, peaks can be distinguished with correspond
to (a) protons attached directly to aromatic rings, (b)
protons attached directly to doubly bonded carbon, (c) methyl
and methylene groups attached to aromatic rings and (d) to
double bonds and (e) normal, branched and cyclic alkanes of
all types.
A recent example of the use of proton resonance spectra
in organic structure proof involves its use in the elucidation
of the structure of derivatives of eucarvone enol6. The
problem was to determine whether the compounds had the
cycloheptatriene structure (I) or the' caradiene structure
[ II ) •
OAc
OAc
II
The N.M.R. spectrum of the enol acetate of eucarvone
showed distinct peaks for the proton resonance for four
ethylenic hydrogens, six gem-dimethyl hydrogens and for the
CH3-C= system, but none for the two tertiary bridge hydrogens
of II. Thus it may be concluded that eucarvone enol acetate
has the structure I.
Directly related to the quantitative estimation of the
number of non-equivalent hydrogens in a molecule is a method
whereby the ratio of keto to enol forms in a tautomeric mixture
may be determined without disturbing the equilibrium.7 For
example, with acetylacetone, four peaks are obtained} two, of
approximately equal area, corresponding to the CH and OH of the
enol form, one for the CH2 of the keto form, and the fourth for
the methyl groups of both species. By comparing the area
under the OH peak with one*half the area under the CH2 peak
(two h's) a good value for the proportions of keto and enol
forms can be obtained.
foov^Mi5tur?s of cis-trans isomers can be analyzed in a similar
5S ?£«V SJnce the enviro™nents of the protons are different
the bLSl0 llTHU thl^s.Siving two peaks. From the area under
the bands, the ratio of isomers can be calculated.
**„ >.SUCh ^n^ses are not limited to mixtures of isomers, but
can be used for quantitative analysis of mixtures of almost
and ?oTue^BS' ^US Wlt£ a„^ure of benzaldehyde, ethanol
and mpj*?,? V„p akS Can be dist^guished for aldehyde, hydroxyl
It if if??; Prom the relative heights of the peaks
it is possible to determine the composition of the mixture.
rt™ ?tnJ a"other use of N.M.R. which might be of great use to
organic chemists is the determination of isotope content of a
sample, although this is limited to use with isotopes which
have a magnetic moment other than zero. In the case of a C12
-36-
Ci3 mixture5, the C13 spin of 1/2 splits the proton resonance
signal into a doublet which is superimposed on the peak for
the Cl2H resonance. By comparing the amplitudes of the three
peaks the relative proportions of the isomers can be determined
Analysis of H20, D20 mixtures may also be carried out by
means of N.M.R.3 This is done simply by comparing H or D
signals of an unknown sample with control samples of known
deuterium content. The method will permit quantitative
determination with an accuracy of ± 0.2$.
Nuclear magnetic resonance has recently been applied to e
number of problems which have puzzled chemists for some time,
For example, it has been postulated9'10 that rotation about ti:'
C-N bond of amides is restricted, an important consideration li-
the structure of peptides, but conclusive proof of this fact
has never been given. Phillips11 recently reported a study of
dimethylformamide and dimetiiylacetamide, where he obtained two
proton resonance peaks for the methyl groups. This indicates
that the two groups are not equivalent and therefore rotation
about the C-N bond must be restricted.
Evidence has also been obtained by means of N.M.R. which
supports the existence of a zwitter ion type configuration in
crystalline glycine12, and a planar structure for urea13.
The use of N.M.R. is by no means limited to proton
resonance spectra. A great deal of work has been done, for
example, on fluorocarbons, and the method can conceivably be
utilized in any case where one is dealing with an isotope of
non-zero spin.
BIBLIOGRAPHY
1. L. H. Meyer, A. Saika and H. S. Gutowsky, J. Am. Chem. Soc.
76, 4567 (1953).
2. H. S. Gutowsky, Ann. Rev. Phys. Chem., £, 333 (195*0.
3. Varian Associates, Inc., Palo Alto, Calif., Pub. 142.
4. J. T. Arnold, S. S. Dharmatti and M. E. Packard, J. Chem.
Phys., 19, 507 (1951).
5. Varian Associates, Inc., Palo Alto, Calif., Pub. 76.
6. E. J. Corey, H. J. Burke and V. A. Remers, J. Am. Chem.
Soc, 77, 494i (1955).
7. H. S. Jarret, M. S. Sadler and J. M. Shoolery, J. Chem.
Phys., 21, 2092 (1953).
o. E. Rogers, Industrial Laboratories, 6 (9) September (1955).
9. S. Mizushima, T. Shimanouchi, S. Nagakura, K. Kuratani,
M. Tsuboi, H. Baba and 0. Fujioka, J, Am. Chem. Soc, 72,
3490 (1950). "~
10. L. Pauling, The Nature of the Chemical Bond, p. 207,
Cornell University Press (1948).
11. W. D. Phillips, J. Chem. Phys., 23, 1363 (1955).
12. T. M. Shaw, R. H. Elsken and K. J. Palmer, Phys. Rev.,
85, 762 A (1952).
13. E. R. Andrew and D. Hyndman, Proc Phys. Soc. (London), A,
66, II87 (1953).
-37-
ORGANIC FLUORINE COMPOUNDS
Reported by R. J. Crawford
October 28, 1955
Since World war II great progress has been made in the
chemistry of organic fluorine compounds. The initial stimulus
along this line came during the war with the discovery of
efficient electrolytic methods for producing fluorine , and
the preparation of the perf luorocarbons2 . The main object
at that time was to produce particularly inert materials
which could not be affected by uranium hexaf luoride .
Perf luoroalkanes . Because of their remarkable physical
properties these compounds have become important industrial
commodities. Their main characteristic being the inertness
of the C-P bond, by virtue of which they show extreme
stability to chemical and thermal processes. Their surface
tensions, viscosities, refractive indexes and boiling points
are very low whereas their densities are high. Reactions
of these compounds are few and occur only at high temperatures.
Recent investigations3 have illustrated their ability to
partake in free radical reactions at high temperatures. It is
assumed that the bond between the two tertiary carbons is
cleaved homolytically and the radicals react with the halogens.
Fx XCF3
F3C-C
F
F2
F2
F2
iF2
CF3
X;
X F
K
F;
F2f
I
F2l ^*F2
F CP«
CF3
CXF
CF3
Br, CI, I
Support for this view was gained by heating perfluoro (1-methyl
4-isopropylcyclohexane) in the presence of toluene, whereupon
dibenzyl and the analogous H substituted products were obtained.
Alkenes. The reactions of fluorinated olefins follow the
same general trend as do the hydrocarbon olefins, but their
products are not always as easily predicted. Bearing in mind
the strong positive inductive effect, and the hyperconjugative
effect of the trifluoromethyl group one can predict the
products of addition reactions4.
CF3-C=CH2 +
H
i
CF3~C— CF2X
F
Nucleophilic addition occurs in the presence of alkaline
catalysts and certainly in the case of highly fluorinated
olefins, more readily than electrophilic addition. Amines,
thiols, alcohols, phenols and Grignard reagents are added in
the presence of basic catalysts5.
The ability to form cyclic dimers appears to be unique to
fluorinated olefins. Not only do they react with themselves
but with other olefins to form cyclobutane derivatives. With
-38-
butadiene the formation of a cyclobutane occurs in preference
to a Diels Alder reaction6. When heated to I50-I800 hexa-
f luorobutadiene is converted to hexafluorocyclobutene and a
mixture of dimers and trimers7'.
2C2F4
"7
Fc
2CF2~C^pn
r»r
F
-Uci
._C1
F F F2„
F2C=C-C=CF2 -}
Fa I
F
y
Fp >
C— CF2 F2 »
F
F F
C— CF2 F2 '
Tetrafluoroethylene has been found to react in a similar
fashion with trif luoronitrosomethane to produce the substituted
1,2-oxazetidine and a polymer. The ratio of the products
are controlled by the temperature of the reaction8.
F3C
CF«
CF2 N
I! + II
CF2 0
■N 0
550(
9 CF20 + CF3-N=CF2
F2 C C F2
+
CF<
-CF2 (CF2 -N-O-CFa )CF2 -N-
Various reagents have been used to telomerize tetra-
fluoroethylene and products of various chain length may be
obtained depending upon the concentration of the chain
transfer agent9.
Alkynes. Allowing for the effect of the trif luoromethyl
group on the direction of addition to the triple bond, the
perfluoroalkynes which have been investigated in any detail
are very similar to the corresponding hydrocarbons10'11 .
Thus if there is an acetylenic hydrogen in the molecule it can
react with Grignard reagents, and the silver, cuprous and
mercury acetylides may be prepared in the usual fashion; the
acetylene may be regenerated with acid.
Ac_ids. The various fluoro acids have been prepared and their
strengths determined. Trif luoromethylsulphonic acid is of
comparable strength to perchloric acid12. The perfluoro
saturated acids are found to be much stronger than their fatty
acid analogues, but the f luoroacrylic acids are not as strong
as the corresponding chloro-acids. This may be explained by
the increased importance of the resonance structures I and II13
-39-
@p (-) ©F /H
F2C=C-C02H ^ -£ ^C-C-C02H < > ^C cl.r/°"H
H P ' F
C
H r N0 (-)
II
BIBLIOGRAPHY
1. H. R. Leech, Quat . Rev., 3, 22 (1949).
2. Slesser and Schram, "Preparation, Properties, and
Technology of Fluorine and Organic Fluorocompounds"
McGraw-Hill, New York, 1951.
3. G. B. Barlow, M. Stacey and J. C. Tat low, J. Chem. Soc . ,
1749 (1955).
4. w. K. R. Musgrave, Quat. Rev., 8, 334 (1954).
5. P. Tarrant and D. A. Warner, J. Am. Chem. Soc, 76, 1624
(1954). —
W. R. James, W. H. Pearlson and J. H. Simons, ibid., 72,
1761 (1950). —
6. M. W. Buxton and J. C. Tatlow, J. Chem. Soc, 1177 (1954).
7. R. N. Haszeldine in Annual Reports of the Chemical Society,
Vol. LI, p. 289 (1954).
8. D. A. Bar»rand R. N. Haszeldine, J. Chem. Soc, l88l (1955).
9. R. N. Haszeldine, ibid., 3761 (1953).
10. R. N. Haszeldine, ibid., 588 (1951).
11. A. L. Henne and M. Nager, J. Am. Chem. Soc, 74, 650 (1955)
12. H. J. Emelius, R. N. Plaszeldine and Ram Chand Paul, J.
Chem. Soc, 563 (1955).
13. A. L. Henne and C. J. Fox, J. Am. Chem. Soc, 76, 479
(1954). —
-40-
ORGANIC REACTIONS EFFECTED BY IONIZING RADIATION
PART ONE: NON AQUEOUS SYSTEMS
Reported by R. A. Scherrer October 28, 1955
Real progress toward illucidation of the chemical re-
actions that have been going on for thousands of years due to
cosmic radiation has only been made in the last ten years.
During early investigations, products were so many and complex
it was difficult to grasp the fundamentals. These reactions
are not as haphazard as was once thought , however. Recent
investigations have been fruitful from the standpoint of
possible commercial applications1'2 as well as that of in-
creasing our understanding of mechanisms and excited states.
With a reasonable certainty of inexpensive radiation in the
future more investigators are looking into its sometimes unique
action on organic compounds.
In the category of ionizing radiation are a,p, 2f rays,
X-rays and neutrons. Except for neutrons, the primary inter-
action is with the target electrons, the photons or particles
knocking them to a higher level or from their orbit with enough
energy that they in turn cause further ionization. A one Mev
electron has the equivalent energy of about 50,000 bonds.
Neutrons interact with the nuclei [(m,Z ), (n, a), (n, 2n),
etc.] giving particles which interact as above. In general it
can be said that the products obtained using different
radiations will be the same, varying in relative amounts, but
not type3.
These interactions can result in the following:
ionization (ratio
excited state not
then e~ + M, * VT known
or
The process is not completely understood. Spiers, in "The
Primary Act"4 lists 32 further interactions leading to positive
ions, negative ions, changes of one to the other, loss of
electrons from negative ions and recombinations that might
occur.
An interesting application of "Jf rays is in the chlorination
of benzene and toluene5'6.
C6H6 + 3 Cl2 oU^ — 1_) 1,2,3,4,5,6-hexachlorocyclohexane
CC14 (mixture of isomers) (l)
This reaction is rapid at R.T. and gives the same product as
photochlorination (same % gamma isomer). Toluene, however,
does not.
x(co6°)
C6HS'CH3 3 Cl2 toluene > l-methyl-l,2,3,4,5,6-hexachloro-
cyclohexane (2)
-41-
Since this latter reaction has a chain length of about 103, the
authors suggest that this means the propagation goes by a
mechanism different from any known at present. Other observa-
tions were a) neither benzyl-, benzal-, nor benzochlorides
underwent the above reaction, b) > 1% benzyl chloride caused
reaction 1 above "to virtually stop", and c) benzene reacted
faster than chlorobenzene which reacted faster than toluene.
It is possible to postulate a mechanism based on the work of
Burton and Patrick concerning the protection by benzene of
cyclohexane toward dehydrogenation7'8, the transfer of energy
from an alkyl side chain to the benzene ring9 and the stability
of benzyl chloride hexachloride .
Studies10 on the beta particle (tritium), radiolysis of
acetylene and deuteroacetylene to form benzene and cuprene (a
polymer) indicate that the products result from initially
different excited states of acetylene, since benzene formation
is independent of acetylene pressure. Ingoid's11 picture of
the first excited state of acetylene fits into this picture
nicely.
Radiation can make an ordinarily soft sheet of plastic
stronger than steel. This is the effect of cross linking
already formed polymers. The mechanism of this action13'14 is
first, rupture of the H-C bond, combination of H* with a
hydrogen of another chain, and linking of the carbon radicals
formed. When there is approximately one crosslink per
molecule, the mass suddenly becomes infusable and insoluble in
most organic solvents. A possible commercial application is
gamma ray vulcanization of rubber15. Not all polymers cross-
link. A competing, and in some cases the only action is
splitting of the C-C bonds. Even this degradation is useful
in special cases1.
Radiation can be used to polymerize olefins. Advantages
are: there is no catalyst contamination; the reaction can be
run at room temperature, thus lessening decomposition of heat
sensitive molecules and lowering branching; polymers can be
made that have never been obtained before (polyperfluoro-
propylene, polyperfluorobutadiene, polyperfluoroacrylonitrile)2 .
Polymerizations can even be run in the solid state16.
Pure crystals of sublimed acrylamide (m.p. 88°) have been
polymerized to a M.VT. :_*> 50,000 by gamma rays at 35°.
A feeling for the action of ionizing radiation can
possibly best be gained by looking at its effects on pure com-
pounds. Let us consider the reaction of methyl alcohol17.
This reaction has possibilities as a commercial method for
preparing ethylene glycol. The mechanism of this reaction
has recently been studied. The products and their corresponding
G values (lOOev yield) are given in Table I. The mechanism
postulated is given at the left.
-42-
Table I
Product G(C060)y 0 28Hev He++ ions
CH3OH ■> -4 CH2OH + H (1) H2 4.0 3.46
CH20H — ^ H2C0 + H (2) CO 0.16 0.23
H + CH30H-,CH20H + H2 (3) CH4 0.24 O.36
2CH20H __>CH20HCH20H (4) CH20 1.3 1.67
2H_jH2 (5) HOCH2CH2OH 3.0 1.74
H + CH20H __>CH30H (6)
The fact that He++ ions, which produce a path of higher ion
(radical) density, give a lower yield of glycol to aldehyde
is taken as an indication that reactions 5 and 6 occur to a
greater extent. Further information that Gald. is the same
at 0°C, but that Ggiycoi is lower at that temperature indicates
that formation of the latter takes place as a secondary react ic.
outside of the ionized track:, where bulk temperature is
important .
McDonell and Newton18 have made one of the most complete
radiation decomposition studies to date in work on the alpha
bombardment of ten normal, iso, and tertiary aliphatic
alcohols. The products are consistent with principal bond
rupture at the carbinol carbon.
In all, radiation studies have been done on about 100 pure
organic compounds. The results of nearly all of these
have been compiled by Tolbert and Lemmon19 .
BIBLIOGRAPHY
1. S. S. Jones, Can. Chem. Processing 39, Vol. 4, p. 36 (1955).
2. Editors, Chem. Week Jan. 29, 1955, p. 48.
3. G. Frledlander and J. Kennedy, Introduction to Radio-
chemistry (1949) John Wiley and Sons, Inc., New York.
4. F. W. Spiers, Disc. Faraday Soc . 12, 13 (1952).
5. D. Harmer, L. Anderson and J. Martin, Chem. Eng. Progress
Sym. No. 11, 50, 253 (1954).
6. B. G. Bray, Geneva Conference Aug. 22, 1955, paper Mo. 168.
Nucleonics 13 (9) 92 (1955).
7. M. Burton and W. Patrick, J. Phys. Chem. f>8, 421 (1954).
8. R. R. Hentz, J. Phys. Chem., 59, 380 (1955T.
9. R. R. Hentz and M. Burton, J. Arn. Chem. Soc, J2> 532 (1951)
10. L. Dorfman and F. Shipko, J. Am. Chem. Soc. , 77, 4723 (1955).
11. C. K. Ingold and G. VI. King, J. Chem. Soc, 2702 (1953).
12. Editors, Modern Plastics 32, (7) 83 (1955).
13. E. Henley, Modern Plastics 32, (7) 88 (1955).
14. A. Charlesby, Radiation Res. 2, 96 (1955).
15. C. Bopp and 0. Sisman Nucleonics 13 (7) 28 (1955).
16. R. Mesrobian et. al., J. Chem. Phys. 22, 565 (1954).
17. W. R. McDonell and S. Gordon, J. Chem. Phys. 23, 208 (1955).
18. VI. McDonell and A. Newton, J. Am. Chem. Soc, 76, 4651 (1954)
19. B. Tolbert and R. Lemmon, Radiation Res. 3, 52~Tl955) .
-43-
ORGANIC REACTIONS EFFECTED BY IONIZING RADIATIONS
PART TWO: AQUEOUS SYSTEMS
Reported by W. DeJarlais
November 4, 1955
Reactions of organic compounds in aqueous solution with
x, a, p and Y rays and neutrons are primarily those of indirect
action, i.e. the radiation is absorbed by the water molecules,
producing species which then interact with any solute present.
The assumption is made that the solute's concentration be
small enough that direct activation by the radiation is
negligible. The nature of the effect on an organic compound
is dependent on the nature of the radiation, its intensity,
the presence of oxygen in the solution as well as the nature
of the organic solute. The exact mechanism of these Inter-
actions is obscure.
According to the general theory advanced by Weiss1, the
net effect is the production of hydroxyl radicals and hydrogen
atoms, by way of charged intermediates. It is supposed that
the interaction of the radiation with water involves the two
processes of excitation and ionization:
then,
H20
H20
H20
H20
-> H20
+
H
+
+ e
■OH
The ejected electron may have sufficient energy to cause
further ionization, depending upon the energy of the radiation.
Such an electron quickly loses energy by collisions with water
molecules and when it has energy of the order kT (the
Boltzman constant times the absolute temperature) the reaction2
HpO +
-> OH + H-
can occur. This last step usually takes place at some
distance from the site of the original ionization and hence,
radical recombination:
H
+
•OH
4H0H
-7
is not as effective as in the case of the dissociation of the
activated water molecules, where the radicals have little
chance to diffuse away from each other. To the net processes
proposed by Weiss:
H20 -
2H20
-^•H +
-) H2
-OH
H202
it has recently been shown that a third must be added3:
2H20 _» 2H* + H202
Since H* and HO- may not be produced in equivalent amounts.
-44-
Direct evidence in support of this mechanism is obtained
in the polymerization of aqueous acrylonitrile by Y -rays or
x-rays4. The 0-H absorption band is observed in the polymer,
and when D20 is used as a solvent the C-D stretching band in
the infrared is seen.
Stein and Weiss5 found that when a saturated aqueous
solution of benzene was subjected to mixed neutron and
v -radiation, the products were phenol, catechol, hydro-
quinone, biphenyl and an unidentified aliphatic aldehyde or
a mixture of aliphatic dialdehydes. The presence of dissolved
oxygen has the effect of increasing oxidation reactions. Its
action is:
H- + 02 > H02'
In the absence of air more biphenyl and some terphenyl were
formed8. Air caused the yield of phenol to increase by a
factor of five. It is of note that no resorcinol was found.
When solutions of phenol were treated with x-rays in the
presence of dissolved oxygen the products were: catechol,
hydroquinone, o-benzoquinone and some p-benzoquinoneT .
Aut oxidation was shown not to be the cause of the quinone
formation. Quinone formation does not take place from
catechol or hydroquinone as: 1. addition of either catechol
or hydroquinone did not increase the quinone yield, 2. quinone
formation is linearly dependent upon dose and doesn't show
the characteristic induction period of a secondary reaction,
3. in neutral solutions where catechol and hydroquinone are
more easily oxidized, quinone formation does not take place.
Again no resorcinol was found. Comparison with the action of
Fenton's reagent8, a known free hydroxyl radical producing
agent, showed no qualitative difference in the results as far
as could be determined.
Investigation of the action of x-rays on sodium benzoate
in aqueous solutions in the presence of dissolved air showed
that all three mono-hydroxy benzoic acids were produced in the
ratio of 5:2:10 for ortho, meta and para, respectively9.
Some decarboxylation occurred with trie formation of biphenyl.
Decarboxylation has also been observed in the case of high
energy p-rays acting upon p-aminobenzoic acid and niacin10'11 .
If the substitution were haphazard, the expected ortho:
meta: para ratio would be 2:2:1, in the absence of steric
effects. It has been shown on theoretical grounds that all
mono-substituted benzenes should have the same orientation
effect in free radical substitutions12.
Further work has shown that when saturated aqueous
solutions of nitrobenzene are irradiated with x-rays, all three
mono-hydroxyl nitrobenzene s are formed, the para in about twice
the amount of either the ortho or meta13. The formation of
nitric acid was observed. When saturated aqueous solutions of
chlorobenzene were irradiated with x-rays, the three mono-
hydroxy chlorobenzenes were obtained14. The para isomer was
the chief product. Treatment of chlorobenzene in saturated
-45-
aquecus solution with Fenton's reagent gave the same results,
so far as could be determined. Eiphenyl was formed in each
case but no chlorobiphenyls. It is remarkable that the
formation of biphenyl is favored by the presence of oxygen
as the reductive dechlorination of chlorobenzene is known to
occur readily15.
Keller and Weiss16 investigated the effects of 200 kv.
x-rays on cholesterol and two of its esters, sodium
cholesteryl succinate and cholesteryl acetate. Some of these
irradiations :.rere run in 90$ acetic acido This was shown to
yield the same results as with water except for the production
of esterified alcohol groups in some cases. The chief effects
of the radiations are "nydroxylation of the 5-6 double bond,
and, in the case of large doses, oxidation of the 7 carbon
atom to a keto group. Again Penton's reagent was found to
give agreement with the x-ray results17. The results were
later confirmed using aqueous methanol solutions instead of
acetic acid -water18. In runs using methanol-water the inter-
mediate oxidation product, 7-hydroxychole sterol, was also
isolated.
With cholic acid Keller and Weiss observed the convers-
ion of a 3 -hydroxy group to a keto group19. More recently
cortisone and desoxycorticosterone have been investigated
by Weiss and co-workers?0 X-radiation of these compounds were
carried out both in the presence of air and in its absense.
In a vacuum, dehydroxylation and reduction of a double bond
occur. Weiss and co-workers also claim to have evidence that
trie following occur:
1. Complete reduction of the <:!^4-j5-keto group to give 33-
hydroxyl derivatives.
2. Reduction of the 3-keto group before reduction of the
double bond.
3. Addition of one •OH and one »K to the double bond.
4* Elimination of a carbon atom from ring A to give A-nor-3-
keto derivatives. It was shown that hydrogen and hydrogen
peroxide in the concentration produced in the radiolysis were
without action. Therefore, the effects are due to the presence
of »0H and *K alone. With oxygen present the results were
considerably different, as might be expected. However, except
for the small amount of adrenocorticosterone and some of the
suspected 17a, 2 1-dihydroxy-A-norpregnane -3, 11,20-trione, the
products could not be identified* It has now been shown that
ring contraction does take place. It is not certain what
becomes of the lost carbon atom. The yield of carbon dioxide
was far too small to account for it* No carbon monoxide,
formic acid or formaldehyde was detected. At present studies
are under way using C14 in the 4 position to see if the
missing carbon is possibly present as an angular methyl group
on carbon 5.
Studies have also been carried out in aqueous solutions
using indole, lactic acid, amino acids, amines and dyes as
SOluteS 21"25
-46-
BIBLIOGRAPHY
1. J. Weiss, Nature 153, 148 (1944).
2. M. Burton, Brit. J. Radiol. 24, 4l6 (1951).
3. A. 0. Allen, Radirtion Res. 1, 85 (1954).
4. F. J. Dainton, Brit. J. Radiol. 24, 428 (1951).
5. G. Stein, J. Weiss, J. Chem. Soc . , 3249 (1949).
6. G. Stein, J. 'Teiss, ibid . , 3254 (1949).
7. G. Stein, J. Weiss, ibid. , 3265 (1951).
8. F. Harber, J. Weiss, Proc . Roy. Soc. A. 146, 332 (1934).
9. H. Loebl, G. Stein, J. Weiss, J. Chem. Soc, 405 (1951).
10. M. Corson, S. A. Goldblith, S. E. Proctor, J. R. Hogness,
W. H. Longham, Arch. Biochem.Blophys. 33 > 263 (1951).
11. S. A. Goldblith, B. E. Proctor, J. R. Hogness, W. H.
Longham, J. Biol. Chem. 179, H63 (1949).
12. G. w. Wheland, J. A. C. S. 64, 90 (1^42).
13. S. Loebl, g. Stein, J. T'eiss, J. Chem. Soc, 27C4 (1950).
14. G. R. A. Johnson, G. Scholes, J. Weiss, ibid., 3275 (1951)
15. C. Kelber, Ber. 50, 309 (1907).
16. M. Keller, J. Weiss, J. Chem. Soc 2709 (1950).
17. G. K. Clemo, M. Keller, J. Weiss, ibid. 3470 (1950).
18. B. Coleby, M. Keller, J. Weiss, ibid., 1250 (1954).
19. M. Keller, J. Weiss, ibid. , 25 (1951).
20. R. Allenson, B. Coleby, J. Weiss, Nature 175, 720 (1955).
21. C. B. Alsopp, Disc. Faraday Soc 229 (1952*77
22. G. R. A. Johnson, G. Scholes, J. Weiss, J. Chem. Soc . ,
3091 (1953).
23. G. R. A. Johnson, G. Scholes, J. Weiss, Science 114, 412
(1951).
24. G. G. Jay son, G. Scholes, J. Weiss, J. Chem. Soc, 2594
(1955).
25. Day and Stein, Nucleonics 8, II 34 (1950) for example.
-47-
TRANSANNULAR REACTIONS AND INTERACTIONS
Reported by Kenneth Conrow November 4, 1955
The non-classical view that functions on opposite sides of
ring compounds of the right size (8 to 11 members, inclusive)
can interact has been conclusively established in a number of
cases. This ability is ascribed to the proximity of the groups
which is induced by the pucker of the ring system.
Cope1, Pre log2' 3'4 and coworkers have shown that cyclo-
blefins of the 8,9,10 and 11 membered carbocyclic series give
unexpected products when oxidized with performic acid, giving
1,4, 1,5, 1,6, and unidentified diols respectively. In the
case of the 9,10 and 11 membered rings none of the normal
1,2-glyccl can be detected; in the 7 and 12 membered rings, only
the 1,2-glyccl is isolated. The reaction is stereo-specific in
the 8 and 10 membered rin';;s; the cis-cyclooctene , cis-cyclo-
decene and trans- eye 1 ode cene each give only one of the possible
stereoisomers diols. In contrast cis and trans-cyclononene
both give a mixture of the suere ©isomeric 1,5-cyclononanediols.
The configuration of the diols has not been established, but a
consideration of the mechanism postulated by Cope and Prelog
which involves a double Walden inversion leads, for example,
to the lfelihood that the cis-cyclodecene gives cis-l,6-cyclo-
decanediol.5
The production of these non-classical products is ex-
plained on the basis of a transannular hydride ion shift under
influence of an attacking basic group to open the protonated
form of the epoxide ring at first formed by the action of
performic acid on the double bond. Some support for this
sequence is gained from the hydrolysis of cyclcb'ctene-cis-
oxide with formic acid to give exactly the same mixture~of
classical and transannular products as was obtained by direct
action of performic acid on the olefin.1
^H2)X-CH (CH2) -C-OH
OH > H-C-H OH > HO-C-H
I N» /J i
(CH2)y-CH- (CH2)V-CH2
Prelog4 used l,2-Cl4-cyclodecylamine to get quantitative
data on the relative amounts of classical and transannular
reaction upon treatment with nitrous acid. The main product,
cyclodecene, was oxidized without further rearrangement to
sebacic acid which was subjected to successive Schmidt de-
gradations; the C02 evolved in each degradative step was
collected ana measured for radioactivity. The minor product,
cyclodecanol, was oxidized to the ketone, formylated and
oxidizea to sebacic acid which was then degraded as in the
case of cyclodecene. A system of equations was then set up
fLf\Athe found radioactivity of each pair of carbon atoms to
i 2 \ ? ^S expected in the possible classical, 1,2, 1,5, and
1,6-hydride shift reaction courses. A solution of the system
-48-
shows that in the elimination reaction 62$ of the product re-
sults from classical elimination 24$ from a 1,2 -hydride shift,
6$ from a 1,5-hydride shift and 8$ from a 1,6-hydride shift- - a
total of 14$ by transannular reaction. In the substitution
product, 46$ of the cyclodecanoi was produced without a hydride
ion shift, 55$ with a 1,2-shift and 21$ by a transannular shift
These results are roughly comparable to the yields (5-30$)
of transannular products from the performic oxidation of the
cyclic olefins.
Other examples of transannular reactions include: Heating
l^-ditosylcyclodecanediol with diethylaniMne results in a
mixture of 1,9 and 9,10-octalins.6 Similai- treatment of trans-
tosylcyclodecene-6-ol gives a mixture of cis -1,2-octalin and"
1,9-octalin.7 In a similar reaction, cyclodecanone is con-
verted to a mixture of l-keto-9,10-octalin and trans-decalone
by the action of two moles of N-bromosuccinimide followed by
heating with dimethylaniline . Treated in the same manner,
cyclononanone gives l-[:eto-8,9-hydrindene.8 Rearrangement of
trans-cyclodecene to the cis isomer (85$ yield, 2-naphthalene
sulfonic acid as catalyst) gives also 7$ of a mixture of the
isomeric decalins.9
An example of transannular interaction, as opposed to
reaction, in the carbocyclic series is provided by a comparison
of (4.4) paracyclophane with (6.6) paracyclophane -10'11 %/hen
(4.4) paracyclophane is acetylated a monoacetyl derivative is
produced, even in the presence of two moles of acetyl chloride.
The presence of the acetyl group in the first ring deactivates
the second ring toward acetylation by a mechanism which can only
be transannular. Similar treatment of (6.6) paracyclophane •
gives a diacetyl derivative. Hydrogenation with three moles of
hydrogen over Pt gives principally the half reduced compound
from (4.4) paracyclophane, but gives a random mixture from
(6.6) paracyclophane. The explanation is that the interaction
is such that the first ring is more easily reduced than the
second which becomes an isolated benzene ring after the :
reduction of the first. In the case of the T^.6) paracyclophane
both rings are effectively isolated and hence are reduced
independently. The consequences of T: electron interaction in
this type of system are also evident in a study of the u.v.
spectra of a series of cyclophanes.12
The alkaloids N-mechyl pseudostrychnidine (III, R = 2H,
R' = H) and N-methyl pseudostrychnine (III, R = 0, R' = H) and
probably vomicine (ill, R = 0, R' = OH) exhibit a transannular
tertiary nitrogen-carbonyl interaction. l3' l4 ' 15 what is
apparently the first published idea of transannular inter-
action 6 was in connection with the protopine family of
alkaloids which contain the large ring system IV. Members of
this family form transannular salts of type II17'18 and
exhibit carbonyl absorbtions in the infrared at loitered
frequency i.e. 1661-1658 cm."1.19 Cryptocavine, originally
thought to possess a 5 rather than 6 keto group, was in-
vestigated with respect to its ability to form transannular
salts and shewn to be identical with crypt opine.18
-49-
X
!
nH
(CH2)
x
V
x v"
... N*
He
II
(CH2)
v
^
?
°
I!
-CH;
N''
R
//
R'
T y
KJ
0
Ay j \
Me
III
IV
BIBLIOGRAPHY
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
5885' (1952 5 S# W* Fent°n and C' F* sPencer> J.A.C.S., 74,
^71?U95f • K" Schenker and w" K^ng> Helv- chim- Acta, 16,
V. Prelog and K. Schenker, Helv. Chim. Acta, 35, 2048 (1952)
l^lrer^' H; ?• U^Ch' A' A' Bothner-By and J? wSrsch '"
Hej.v. Chim. Acta, 38, 1095 (1955).
K. R. Henery-Logan, MIT Seminars, 1952-1955, p. 188
A. C. Cope and George Holzman, J.A.C.S., 72, 3062 (1950).
3594 (1955) R# J* C°tter aM G* °" Roller, J.A.C.S., 77,
K. Schenker and V. Prelog, Helv. Chim. Acta, 36, 896 (1953)
1628* (19P) D# C# McLean and N* A* Nelson, J.aTc.S., 77*
D. J. Cram and J. Abell, J.A.C.S., 77, 1179 (1955)
D. J. cram and R. w. Kierstead, J.A.C.S., 71, 1186 (1955).
6132 (1954). W# L* Allinger and H* Steinberg, J.A.C.S., 76,
and^ndi/^^l^^).^11^ *"* S±r R°bert Roblns™> Chem.
R. H^isgen, H. Hie land and H. Eder, Ann., 561, 193 (1949)
0. Hafliger and V. Prelog, Helv. Chim. Acta7~32, 1851(1949).
y- 0. Kermack and R. Robinson, J. chem. Soo., 121, 435f
«' 5' ™ Anet and Leo Mari°n> Can. j. Chem., 32, 452 0954).
33, 57S teU)1?0 Marl0n ^ *' H> P* Mans'<e> Can J. Chem.
305^ (i^' A' Ramsay and R- N- Jones, J.A.C.S., 71,
-50-
STEREOCHEMISTRY OF RESERPINE AND DESERPIDINE
Reported by Ralph J. Leary November 11, 1955
Reactions of reserpine1 I
1. I + alcoholic NaOH -» Reserpic acid II
2. II + CH2N2 ■* Methyl reserpate III
3 -III + p-toluenesulfonyl chloride -» methyl reserpate-l8-
. tosylate IV
4. IV + LiAlH4 -> Reserpinol V
5- I + LiAlH4 -> Reserpindiol VI
6. IV + Collidine -> methyl anhydroreserpate + Product
isomeric with IV5
!Ej
CH3OOC xy
CH
3
Deserpidine VII reacts in a manner similar to reserpine
except for the detosylation of methyl deserpidate tosylate
with collidine.
^7
o N
H L 1
•- 19
r.
8
R^>S3
R2
0
,1 ^2 _., !i
I R=0CH3 R1=C00CH3 R2=0CH3 R3=0-C-^ ^
II R=0CH3 R1=C00H R2=0CH3 R3=0H
III R=0CH3 R1=C00CH3 R2=0CH3 R3=0H
IV R=0CH3 R1=C00CH3 R2=0CH3 R3=-02SC7H7
V R=0CH3 Ri=CH20H R2=0CH3 R3=H 0CH3
VI R=0CH3 R^CHsOH R2=0CH3 R3=0H . /
VII R=H R1=C00CH3 R2=0CH3 R3=0-C-<^ ^-0CH3
61 ^=S
OCH
3
During the course of conversions reserpine and deserpidine are
converted to a-yohimbine VIII and 3-epialloyohimbine IX.
-51-
CH3OOC *^y
OH
\ N
H /
v
CH3OOC
OH
Alloyohimbane Configuration3 Epialloyohimbane Configuration3
VIII
IX
VIII and IX are not absolute configurations
VIII defines the hydrogen at C-3 cis to the hydrogens at C-15
and 20
IX defines the hydrogen at C-3> trans to the hydrogens at C-15
and 20
Methyl deserpidate tosylate is converted to a-yohimbine
VIII by the following reactions4:
CH3OOC
v0TS
Nal v
LiBr
CH3OOC
OCH3
OCH
Zn
CH3COOH
->
CH3OOC
HBr
■)
HOOC
s
E
OH
CH2N2
4 VIII
It would seem logical on the basis of the reactions above to
assign the alloyohimbane configuration to the basic ring
system of deserpidine. However, there is evidence which shows
that reserpine, deserpidine and their derivatives undergo
acid or base catalyzed epimerization at the C-3 center. It
can also be shown that the C-J> center is the only center
epimerized. It therefore seems probable that reserpine and
deserpidine are derivatives of 3-epi -a-yohimbine .
Since reserpic acid II readily lactonizes the
substituents at C-1S and 13 are postulated to be cis to each
other.4 5
-52-
Evidence for the els relationship of the hydrogens at
C-15 and 20 was obtained by the collidine detosylation of
methyl reserpate-l8-tosylate IV5. Not only was methyl
anhydroreserpate formed but also a product that was isomeric
with the starting tosylate. This compound was shown to be a
quaternary salt and its structure was formulated as:
(-)
0TS
CHsOOC^ \^
0CH3
The formation of the N^-C-lS bond requires a cis D/E ring
juncture. The cis D/E ring juncture of 'reserpine has also
been proved by synthesis6. Selection of configuration B over
A was based upon the following observations.
R
• \
H
N
ch3ooc-x;\^ '^
6ch3
CH300C •
B
OR
0CH<
It was assumed previously that the driving force for the
epimerization reaction at C-27'8 of the alkaloids resided in
the greater stability of alloyohimbane over the 3-epiallc-
yohimbane skeleton. However, further investigation revealed
that alio- and 3-epialloyohimbane, without asymmetric
substitution at C-16, 17 and 18, under conditions of
isomerization are of approximately equal stability. The
reason for complete epimerization of the alkaloids and their
derivatives must therefore lie in the steric relationship of
the substitution in ring E. On the basis of A, the iso com-
pound (conformation I), with 1,3-diaxial interaction not
possessed by the normal compound, would be the less stable of
the isomer pair. However, B (conformation II) gives a clear
explanation for the greater stability of the iso compound.
-53-
1SO
normal
-)
A — -R
R
r~
/ .
N.-_
""' ■■•-
A]
/
f
i
ft
H
R
+
II
Further, 3-isoreserpic acid does not form a lactone as is ob-
tained from reserpic acid. On the basis of I, 3-isoreserpic
acid should readily lactonize whereas the conformation II for
the iso compound v:ould explain the difficulty encountered in
lactone formation.
The absolute configuration for yohimbine indicates that
the hydrogen at C-3 is in the a --orientation. The contribution
of such an axial H is shown by the difference in molecular
rotation between a series of 3 yohimbane derivatives and their
corresponding tetradehydro compounds (in which the asymmetry
at C-3 is destroyed). The values vary from -536 to -602°.
The difference between a series of 3 alloyohimbane derivatives
and their corresponding tetradehydro derivatives are likewise
highly negative. Therefore, the hydrogen at C-3 in
alloyohimbane is a and 3-spialloyohimbane possesses absolute
configuration at C-3, 15, 20 indicated in b.b'9s10}11
By application of Hudson's Lactone Rule the groups at C-16
and C-l8 are oriented in the ^-position.5"8"10"11
Finally, the stereochemical course of the detosylation of
methyl reserpate tosylate to methyl anhydroreserpate and the
concurrent internal quaternization of methyl reserpate
tosylate can be most readily explained by neighboring group
participation of a C-17 methoxyl placed trans to the groups
at C-16 and C-l8.7~8-ii-i2
-54-
^
CH3OOC
OCH-
9©
Clia
CH3OOC
OCH-
The internal quaternization can be considered to proceed by
double inversion.
Conversion of deserpidinol to rauwolscinyl alcohol also
places the 17-OCH3 trans to the C-16 and 18 substituents.
The stereochemical structure for reserpine and deserpidine
can be written as follows:
Reserpine R=0CH3
Deserpidine R=H
1. University of 111
2. E. Schlittler, et
3. E. Schlittler, et
4. E. Schlittler, et
5. 0. Wintersteiner,
6. E. E. Van Tamele.n
7. E. Wenkert and L.
8. E. Schlittler, et
9. C. F. Huebner and
10. 0. Wintersteiner,
11. E. Schlittler, et
12. E. E. Van Tamelen
(1955).
1 ori
BIBLIOGRAPHY
inois Organic Seminars May 20, xyj
.al., Exper. 11, 64 (1935).
.al., J.A.C.S., 77, 35^7 (1955).
.al., J.A.C.S., 77, 1071 (1955).
et.al., J.A.C.S., 77, 2028 (1955).
, et.al., J.A.C.S., 77, 3930 (1955).
H. Liu, Exper., 11, 302 (1955).
.al., Exper. 11, 303 (1955).
E. Wenkert, J.A.C.S., 77, 4l8o (1955)
J.A.C.S., 77> 4687 (1955).
.al., J.A.C.S., 77, ^335 (1955).
and P. D. Hance, J.A.C.S., 77, ^692
-55-
THE IVANOFF REAGENT
Reported by Norman Shachat
November 18, 1955
Ivanoff (l) found that phenylacetic acid salts behaved
anomalously toward Grignard reagents. This same effect was
noticed earlier by Grignard (2) in an attempt to prepare
diethylbenzylcarbincl from the salt, C6H5CH2C02MgX, and
ethylmagnesium bromide. Ethylene was evolved, and after
hydrolysis, phenylacetic acid was obtained in accordance with
the following sequence:
C6H5CH2C02MgCl + C2H5MgBr » C6H5CHC02MgCl + C2H6
MgBr
C6H5CHC02MgCl ^9^ C6H5CH2C02H + Mg(OH)Br + Mg(OH)Cl
MgBr
Ivanoff proved the existence of the complex, now called the
Ivanoff reagent, by obtaining phenylmalonic acid by carbonation
He further showed that aliphatic Grignard reagents, with the
exception of methylmagnesium iodide, and a few aryl Grignard
reagents react similarly to give phenylmalonic acid in yields
of 40-60$. Most aryl Grignard reagents gave substituted
P-hydroxybutyric acids (3). For example, 2,3,4-triphenyl-3-
hydroxybutyric acid was obtained in 6lfj yield:
I C6H5CH2C02MgCl + C6H5MgBr ^ C6H5CHC02MgCl + C6H6
II C6H5CH2C02MgCl + C6H5MgBr
MgBr
9
^ C6H5CH2CC6H5
III C6H5CHC02MgCl
MgBr
0
I!
+ CgH5CH2CCgH5
The difference
with most aryl
in the reactivity of alkyl reagents as compared
reagents was attributed to the difference in
the rate of reaction I as compared to reaction II (4,5) •
Ortho halogen substituents in the phenyl ring of the salt,
C6HsCH2C02MgX, because of the inductive effect, activate the
methylene hydrogens, so that even aryl Grignard reagents give
good yields of Ivanoff reagent (1,4,6).
The sodium salt of phenylacetic acid was found to react
with Grignard reagents in a somewhat similar manner to the
magnesium chloride salt (4,7) •
typical
As might be anticipated, the Ivanoff reagent behaves as
Grignard reagent, thereby making available a useful
synthetic tool. With ketones (7,16,18), substituted
P-hydroxypropionic acids can be obtained in high yields.
For example, Koelsch and Prill (15) made use of this reaction
in the following synthesis:
OCH-
-56-
+ C6H5CHC02MgCl
MgCl
OCH3
Poly phosphoric
Acid
COOH
OCH3
j OH
nN C-C6H5
I
A CH-C6H5
COOH
OCH3
OCH<
HOH
/\
Substituted P-hydroxyaliphatic acids are formed similarly
from aldehydes in high yields (8). Acyl halides react to give
very pure ketones in 50-75$ yields, and substituted hydroxy -
glutaric acids in 10-15$ yields (9)- More recently attempts
to prepare diketones by reaction with diacyl halides proved
much less successful (13,1*0 •
A recent interesting synthetic application is the reaction
of the Ivanoff reagent with isocyanates, carbamyl chlorides,
and isothiocyanates to yield substituted phenylacetamides and
phenylthioacetamides (17). For example, diethylphenylacetamide
can be prepared in approximately 71$ yield as follows:
C2H5
C2H5
C2H5.
,0
N-C
^Cl
C6H5
C6H5
C2H5 i
+ C6H5CHC02MgCl— * vN-C-CH-C00H
C2H5" l|
MgCl
C2H5
/
N-C-CH-COOH
0
-CO;
C2H
2H5
C2H5"
0
N-C-CH2-C6H5
II
0
C6H5CH2CN (10), C6H5CH=CHCH2C02H (11), CH3CH=CHCH2C02H (11),
and 2-furylacetic acid (12) were shown to react with some
Grignard reagents in an analagous manner to the salt,
C6H5CH2C02MgX.
-57-
BIBLIOGRAPHY
1. Ivanoff and Spassoff, Bull. Soc . Chim. [4], 4Q, 19-23
(1931).
2. Grignard, Bull. Soc. Chim., 31, 751-757 (1904).
3. Ivanoff and Spassoff, Bull. Soc. Chim. [4], kg, 371-380
(1931).
4. Ivanoff, Bull. Soc. Chim. [5], 4, 682 (1937).
5. Ivanoff and Spassoff, Bull. Soc. Chim. [4], 51, 619 (1932)
6. Ivanoff and Pchenitchny, Bull. Soc. Chim. [5T7 1, 223-233
(1934).
7. Ivanoff and Spassoff, Bull. Soc. Chim. [4], kg, 377-379
(1931).
8. Ivanoff and Nicoloff, Bull. Soc. Chim. [4], 51, 1325-1331
(1932).
9. Ivanoff and Nicoloff, Bull. Soc. Chim. [4], 51, 1331-1337
(1932).
10. Ivanoff and Paounoff, Compt. Rend., 197, 923-925 (1933).
11. Ivanoff and Pchenitchny, Bull. Soc. Chim. [5], 1, 233-235
(1934).
12. Ivanoff and Shopoff, C. A., 49, 8l90a (1955).
13. Stefanova, C. A., 42, 4156 (1948).
14. Ivanoff and Marekoff, C. A., 48, 10591a: (1954).
15- Koelsch and Prill, J. A. C. S., 67, 1296 (1945).
16. Blicke and Zinnes, J. A. C. S., 77, 5168 (1955).
17. Blicke and Zinnes, J. A. C. S., 77, ^9 (1955).
18. Ivanoff, Mihova and Christova, Bull. Soc. Chim. 4, 51,
1321-1325 (1932).
19. Blicke, Zinnes, J. A. C. S., 77, 5399 (1955).
j >./i!
>•' '. :
-58-
STERIC EFFECTS IN UNIMOLECULAR OLEFIN -FORMING ELIMINATION
REACTIONS
Reported by Joe A. Adamcik
November 18, 1955
In 1927 Hanhart and Ingold1 recognized the bimolecular
mechanism in certain olefin-forming elimination reactions
and in 1955 Hughes2 recognized the unimolecular mechanism in
other examples of the same reaction.
Bimolecular:
R1 R3
Z-.+H-C-C-Y
R R
R1 XR3
4 ZH + VC = C + :Y"
R2 NR4
Unimolecular:
R1 R3
'>
H - C - C - Y
I I
R2 R4
R1 R3
Z: + H - C - C
slow
R1 R3
H - C - C @ + :Y"
R'
R
fast
(+ '
R1
^ ZH + /C = C
K
/
R'
R'
R'
R'
(Charges shown on Y and Z are relative, not absolute.)
Since the bimolecular olefin-forming elimination re-
actions of quaternary ammonium ions were fundamentally
similar, it was puzzling that the contradictory orientation
rules of Hofmann3 and Saytzeff4 should exist. The Hofmann
rule, which originally referred to elimination reactions in
quaternary ammonium hydroxides, requires, in its general form,
the preferential formation of the least alkylated ethylene.
The Saytzeff rule, developed to apply to the elimination
reactions of alkyl halides, requires that the formation of
the most alkylated olefin should be favored.
Hanhart and Ingold1 proposed an explanation for Hofmann
rule orientation. In 19'4l5 and in more complete form in
19486 Hughes, Ingold and their coworkers proposed an
explanation for the operation of these two rules within their
respective spheres. According to their proposal, Hofmann
rule elimination was the result of the dominance of the
inductive effect. The inductive effect would be strongest
if «Y were positively charged, explaining Hofmann rule
orientation in bimolecular decompositions of ' onium ions. The
Saytzeff rule was considered to be the result of the dominance
of the electromeric effect, i.e., stabilization of the
incipient double bond of the transition state by hyper-
conjugation. It was proposed that the electromeric effect was
dominant in bimolecular eliminations involving alkyl halides,
and all unimolecular eliminations.
-59-
Unimolecular eliminations almost invariably proceed with
concurrent substitution. As has been pointed out6, the
proportion of olefin formed is often more simply related to
structure than the separate rate of the elimination process.
The proportion of olefin formed7 is identical with the ratio
kg/kg + ks where kE is the rate of the elimination step and kg
is the rate of the substitution step.
Hughes, Ingold and coworkers6 presented considerable
experimental evidence, both olefin yield and orientational
data, which was consistent with their interpretation. However,
in the case of unimolecular elimination reactions of tertiary
alkyl halides and sulfonium ions, only two alkyl groups,
t -butyl and t-amyl, were considered.
Previously, Brown and coworkers8'9 had introduced the
concept of B strain and had proposed, among other things, that
B strain was important in de terming the direction of dehydra-
tion of alcohols. In subsequent papers they7,1°> 1X > 12' 13
have developed evidence for the participation of steric strain
in determining the rate and direction of unimolecular
elimination reactions. They have presented considerable
evidence that B strain is of importance in determining the
rate of ionization of tertiary halides and alcohols since the
formation of the planar carbonium ions would involve release
of strain. This factor does not, of course, affect olefin
yield or orientation.
It is important to distinguish the separate steric
effects envisaged by Brown and coworkers7 > 13 which can affect
olefin yield and the direction of elimination. They are (l)
steric assistance of proton expulsion (2) steric hindrance to
substitution and (3) steric destabilization of the transition
state leading to the olefin. Effect (l) would increase kE
while effect (2) would decrease kg. Since it has not been
possible to determine kg or kg individually, but only the
ratio k /kE + k the separate contributions of effects (l)
and {2)bjhave not been observed. However, Brown and coworkers
have obtained considerable evidence which they interpret as
showing that the olefin proportion does in fact rise with in-
creasing steric requirements in the manner expected.
Effect (3) would be expected to affect the orientation of
the entering double bond. Brown and Berneis11 showed that
dimethylneopentylcarbinyl chloride, when decomposed in an
aqueous medium, produced the 1 -olefin as the major olefinic
product thereby exhibiting elimination according to the
Hofmann rule. This fact was interpreted as being due to the
interference of the cis -methyl and t -butyl groups.
The proposals of Brown and coworkers have been criticized
by Hughes, Ingold and Shiner14. Brown and Fletcher7 con-
sidered the olefin yields from the series EtxMe-z XCC1, which
showed an initial increase with increasing x but remained
nearly constant for the last two members, to provide evidence
for a steric effect. Hughes, Ingold and Shiner pointed out
that Brown and Fletcher neglected an important statistical
factor and were able to reproduce Brown and Fletcher's olefin
-60-
yields on the basis of certain assumptions based on the
electromeric effect. Brown and coworkers13 have shown that
the procedure of Hughes, Ingold and Shiner is not satisfactory
for two other series of compounds and therefore the agreement
in the first series is probably fortuitous. As Brown and
Fletcher's original explanation is not adequate the explana-
tion of this series is rather obscure. Brown and coworkers13
state that there may be steric hindrance to the expulsion of
a proton.
The high olefin yields obtained from the solvolysis of
dimethyl- and diethyl -t-butyl carbinyl chlorides were also
considered by Brown and Fletcher? to be evidence for the
participation of steric effects. Hughes, Ingold and Shiner14
considered that the possibility of Wagner-Meerwein rearrange-
ment made these cases unsuitable for comparison with the
others. Brown and coworkers13 have shown, however, that the
related halides dimethyl -t-amylcarbinyl chloride and methyl -
ethyl -t-butylcarbinyl chloride undergo unimolecular elimination
without rearrangement, although they also lead to high olefin
yields .
Finally, Hughes, Ingold and Shiner14 stated that elim-
ination according to the Hofmann rule in the case of
dimethylneopentylcarbinyl chloride1 1 ' 13 could be due to
hyperconjugation of the t-butyl-to-carbon bond. However, their
objection to Brown and coworkers'11'13 original interpretation
is based upon the impossibility of explaining the results in
terms of effects (l) and (2) rather than in terms of effect
(3) which would explain them. Furthermore, Brown and co-
workers13 show that the regular increase in the ratio of 1-
to 2- olefin v/hich would be expected in the series
RCHsCBr (CH3)2 as R is varied through methyl, ethyl, isopropyl,
and t-butyl if this explanation is valid is not observed;
rather there is a sharp increase when R is t-butyl as would
be expected on the basis of the steric strain hypothesis.
BIBLIOGRAPHY
1. W. Hanhart and C. K. Ingold, J. Chem. Soc, 997 (1Q27)
2. E. D. Hughes, J. Am. Chem. Soc, 57, 708 (1935).
3- A. w. Hofmann, Ann. 78, 253 (l85l"JT 79, 11 (1851 ).
4. A. Saytzeff, Ann. 179, 296 (1875). —
5' 657D?iQ4l^eS and C* K' Ingold' Trans- Faraday Soc. 37,
6* n" £' £har' E* D* HuShes> c- K- Ingold, A. M. M. Mandour,
G. A. Maw and L. I. Woolf, J. Chem. Soc, 2093 (1948) and
preceding papers (ibid., 2038-2093). C. K. Ingold
Structure and Mechanism in Organic Chemistry", Cornell
University Press, 1953, pp. 419-472 also contains a
discussion of this proposal.
?' 1223* (1orW? and R' S* Fletcner> J« Am- Che™- Soc, 72,
8. H. C. Brown, H. Bartholomay, Jr. and M. D. Taylor,
J. Am. Chem. Soc, 66, 435 (1944).
-61-
9- H. C. Brown, Science 103, 385 (1946).
10. H. C. Brown and R. S. Fletcher, J. Am. Chern. Soc . , 71 j
1845 (1949).
11. H. C. Brown and H. L. Berneis, J. Am. Chem. Soc, 75, 10
(1953).
12. H. C. Brown and R. B. Xornblum, J. Am. Chem. Soc, 76,
4510 (1954).
13. H. C. Brown and I. Moritani, J. Am. Chem. Soc, 77, 3623
(1955) and preceding papers in this series (ibid., pp.
3607-3622).
14. E. D. Hughes, C. K. Ingold and V. J. Shiner, Jr., J.
Chem. Soc, 3827 (1953).
-62-
A NEW ROUTE TO TERTIARY a-KETO ALCOHOLS
Reported by H. S. Killam December 2, 1955
Tertiary a-keto alcohols have been the object of numerous
investigations not only in the synthetic field but also in
the study of reaction mechanisms.
The acid catalyzed isomerization of compounds similar to
(I) has been studied by Favorsky.1
Ct-R'
^C C<— R
R^ X0H
^
n
R
R^ N0H
I
R=H; R'=Me, Et; R"=Pr,
t-Bu, 0
R=Me; R'=Me; R"=iPr
Interest has also been shown in the possibility of the
conversion of this type of compound into the asymmetric
bitertiary glycols (II) and amino alcohols (III).2'3*4
R1 HO R" R' OH R"
^C ^c' ^C- c' ,,,
Rx V0H NRr" R^ H2N/ VR
II III
Recently,5 cycloketols have been prepared with a view to
subsequent conversion into a, a' -dihydroxy ketones. This
sequence appears not only in the cortisone series but also
in other compounds which exhibit biological activity.
Preparation:
1. Probably the oldest and most frequently used method of
preparation of tertiary a-ketols is the alkaline hydrolysis
of the corresponding a-haloketone.
Rx *° » OH" R. 8 n
>C C— R — — > NC C-R
Rf XX r' X0H
Undesired characteristics of this reaction are the
following:
(l) The preparation of the desired a-haloketone is
complicated by isomer formation. 6
-63-
(2) Preparation of the haloketone may also be accompanied
by formation of the a, a' -dihaloketone.
(5) The hydrolysis of the haloketone may be followed
by isomerization of the product.7"
(4) Hydrolysis may lead to the formation of the
carboxylic acid.8
2. Satisfactory results have been obtained by the hydration
of the a-acetylenic alcohol to the corresponding a-ketol.10
yC C— CH ' / yC ' C-CH3
R1 X0H R' OH
In the cyclic series this method affords good yields of the
cyclopentane, -hexane and -heptane derivatives.5
Although the reaction conditions are ideal for isomeriz-
ation, abnormal results have been observed in only one
case.11'12 However, attempts to prepare a-ketols by hydration
of substituted acetylenic alcohols has led to the formation
of the corresponding (3-ketol instead of the desired a-ketol. 13
J>. A comparatively new method of a-ketol preparation**
consists of treating the a-hydroxy acid with methyllithium.
In this manner the cyclohexyl and cyclopentyl ketols were
prepared in good yields.
C C-OH + CH3Li
4. One of the simplest methods of preparing I should be the
treatment of the cyanohydrin of the ketone with a Grignard
reagent. This reaction would lead to the a-imino-alcohol and
thence by hydrolysis to the a-ketol in a manner analogous
to the Blaise reaction.
R-CH-C=N + R'MgBr > R-CH-C=NH } R-CH-C=0
OH OH R' OH R1
Investigations9 indicated that this reaction did not
proceed as smoothly or as directly as would be predicted.
Only in special cases was it found to be of preparative value.
Elphimoff-Felkin,17 on exploring the possibilities of
modifying this procedure, found that its shortcomings were
due to the decomposition of the cyanohydrin at the temperature
necessary for reaction to occur. Further work showed that
if the carbinol were first protected by reaction with 2,3-
dihydropyran the subsequent treatment with the Grignard
reagent did not cause decomposition of the starting material.
Acetals of this type had been shown not only to be easily
decomposed in acid but also to be unreactive toward the
Grignard reagent. is During the course of this study it was
-64-
found that reduction of the imino intermediate with lithium
aluminium hydride produced the corresponding tertiary
a-amino alcohol in good yields.
The reaction of alcohols with 2,3-dihydropyran had been
reported earlier by Paul.15
R'
R-C-OH
CN
/ \
0 \
W
R'
I
R-C-C-R
Py-O' %H
R MgX
R" 0
R-C-C-R
i
OH
LiAlHY
"S
R' H
i / ii
R-C-C-R
OH NH2
BIBLIOGRAPHY
1. A. E. Favorsky, Bull. soc. chim., 39, 216 (1926).
2. W. J. Hickinbottom, A. Hyatt and M. Sparke, J. Chem.
Soc, 2533 (195^).
3. I. Elphimoff-Felkin and B. Tchoubar, Compt. rend., 231,
1314 (1950).
4. I. Elphimoff-Felkin and B. Tchoubar, ibid., 236, 387 (1953
5. J. Billimoria and N. Maclagan, J. Chem. Soc, 3257 (1954).
6. A. Smith, W. Wilson and R. Woodger, Chem. and Ind., 309
(1954).
7. A. Oumnoff, Bull, soc chim., 43, 563 (1928).
8. B. Tchoubar and 0. Sackur, Compt. rend., 208, 1020 (1939).
9. D. Gauthier, ibid., 152, 1259 (1911).
10. W. J. Hickinbottom, A. Hyatt and M. Sparke, J. Chem. Soc,
2529 (1954).
11. H. E. Stavley, J. Am. Chem. Soc, 61, 79 (1939).
12. M. W. Goldberg, R. Aeschbacher and E. Hardegger, Helv.
Chim. Acta, 26, 680 (1943).
13. A. W. Johnson, The Acetylenic Alcohols, E. Arnold and Co.,
London, pp. 102-105, 355-356.
14. J. D. Billimoria and N. P. Maclagan, J. Chem. Soc,
3067 (1951).
15- R. Paul, Bull. soc. chim. France, 1, 971 (1934).
16. W. E. Parham and E. L. Anderson, J. Am. Chem. Soc, 70,
4987 (1948).
17. I. Elphimoff-Felkin, Bull. soc. chim. France, 748 (1955).
-65-
ACID HYDROLYSIS OF REISSERT COMPOUNDS
Reported by J . S. Dix
December 2, 1955
Reissert compounds are valuable as reagents for the
preparation of aldehydes1'2'3, and in the synthesis of sub-
stituted isoquinolines and quinolines4. The formation of an
aldehyde is achieved by the acid hydrolysis of its correspond-
ing Reissert compound.
A typical Reissert compound, l-cyano-2-benzoyl-l,2-dihydro-
isoquinoline (I) yields upon acid hydrolysis a variety of
products besides benzaldehyde: (II), (III), (IV)1, and (V)5.
Analogous products are formed by the quinoline Reissert
c ompound .
^ V>CHO
CONH2
II
H20
SF
7>
In addition to being able to account for these products,
any proposed mechanism must be consistent with the investiga-
tion of Swain and Sheppard6, who found a small isotope effect
in the hydrolysis of (VI) with H2S04-t.
Mechanisms which deal only with the primary products of
hydrolysis -i.e., benzaldehyde and quinaldonitrile (VII ) or
its derivatives - have been proposed for VI by Swain
-66-
(Mechanism A)6, and also by Colonna (Mechanism B)7", who
suggests an analogy with the reaction of quinoline N-oxide,
benzoyl chloride, and potassium cyanide.
Mech. A
/,
+
-CN
^CHO + H30
e
VII
(as activated complex)
Mech. B
H
vj>
<"^V^ „ (+)
-H
H"
C=0
H/c^C=0
\fat
'S-
CN
H
Izl.
/
/y
C=0
\l/
H © from
sol 'n
A
CHO
McEwen and his co-workers5' 8 originally proposed a
mechanism much like mechanism A, but which would account for
the other products by postulating competition between the
conjugate acid of the benzaldehyde formed and a proton for
acceptance of an electron pair of the original carbonyl
carbon:
-67-
Mech. C
H
IV f
H20
N=C
H CN
VIII
+ H
©
1<Z>
(H©)
-H20
■> V
XII
The mechanisms considered thus far have assumed the
nitrile which is formed (as IX) is hydrolyzed to its amide or
acid and therefore cannot be isolated from the reaction mixture.
However, McEwen and Cobb9 in further studies have obtained
results which lead them to believe that quinaldonitrile (or
isoquinaldonitrile) cannot be an intermediate in the reaction.
Hydrolysis of VI in concentrated hydrochloric acid was allowed
to go to partial completion. Unreacted VI, quinaldamide,
quinaldic acid, benzoin quinaldate, and benzaldehyde were
recovered, but no VII. An amount of VII equal to that of the
-68-
benzaldehyde isolated, and therefore equal to the minimum
amount of VI hydrolyzed, was hydrolyzed under the same
conditions. In two trials, 14<J6 and 39$ of VII were recovered.
When approximately equimolar amounts of VI and VII were used,
11$ of VII was recovered. In accordance with their belief that
these results show that no nitrile can be formed during
hydrolysis, McEwen and Cobb formulate the mechanism below for
acid hydrolysis of VT (hydrolysis of I would proceed by an
analogous mechanism).
Mech. D
VI
HC1
CI
^
H
-HC1
©
N^VC=NH
^ A
-C
0
— -NH
XIII
XIV
HC1
v
0-H
^•^N^ SC-NH2
H20
&% C=NH
C3® HC-JlO
CI
f-\
H-C 0
I
\^
XVI
^
XV
sX
• i
r lconh2
S >N
<N >CH0
+ HC1
The other products can be accounted for by assuming addition of
the conjugate acid of the benzaldehyde to either XIV or XIII
-69-
XIV }
x»^>N;f XC=NH
J>CH-C 0
^
XVII
's
w>
© o
<\ NH2 C
C-O-CH
^
v
XX
H20
\
^
\fc»
-H
&
XVIII
v^*
XX
I I
XIX
-V-
\N
w>
XXI
0
•C-O-CH-
0
I!
■C
\y \fi>
-h2o
> vA-
i
<
OH
VNl^
c' c
^ ^
XXII
0 CH
■'/
x1
0 C_^"'"
XXIII
-70-
Unstable compounds have been formed by the reaction of a
benzoyl Reissert compound with anhydrous hydrogen chloride
in an inert solvent5*©* 10 >n . Such a compound isolated by
McEwen and Cobb yielded benzaldehyde by hydrolysis in acidic,
basic, or neutral media. The compound contained chlorine,
but elemental analysis did not agree with XIII or XV. The
authors considered it to be a mixture, evidently too unstable
to purify, but regarded its behavior as strong evidence in
favor of mechanism D.
BIBLIOGRAPHY
1. Reissert, Ber. 38, 1603, 3426 (1905).
2. Woodward, J. Am. Chem. Soc . , 62, 1626 (1940).
3. Grosheintz and Fischer, ibid., 63, 2021 (194l ).
4. Samuels, Org. Chem. Seminar, U. of 111., 1953-1954, I, 18
5. McEwen, Kindall, Hazlett and Glazier, J. Am. Chem. Soc,
73, 4591 (1951).
6. Swain and Sheppard, Abst. of Papers of 127th Meeting
A.C.S., March 29 to April 7, 1955, p. 40N.
7. Colonna, Gazz. chim. ital., 82, 503 (1952).
8. McEwen and Hazlett, J. Am. Chem. Soc, 71, 19^9 (1949).
9. McEwen and Cobb, ibid., 77, 5042 (1955).
10. Kaufmann and Dandliker, Ber., 46, 2924 (1914).
11. Haworth and Perkin, J. Chem. Soc, 127, 1434 (1925 ).
-71-
MECHANISMS FOR THE HYDROLYSIS OF ORGANIC PHOSPHATES
Reported by John F. Zack, Jr.
December 9>
1955
Monoaliphatic Phosphates: Early kinetic studies1' 2 showed
ths,t the rate of hydrolysis of simple monoaliphatic phos-
phates is related to the pH of the reaction medium. The
rate of hydrolysis of methyl phosphate is slow in alkaline
solution, rises to a maximum around pH 4, falls to a minimum
at pH 1-2 and then rises again in strong acid. The kinetics
of the hydrolysis are first-order3. The maximum rate occurs
at the pH where the monoionic form is present in the greatest
concentration. With the aid of the dissociation constants
of monomethyl phosphate, and on the assumption that the mono-
ionic form is the reacting species, it is possible to construct
a theoretical curve of first order rate coefficients against
pH which closely fits the observed rate curve in the pH
range 1.5-9* Tracer studies using 018 have shown that a
fission of the phosphorus -oxygen bond is involved. The same
observations have been made for a great variety of mono-
alkyl phosphates3'7.
Several mechanisms for the hydrolysis have been postulated
to fit these data. The most probable mechanism involves a
cyclic transition state4'5:
RO-P03H^+ H20 ^
0 0
R-0 '0
H H
"••o--"
I
H
e
-» ROH + H20 + POs3 (slow)
H20
PO:
■* H2PO4 " (fast)
The dianionic form of the phosphate is stable to attack
by OH- because of electrostatic repulsion.
In strong acid the rate of hydrolysis of monomethyl phos-
phate is second order3. The rate determining step involves
attack by solvent. Isotope studies show that both C-0 and
P-0 bonds are broken. Therefore two reactions are taking
place simultaneously:
H
. I
H20 + CH37O-PO3H2 •»
'©
HOCH3 + H
©
+ H3PO4
SN2(C)
HO OH . ©
H20 + XP- -OCH3
II ; H
0
H3PO.
H
© +
HOCH3
SN2(P)
-72-
Monoaromatlc Phosphates: Monoaromatic phosphate esters behave
In the same manner as monoaliphatic phosphates in the pH range
1-93. However, the aromatic esters are more reative. Greater
stabilization of the transition state may explain this fact.
In contrast to aliphatic phosphates, no acid-catalyzed
reactions were found in strong acid solutions3. Instead, a
limiting rate of hydrolysis is approached. Isotope studies
show that only the P-0 bond is broken. The actual molecular-
ity cannot be unequivocally assigned. The absence of acid
catalyzed reactions with aryl phosphates results, no doubt,
from the decreased basicity of the oxygen atom linking the
phenyl group to the phosphorus atom.
Diesters of Phosphoric Acid: The rate of hydrolysis of
dibenzyl phosphate in strong acid is very rapid5. This may
be due to the ease with which the benzyl group forms a
carbonium ion and enters Into displacement reactions. Di-
methyl phosphate is hydrolyzed in acid or neutral solutions
but is stable in alkali3. On the other hand, diphenyl
phosphate is hydrolyzed in basic solution6. The initial rate
is proportional to the concentration of NaOH, although the
rate with Ba(0H)2 is much faster.
Triesters of Phosphoric Acid: The hydrolysis of trimethyl
phosphate in the presence of NaOH is second order3. A P-0
bond is broken and only one methyl group is displaced:
<- — n MeO OMe r.
H0<=>+^ XP- OMe -» HOP (OMe) 2 +^OMe
I
11
0
In acid, trimethyl phosphate is hydrolyzed in a bimolecular
reaction which is not acid catalyzed. In this case, a C-0
bond is broken:
0
>t II
■OP (OMe) 2 -> HOMe + (MeO)2POH
0
A bimolecular reaction which forms methyl iodide takes place
in the presence of iodide Ion3.
Neighboring Carboxyl: In aromatic phosphates, when a carboxyl
group is present in an ortho-position the rate constant for
the hydrolysis is about 105 times greater than for un-
substituted phosphates3 -10. The maximum rate occurs at about
pH 5»3« Evaluation of dissociation constants and partial
rate constants indicate that the following are the principal
reactive species: X0P03H2 /0P03H"
R and R
VC00" XC00"
-?:;.■)
e f: b i :">£ ;.•.;•■ r'iJ -■• /;
i9cf $.r(ri no • •■. ■ ■ j ;,
» i
'':• /"I \ ' ■ '''
' ). i i V
-73-
Chanley ejb a_l. propose the following mechanism to explain
the carboxylate participation:
/>
v\
°-P0H
CO'
^ Products
Lanthanum hydroxide has been found to be a very effective
catalyst in the hydrolysis of monophosphates4. The rate is
increased considerably by a substituent in the ^-position of
the ester. A cyclic intermediate has been postulated in this
case also.
Bibliography
1. Bailly, Bull. soc. chem. (5), 9, 314 (19^2).
2. Desjobert, ibid., 14, 809 (1947).
3. Barnard et al. , Chem. and Ind., 760 (1955).
4. Butcher and Westheimer, J. Am. Chem. Soc, 77, 2420 (1955)
5. Kumamoto and V/estheimer, ibid. , 77, 2515 (1955).
6. Helleiner and Butler, Canad. J. Chem., 33, 705 (1955).
7. Swoboda and Crook, Biochem. J. 59, XXIV~Tl955).
8. Chanley, Gindler and Sobotka, J. Am. Chem. Soc, 7^, 4387
(1952).
9. Chanley and Gindler, ibid., 75, 4035 (1953).
10. Chanley and Feageson, ibid., 77, 4002 (1955).
-74-
EPOXYETHERS
Reported by Willis E. Cupery
December 9, 1955
Epoxyethers have long been suggested intermediates in
the reaction of a-haloketones with base to form a-hydroxy-
ketals, acids, and esters. 1,2,3,4r It is only since 19^9, 5
that general synthetic methods have been available and
detailed studies of this type of compound made.
A general method for the preparation of epoxyethers in-
volves attack by alcoholate ion at the carbonyl carbon of an
a-haloketone or aldehyde:
CH30
O
+
CH3
R-C-C-R'
6 vr"
CH3
xe
A few epoxyethers can be prepared from vinyl ethers and
a peracid, but precautions against further reaction of the
epoxide with the acids present must be taken. is, 13
The cyclic epoxyether, l,2-epoxy-3,4,6-triacetyl glucose
has been prepared by treating 3,4,6-triacetylglucosylchloride
with ammonia.15
/°v
R-C-C-R'
6
CH3
V
R
R'
R
Yield
Reference
I C6H5
II C6H5
III C6H5
IV H
V H
CH3
C6H5
C2H5
C5H11
VI p-C6H5-C6H4 CH3
VII £-C6H5-C6H4 CH3
VIII C6H5 C6H5
IX CgHs CH3
H
H
H
H
CH3
C2H5
C6Hs
CH3
0
X C6H5-C-C-CH3
9 NCH3
CH2-CH2-N(CH3)2
66^
Q3fo
337
Wo
Qkfo
83^
8o£
10%
8o#
5,6
7
8
9
9
10
11
12
13
14
The following reactions of epoxyethers have been studied
and appear to be general.
-75-
Hydrolysis
R-C-C-R'
6 vr"
i
CH3
H
+
H20
0 OH
n l
R-C-C-R'
This reaction goes in good yield and has been used to
characterize epoxyethers. With V, the a-hydroxyheptaldehyde
dimer was obtained.9 The aminoepoxyether, X, reacted very
much more slowly, as would be expected from the positive
charge the molecule would assume in acidic media.14
Alcoholysis
R-C-C-R'
0 R"
CH3
<C~5
CH3OH (CH30 ^)
->
CH3
0 OH
R-C-C-R'
6 V
CH3
1 2
Ward and Kohler both proposed an epoxyether as an
intermediate in the formation of a-hydroxyketals from certain
haloketones with alcoholate ion. This has been supported
by the demonstration that this reaction is general for
epoxyethers. VIII required dilute acid to undergo this
reaction.12 The reaction was greatly hindered by the amino
group
n Y 1 4
.11 /Y .
Ring Opening With Organic Acids10
Epoxyethers undergo ring opening reactions with organic
acids to produce a-ketoesters. This is pictured as an attack
at the more positive of the epoxide carbons by the anion of
the acid, followed, in turn, by internal ester interchange and
the irreversible loss of methanol.
0
R-C-C-R'
6 V
CH3
+ RCOOH
RCOO OH
R-C-C-R' >
CK<
XR"
HOC-R
0 0
R-C-C-R'
1 \ ..
0
CH3
R'
-CH3OH
>
0
11
0 OCR
11 1
R-C-C-R'
1
R"
This reaction has been most studied for VI with 3*5-dinitro-
benzoic acid. Intermediates assigned structure A have been
isolated in two cases.9'10
Rearrangements with Lewis Acids
11
The rearrangement of epoxides with Lewis acids has long
been recognized as a form of pinacol rearrangement, and subject
to the same general considerations. In this case, the opening
of the epoxide ring corresponds to carbonium ion formation in
an ordinary pinacol rearrangement. In every case, the a-rneth-
oxyketone is the only product isolated. The relative ease of
migration of groups was found to be: H;>alkyl :> phenyl, and
-76-
H:>C2H5>CH3. An interesting tropolone derivative ^
was formed from II in 72$ yield.
Reactions with Grignard Reagents16
The reactions of epoxides with
Grignard reagents are well known and have
been extensively reviewed.17 Epoxyethers undergo Grignard
attack more easily than other epoxides, but they share the
complication caused by Lewis acid ring opening before Grignard
attack. With phenylmagnesium bromide, I gave a 42$ yield of
the product formed by normal attack at the more positive
epoxide carbon, and a 24$ yield of the product formed by
attack at the carbonyl carbon following rearrangement.
A hindered Grignard reagent, such as t-butylmagnesium
chloride gives only "rearrangement product", while diphenyl-
magnesium, which does not catalyze rearrangement, gives only
the normal product.
A Special Reaction of an Amino Epoxyether
14
The hydrochloride of the aminoepoxyether, X, when heated
to 150° gives a good yield of a-methylacrylophenone, and
a-chloroisobutyrophenone can be isolated as an intermediate.
This indicates an attack by a nucleophilic agent at the less
positive of the epoxide carbons, after the following scheme:
0 CH3 0 CH3 P CH3
/\/ il / II /
C6H5-C-C-CH3 — * _^C6H5-C-C-CH3 > s C6H5-C-C=CH2
o -~- CI (- CI
CH2-CH2-N(CH"3)2 +
H ±'
H0-CH2-CH2-N(CH3)a
If attack at the other carbon atom took place, a chlorohydrin
would result, which would doubtless be dehydrohalogenated to
give the starting epoxide and thus be fruitless from the point
of view of reaction.
BIBLIOGRAPHY
1. A. M. Ward, J. C. S., 1929, 154l.
2. E. P. Kohler and C. R. Addinall, J. A. C. S., 52, 3729
(1930).
3. A. E. Pavorski, J. Russ. Phys. Chem. Soc, 26, 559 (1894).
4. W. D. McPhee and E. Klingsberg, J. A. C. S., 66, 1132
(1944). ~~
5. T. I. Temnikova and E. N. Kropacheva, J. Gen. Chem.,
U.S.S.R., 19, 1917 (1949).
6. C. L. Stevens, W. Malik and R. Pratt, J. A. C. S., 72,
4758 (1950).
7. C. L. Stevens and E. Parkas, J. A. C. S., 74, 618 (1952).
8. C. L. Stevens, M. L. Weiner and R. C. Freeman, J. A. C. S.
75, 3977 (1953).
9. C. L. Stevens, E. Parkas and B. Gillis, J. A. C. S., 76,
2695 (1954). ~~
10. C. L. Stevens and S. J. Dykstra, J. A. C. S., 75, 5975
(1953). ~"
-77-
11. C. L. Stevens and S. J. Dykstra, J. A. C. S., 76, 4402
(1954).
12. C. L. Stevens and J. J. DeYoung, J. A. C. S., 76, 718
(195^).
15. C. L. Stevens and J. Tazuma, J. A. C. S., 76, 715 (1954).
14. C. L. Stevens and B. V. Ettllng, J. A. C. S., 77, 5412
(1955).
15. a) P. Brigl, Z. Physiol. Chem. 122, 245 (1922).
b) W. J. Hickenbottom, J. C. S., 1928, 3l4o.
16. C. L. Stevens, M. L. Weiner and C. T. Lenk, J. A. C. S.,
76, 2698 (1954).
17. N. C. Gaylord and E. I. Becker, Chem. Revs. 49, 413 (1951)
18. for example: 3. Belleau and T. F. Gallagher, J. A. C. S.,
74, 2816 (1952).
-78-
REDUCTIONS WITH FORMIC ACID
Reported by C. W. Schimelpfenig
December 9, 1955
Formic acid has been observed to serve as a reducing agent
in biological systems, in inorganic oxidation-reduction systems,
and with organic compounds over catalysts specific for the
dehydrogenation of formic acid. However, attention should be
given to the recent advances in the use of formic acid and
formate ion (l) in determining the mechanism of the Leuckart
reaction and in extending the reaction to new classes of
compounds, (2) in the reduction of enamlnes and heterocyclic
analogs, and (3) in reactions involving carbonium ions.
The detailed mechanism of the Leuckart reaction has been
the subject of a previous seminar1, the first step of which is:
RR'CO
HCONH;
RR'C-NH2CHO
OH
i
RR'C-NHCHO
The introduction of MgCl2 as a catalyst, which results in
slightly higher yields than usually obtained with refluxing
formamide (95$ from benzophenone compared with 87$),
necessitates the consideration of an alternate first step:
RR'CO
H
©
OH
RR'C©
HCONH2
OH c,
RR'C-NH2CHO
OH
1
RR'C-NHCHO
+ H
®
The stereochemistry of the reaction has been studied3 by
comparing the relative amounts of the isomeric amine products
from fixed-ring ketones
Ketone
2-methylcyclohexanone
camphor
xl-menthone
Products
40% trans ami ne
60$ cis amine
70$ isobornyl amine
30$ bornylamine
72$ ne omen thy 1 amine
28$ menthylamine
Reference
V
These data have been interpreted as the result of an
intermediate stage such as I in which the formate ion approaches
from the least hindered side of the plane
-79-
Early applications of the Leuckart reaction to aliphatic
ketones, aromatic aldehydes and ketones, formaldehyde, hetero-
cyclic aldehydes and ketones, and quinones have been
summarized.7.
If the carbonyl group is located in an optimum position,
the reaction may be used for the production of heterocyclic
compounds. Examples are the formation of 5- (2-carboxyethyl ) -2-
pyrrolidone from ~j'-ketopirnelic acid8, 5-methyl-2~pyrrolidone
from levulinic acid9, and 3-phenylphthalimidine from o-benzoyl-
benzoic acidio.
Previous failure of the Leuckart reaction to give the
normal product with benzoin has been overcome by first
methylating benzoin and then hydrolyzing the amino methyl
ethers produced11.
The first successful application of the Leuckart reaction
to a,P-unsaturated ketones was the reduction of
benzalacetone to 2-amino-J+-phenylbutane12.
An interest!
enamines and hete
of Mayo13 that N
(59$) from pyridi
A large number of
reduced14 to the
coworkers9' 15~2°
reduction of hete
formic acid-potas
are tabulated bel
ng field of reductions, that of aliphatic
rocyclic analogs, was opened with the report
N-dimethylpiperidinium formate was produced
ne, formic acid, and methanol or formaldehyde.
enamines of aliphatic aldehydes have^been
corresponding saturated amines. Lukes and
have made an extensive investigation into the
rocyclic bases by means of formic acid and
sium formate mixtures. Some of their results
ow.
Heterocyclic
N-Base
l,l-dimethyl-2-methylene-
pyrrolidinium hydroxide
Product
1,2-dimethyl-
pyrrolidine
Reference
15
1,1 -dime thy l-/\ -pyrrolinium 1-methylpyrrolidine 16
formate
P-picoline
1 -methyl -5-ethyl- A -2-
pyrrolone
1,2, 6 - trime thy lpyridinium
formate
1,2-dime thy lpyridinium
formate
A, 3
3-methyl-/A - piperidine 17
l-methyl-5-ethyl-2- 9
pyrrolidone
Corresponding tetrahydro- 18
and hexahydro -bases
Corresponding tetrahydro- 19
and hexahydro-bases
methyl betaine of picolinic N-methylpiperidine and 20
acid N-methyl-^x3-piperidine
methyl betaine of nicotinic N-methylpiperidine and 20
acid N -me thy 1-«2ju3 -piperidine
methyl betaine of isonicotinic N-methylpiperidine-4- 20
acid carboxylic acid
-80-
These reductions may be considered as 1,2- and 1,4-
reductions followed by a double bond shift in the acidic
medium.
It has been reported21 that triphenylmethyl formate,
having the characteristic red color, is stable at 20 . How-
ever, at 49° carbon dioxide is evolved and a 74% yield of
triphenylmethane is obtained in ten minutes. It is of interest
that the corresponding silicon compounds22 do not react in
this manner.
BIBLIOGRAPHY
1. R. S. Colgrove, Univ. of Illinois Organic Seminar, Dec. 7,
1051.
2. V. J. Webers and W. F. Bruce, J. Am. Chem. Soc, 70, 1422
(19^8). .
3. D. S. Noyce and F. W. Bachelor, J. Am. Chem. Soc, 74,
4577 (1952).
4. R. Leuckart and E. Bach, Ber. 20, 104 (1897).
5. 0. Wallach and J. Griepenkerl, Ann., 2§9, 347 (lo92).
6. J. Read and G. J. Robertson, J. Chem. Soc, 1£25, 2209-
7. M. L. Moore in Organic Reactions, Vol. V, 301 (John Wiley
and Sons, 1949 )•„ „ 07p
8. R. Lukes and F. Sorm, Coll. Czech. Chem. Commun. , 12, 27«
''1947 ^ .
9. R. Lukes and M. Vecera, Coll. Czech. Chem. Commun. 18, 243
10. G. Caronna, et.al., Gazz. chim. ital. 83, 308 (1953).
11. R. Quelet and E. Frainnet, Compt. rend. 236, 492 (1953).
12. 0. R. Irwin, Thesis, Univ. of Missouri, 1950; Microfilm
Abstracts 10, no. 3, 27-
13. F. R. Mayo, J. Org. Chem. 1, 496 (1936).
14. P. L. deBenneville and J. H. Macartney, J. Am. Chem. Soc,
72, 3073 (1950).
15. R. Lukes', Coll. Czech. Chem. Commun. 10, 66 (193o).
16. R. Lukes' and J. PreuSil, Coll. Czech. Chem. Commun. 10,
384 (1938).
17. R. Lukes and J. Pllral, Coll. Czech. Chem. Commun. 15, 463
(1950) .
18. R. Lukes and J. J izba, Coll. Czech. Chem. Commun. 19, 930
(1954). .
19. R. Lukes and J. Jizba, Coll. Czech. Chem. Commun. 19,
Q4l ( 19^4 ) .
20. R. Lukes', et.al., Coll. Czech. Chem. Commun. 19, 949 (1954)
21. S. T. Bowden and T. F. V/atkins, J. Chem. Soc, 1940, 1333-
22. H. Gilman and K. Oita, J. Am. Chem. Soc, 77, 3386 (1955).
-81-
QUATERENES
Reported by G. W. Griffin
December 16, 1955
The similar formulations for furan and pyrrole might lead
one to expect these heterocycles to display some parallelisms
in chemical properties. Many examples that support this
supposition appear in the literature, although these hetero-
cycles usually differ in reactivity.
The attack of electrophilic agents on derivatives .of both
furan and pyrrole occurs preferentially at the <x position.!'2
Pyrrole, however, also undergoes £ substitution readily. With
furan itself direct P_ substitution has not been conclusively
demonstrated.
In 1,4 -addition reactions furan is extremely reactive.
Diels-Alder additions with furan are so general that this re-
action has been proposed as a means of preparing derivatives
for identification. 3 Ordinary dienophiles such as maleic
anhydride do not add to pyrrole but form a-substituted
products . 4
i —
o
H
.0
CH-C
+
-0
CH-C
IT
— , CH2-C02H
1
-CH— -CO2H
N
In the presence of weak dienophiles even furan fails to react
An illustration of this fact is seen in the attempted prepara-
tion of a cantharidin precursor from furan and dimethylrnaleic
anhydride . 5 ' 6
-f CH3-C-C.
!' + I! 0
\J
*0
CH3-C-C
0
CH3 r\
it 0 I /°
V CH3x0
No adduct can be isolated from this reaction when it is carried
out under a variety of conditions since the equilibrium is in
favor of the dissociation products. Similarly furan does not
form adducts with such dienophiles as vinyl phenyl ketone7,
|3-nitrostyrene8? 8, acrolein, and crotonaldsnyde. 2 However,
in the presence of a variety of acid catalysts an addition
type of reaction occurs with formation of non-cyclic derivative
similar to those encountered with oyrrole. 10>11
1
CH2=CH-CH0
S02
xo/
CH2CH2CHO
0EC(CH2)
/*
2 )2
0'
.(CH2)2CHC
-82-
Furan, like pyrrole, will undergo additions to carbonyl
groups. Thus furan reacts with chloral to form l-furyl-2,2,2-
trichloroethanol . l2
H
+
CHO
CC13
0
/
i* 4ch-cci3
In a similar manner treatment of furfuryl alcohol with
formaldehyde gives a polymeric 2,5-furandimethanol.3
In view of these similarities it is not surprising that
furan has recently been shown to react with several methyl
ketones in a manner reminiscent of pyrrole.13 Substances
called cyclic anhydrote trainers (IV) which are analogous to
porphyrinogens14 19, are isolated in addition to several
intermediate polycondensation products (I, II and III).
\
0'
CH3
R
/
CO
HC1
V"
CH3r-
R
0
1
I
R
H3C-C-
L. ~
\
0
0
R
•C-CH3
0
II
R
i
H3C-C
xo-
'0 0
/
0
R
-C-CH3
+
H3C-C -/ \
R Li!
III
19
T'
R
H3C
20
R2
18X0
J|i_C-CH3
21
14L
;n
024 22 0 J
23 \ -J 5
0 I6
13
H3C-C_Y V-C-CH3
10 ^— '9
IV
-83-
The ratio of the products may be varied by the ratio of
reagents employed. The difurylalkane (I) is converted to
the cyclic anhydrotetramer (IV) by treatment with a ketone
and hydrochloric acid. This reaction has oeen used to
establish the cyclic nature of (IV), since the same pair of
products (cis and trans isomers) is obtained from an un-
symmetrical difurylalkane and a symmetrical ketone or from a
symmetrical difurylalkane and an unsymmetrical ketone. The
cis and trans isomers can be distinguished by dipole moment
measurements .
A cyclic anhydrotetramer cannot be prepared from 2,5-bis-
( dime thy lfurfuryl)— furan (II, R=CIi3 ) and a ketone. Instead a
polymer and an.anhydrohexamer appear to be formed. Unsymmetrica
anhydrotetramers are obtained, however, when III (R=CH3) is
treated with either aldehydes or ketones.
These reactions are assumed to proceed by way of
protonated tertiary alcohols such as (V) .
n ■ ■ n I
i 'l-C-QHa HO-C.-i 1-C-OH
V°" Ck7 H3C N>' 'H3
V VI
It is improbable that the conjugate acid of (VI) is an inter-
mediate because 2,5-diisopropylolfuran (VI, R=CHa) is con-
verted to resins on treatment with HC1 and furan. Since it is
anticipated that cyclic anhydrotetramers will be prepared
containing ring systems other than pyrrole and furan, it has
been suggested by Ackman, Brown and Wright that the name
"quaterene" be used to describe a closed system of four
methylene -bridged 1, 4-disubstituted cyclopentadienes. Thus
IV (R=CH3) becomes 2,2,7,7,12,12,17,17-octamethyl-21,22,23,24-
tetroxaquaterene .
BIBLIOGRAPHY
1. Oilman and Wright, Chem. Revs., 11 3 323 (1932).
2. Elderfield, "Heterocyclic Compounds," John Wiley and Sons,
New York, 1950, Vol. I, p. 145.
3. Wright and Gilman, Ind. Eng. Chem., 4o, 1517 (1948) .
4. Diels and Alder, Ann., 490, 267 (193T7-
5. Bruchhausen and Bersch, Arch. Pharm., 266, 697 (1928).
6. Diels and Olson, J. prackt. Chem., 156, 235 (194o).
7. Allen, Bell, Bell and Van Allan, J. Am. Chem. Soc, 62, 656
(1940).
8. Allen, Bell and Gates, J. Org. Chem., 8, 373 (1943).
9. Allen and Bell, J. Am. Chem. Soc, £1, 521 (1939).
10. Sherlin, Berlin, Serebrennikova and Rabinovich, J. Gen.
Chem. (U.S.S.R.), 8, 7 (1938).
11. Alder and Schmidt, Ber., 76, 183 (1945).
12. Uillard and Hamilton, J. Am. Chem. Soc, 73, 4805 (1951).
13. Ackman, Brown and Wright, J. Org. Chem., 20, 1147 (1955).
-84-
14. Dennstedt and Zimmerman, Ber., 20, 2449 (1387).
15- Tschelincev and Tronov, J. Russ. Phys. Chem. Soc, 48,
1197 (1916)5 C. A., 11, 1418 (1917) 5 cf. C. A., 11, T52
(1917).
16. Rothemund, J. Am. Chem. Soc, 61, 2912 (1939).
17. Arcnoff and Calvin, J. Org. Chem., 8, 205 (1943).
18. Calvin, Ball and Aronoff, J. Am. Chem. Soc, 65, 2259
(1943).
19. Ball, Dorough and Calvin, J. Am. Chem. Soc, 63, 2278
(1945).
-85-
NEW CYCLOBUTANE DERIVATIVES: PREPARATION AND REACTIONS
Reported by J. H. Rassweiler December 16, 1955
Cyclobutanes present two problems in their preparation
and reactions. One is the low yields afforded by most general
preparations and the other is the inability of the cyclobutane
derivatives thus formed to undergo further transformations.
Willstatter ' s preparation of cyclobutane and its im-
provements through the Curtius acid azide method; the attack
of light on cyclopentanone to produce cyclobutane and carbon
monoxide2; and the Wurtz reduction of tetramethylene bromide
all give unusually low yields and, generally, difficulties in
the separation of the products.
Other methods are more effective but not yet completely
acceptable. Perkins malonic ester synthesis3 is limited,
generally, to acid derivatives. The reaction of diazo-
me thane and ketene gives tjood yields but cannot be widely
applied. The preparation of monosubstituted rings with
l,l,l-tri(bromomethylKalkanes4 has proved very effective.
/\
Zn ' \
CH3C<CHaBr)3 Acetamlde ' < V=CH-CH3
V
A large range of monoderivatives can be prepared from these
compounds 5* 6 . Cyclobutane was isolated in an overall yield
of 4C$ by Cason and Way7 from cyclobutane carboxylic acid;
O i\rvwr\ l.Br2,CCl4
,-COOH 2.AgN03 _C02Ag . r MgBr 3u0H r-
I ^ I •> I >
i _. L L_
i i
2.Mg,Bu20
but the scarcity of the starting material limits this re-
action.
The addition of alkyl substituted ethylenes to ethylenes
or acetylenes would be an ideal method for the preparation of
cyclobutane derivatives. Except for a few cases, this has
proved unsuccessful. Dimerization of ketenes8 has long been
recognized but is not a useful preparative method. The
thermal and light catalysed dimerization of unsaturated com-
pounds has proved successful in a few cases such as: acrylo-
nitrile,9 cinnamic acid and its derivatives10' 1X . The addi-
tion of ethylenes to diphenyl ketene12 goes easily but has a
limited scope. Recently, the thermal dimerization of
fluorinated ethylenes13'14 and the addition of fluoroethylenes
to numerous unsaturated compounds has afforded a good
preparative approach to many fluorinated cyclobutanes, but
further transformation was hindered by the inertness of the
resultant fluoro compounds.
Roberts and co-workersis undertook to use the activation
of fluorine in cycloaddition and to develop a method of removing
-86-
fluorine to give reactive cyclic products16. Their in-
"V
100
> w.^c^CH + CF2=CC12 24 hrs.*
\ — y
A
H2S04
/
100°
— _>
> x>
//
V-F
-v
-/
T
Cla
2 I
85^
0 II
/
Cl2
CI,
vestigations proved I to be of considerable interest,
especially in view of the ease with which the fluorine could
then be removed.
If the preparation is undertaken in the presence of
triethylamine, a rearrangement occurs. Ill undergoes
(C2H5J3N
l4o°C 24 hrs.
100
^y \
7
»:0
(C2H5)3N
100° 5 min.
CI,
racemization and ring opening.
In extending the versatility of this reaction, the
phenylcyclobutenedion.es should be mentioned17. These are re-
' "V-C=CH + CP2=CFC1
120
24 hrs.
IV
H2SO4
' A 7
C1P
■
-87-
active compounds and form many derivatives of the type where
X
/
V-o
v
ii
0
X = Cl,Br,I,OCH3,NH2,OH. These are all stable and react in
a manner analogous to benzo or naphthoquinones.
REFERENCES
1. R. V/illstatter, Ber., 38, 1992 (1905).
2. S. W. Benson, J. Am. Chem. Soc, 64, 80 (1942).
3. J. Cason, J. Org. Chem,, 14, 1036~Tl9^9).
4. J. M. Derfer, J. Am. Chem. Soc, 67, 1863 (1945).
5. E. M. Hancock and A. C. Cope, Org. Syn., 26, 38.
6. L. B. Morton, J. Am. Chem. Soc, 55, 4571~Tl933).
7. J. Cason and R. L. Way, J. Org. Chem., 14, 31 (19^9).
8. W. E. Hanford and J. C. Sauer, Org. Reactions, 3 127.
9. E. C. Coyner, J. Am. Chem. Soc, 71, 324 (1949).
10. K. Alder and E. Ruder, Ber., 74B, 905, 920 (194l).
11. Ahmed Mustafa, Chem. Rev., 51~TT- (1952).
12. H. Staudinger and E. Suter, Ber., 53, 1092 (1920).
13- A. L. Henne and R. P. Ruh, J. Am. Chem. Soc, 6J9, 279 (19^7
14. M. Prober and W. Miller, J. Am. Chem. Soc, 71, 598 (1949).
15. J. D. Roberts, l4th National Organic Chemistry Symposium
of the American Chemical Society, Abstracts June 1955
pp. 21.
16. J. D. Roberts and G. B. Kline, J. Am. Chem. Soc, 75, 4765
(1953).
17« J. D. Roberts and E. J. Smutny, J. Am. Chem. Soc, 77,
3^20 (1955).
' i.
d ■ ■ ':
.
, '
.J. -
• ' .'""'.''■ .'•'• -
■
■J ■'■•''■ . T.
• i -> :'■ : • ■•"
-88-
ISOMERIZATION OF 5-AMINOTETRAZOLE3
Reported by M. E. Peterson January 6, 195G
Since Thiele first reported the preparation of 5-amino-
tetrazole,1 many methods have been devised for synthesis of
it and its derivatives. Preparation of the 1-alkyl- and 1-aryl'
5-aminotetrazoies has been accomplished through syntheses
starting with monosubstituted thioureas, cyanamldes, nitriles
and aminoguanidines. 2 Proposed mechanisms for each of these
methods suggest the formation of a substituted guanyl azide as
an intermediate. Theoretically, with the guanyl azide as an
intermediate, ring closure could occur in two directions, thus
forming substituted-5-aminotetrazoles .
N — N
|l H
RNHC N
H
NH NR RN — N
H =^ II I -— > II!
RNH-C-N3 H2N-C-N3 i H2NC N
,3
Stolle and Helntz did report the formation of a small
amount of 5-anilinotetrazole along with 1 -phenyl -5-amino-
tetrazole when phenyl thiourea was treated with sodium azide
and lead oxide. Other early workers were able to isolate only
the l-substituted-5-aminotetrazoles and no consideration seems
to have been given to isolation of the other isomer. Then, in
1951, Lieber, Henry and co-workers made use of an ami noguani dine
with a highly electronegative substituent to cause cyclization
to proceed in the other direction.4 Further proof that cycli-
zation could proceed in both directions was provided when
5-methylamino-(ll^) , 5-cyclohexylamino- (2$) and 5-benzylamino-
tetrazole(2.6$) were recovered from the mother liquors after
the corresponding 1-alkyl isomers had been removed.5
While investigating the properties of some 5-alkyl-
aminotetrazcles Garbrecht and Herbst observed that 5-methyl-
aminotetrazole possessed a double melting point.6 1-Phenyl-
5-aminotetrazole and l-(4-nitrophenyl)-5-aminotetrazole also
exhibited the same property. Henry and co-workers5 identified
the higher melting material from 5-rnethylaminotetrazole as
l-methyl-5-aminotetrazole. Subsequently, the other higher melt-
ing compounds were identified as the isomeric 5-arylamino
compounds. Several other examples of this thermal isomerization
were later reported.
The observed rearrangement of the 5-aminotetrazoles could
be explained by postulating a guanyl azide intermediate.
However, Garbrecht and Herbst thought it unlikely that this
intermediate could explain both the low temperature cyclization
and the thermal rearrangement. If the azide were involved in
the rearrangement, it seemed unlikely that the 1-aryl -5-amino
compound would be formed at all. In order to explain the
rearrangement they proposed a nitrogen bridge structure I.7
-89-
This intermediate would explain both the isomerization of
R-N— : C
I NR'ii
N' N
a, R=Aryl; R'=H
N lK
b, R=H; R'=Alkyl
H
1-aryl- to 5-arylaminotetrazoles (a), and 5 - alky 1 ami no- to
l-alkyl-5-aminotetrazoles (b). Both R-carrying nitrogens are
equivalent in the ring. When R is aryl, rupture of the RN-N
bond would yield the 5-arylamino compound; when R1 is alkyl,
rupture of the RN-N bond would give the 1 -alkyl -5-amino-
tetrazole.
Finnegan, Henry and Lieber also observed the thermal re-
arrangement of the 5-alkylaminotetrazoles to the l-alkyl-5-
amino isomer.5 Recovery of both isomers of the methyl benzyl
substituted derivative and formation of the two isomers in
roughly the same ratio on cyclization of l-benzyl-2-methyl-3-
azido guanidine suggested that the reaction might reach an
equilibrium. Further investigation confirmed the idea of an
equilibrium. 8
These workers propose that the isomerization does involve
an activated guanyl azide intermediate. A ring structure such
as that proposed by Garbrecht and Herbst did not seem feasible
because such an intermediate x^ould not explain the influence of
substituents on the position or relative rate of equilibrium.
So they first proposed the following mechanism8
r h2n
/
RNH
N^ slow, /Nv v UN fast
H2NC |! — I Cx N — N Cy ^N RHNC-NH
\N-N 'fast j JU | || 'slow jj "n
R RN(+)N(-) HN(+)N'-) ! N-N^
L J
A
which adequately accounts for the attainment of equilibrium
and for the product ratio obtained. However, on the basis of
this mechanism, the rate of forward reaction should be decreased
by electronegative groups in the 1-position. Kinetic rate
studies showed the reverse to be true.
A mechanism (B) has since teen proposed that satisfies
the known properties of the substituted 5-aminotetrazoles and,
in addition, accounts for observed rate changes with change
in the electronegativity of substituents.9 This mechanism is
dependent on the shift of a pair of electrons from the 5-amino
group into the tetrazole ring which would facilitate
heterolysis of the N-N bond. Either electronegative substitut-
ion on the 1-position or electropositive substitution on the
5-position would enhance the shift of the electron pair into
the ring.
-90-
,:NH2
C— N
i Ml
RN, N
- N*
-(+)
NH2
\\
C N
I II
RN: N
-(-)N'
NH2 : NH
I C.\\
C — N — i C
RN: N
n
/
RI-IN :
si
(-)
HN:
•' N
—\
N
r-
RIiN( + )
_i
HN:,N'/
RHN : '
B
Data compiled from the kinetic studies is in accord with
the above mechanism. The tetrazole ring is in itself electro-
negative and withdraws electrons from the amino group. The
isomerization has been found to be first order. Calculation
of the entropies of activation and frequency factors indicate
that the isomerizations are not complicated by stearic factors
or the necessity for oriented energetic collisions.9
1
2,
5
4,
7.
8,
Q.
Thiele,
P.
Ann., 270,
B. Benson,
Stolle and Heintz,
E. Lieber, E.
Chem. Soc. , 73,
W. G. Finnegan,
18, 779 (1953).
W. L. Garbrecht
(1953).
W. L. Garbrecht
R. A. Henry, ¥.
Soc. , 76, 8£
R. A. Henry,
(1955).
BIBLIOGRAPHY
1 (1892).
Chem. Revs., 4l, No. 1 (1947).
J. prakt. Chem., 147, 286 (1937).
Sherman, R. A. Henry and J. Cohen, J. Am.
2327 (1951).
R. A. Henry and E. Lieber, J. Org. Chem.,
and R. M. Herbst, J. Org. Chem., 18, 1022
and R. M. Herbst, ibid. ,
G. Finnegan and E. Lieber,
18, 1269 (1953).
J . Am . Chem .
(1954).
W. G. Finnegan
and E. Lieber, ibid. , 77, 2264
-01 -
.y —
STRUCTURE DETERMINATION BY RAMAN SPECTROSCOPY
Reported by W. A. Remers January 6, 1956
INTRODUCTION: Raman discovered1 in 1928 that when monochro-
matic light is scattered by molecules, other frequencies are
present in the spectrum of the scattered light. The
differences between the frequencies of the exciting light
and the scattered light could be correlated with the vibra-
tional and rotational frequencies of the bonds and functional
groups of the molecules. Vrithin a few years, many other
investigators entered th3 field and extended Raman's findings.
During the 1950' s the Raman spectra of thousands of compounds
were measured and classified. These data have been compiled
in several comprehensive volumes. 2-'3,4,5j'6
Most organic chemists have made no use of this wealth of
data because of the cumbersome techniques involved in obtain-
ing Raman spectrograms of their own compounds. Recently, how-
ever, recording Raman spectrophotometers which are efficient,
easy to operate, and relatively inexpensive have been developed
for use in the research laboratory. They should be effective
in the future in promoting a more widespread use of Raman
spectra, giving the organic chemist valuable aid in his re-
search.
THEORY: To produce the Raman effect, molecules are
irradiated with monochromatic light. When these quanta of
energy collide or interact with a molecule, part of the energy
they represent may be distributed throughout the molecule in
all of its vibrational and rotational degrees of freedom.
Light is emitted from the molecule at frequencies lower than
that of the incident light, unless the absorbing molecule is
already in a higher energy level than normal. The
differences in frequencies of the exciting light and the
emitted light may correspond directly to the frequencies of
vibration and rotation of atoms within the molecule.
The Raman effect is similar to infrared absorption in
that the force constants of the bonds determine the frequencies
of the absorbed or scattered light. The frequency of the Raman
displacement for a particular bond or group is equal in
magnitude to the frequency of the infrared absorption of that
bond or group. Infrared absorption occurs only when there
is a change in the electric moment of a molecule, the Raman
effect occurs only when there is a change in polarizabilityj
hence, vibrations which are unsymmetrical with respect to the
symmetry axes of a molecule appear strongest in absorption,
the symmetrical vibrations being strongest in the Raman effect.
Light emitted in the Raman scattering varies from frequency
to frequency in its intensity and in its polarization
characteristics. Determining whether the light at each
frequency is polarized or depolarized is of the greatest
importance in establishing the symmetry class of a molecule.
-92-
APPLI CATIONS: Many bonds and functional groups can be iden-
tified by their characteristic Raman displacements. 2' s>4>s, e
A few of these are listed below:
Bond or Group Raman Displacement, /—a. V (cm."1)
C - H (stretch) 2850-33C0 depending en nature
C - D (stretch) 2080-2260 of compound
-C = CH 2120 for C=C stretch, 33^-0 for C-H
-C s C-(stretch) 2235
C = 0 (stretch) 1710 (unconjugated ketone)
C = C
cis-2-pentene 1248-1266, 1375, 1658
trans-2-pentene 1293-1313, 1373, 1674
Raman spectroscopy is especially useful in detecting these
groups in highly symmetrical molecules. Diphenyl acetylene
shows no acetylenic band in the infrared, but shows a very
strong Raman displacement of 2211 cm.-1.7 Similarly, tetra-
chloroethylene shows no ethylenic band in the infrared, but
does in the Raman.8 In long chain hydrocarbons containing a
single acetylenic bond, the intensity of infrared absorption
is strongest when the bond is terminal, weakest when it is in
the center of the molecule. The intensity of its Raman
scattering is opposite to this.9
Since Raman spectrophotometers are effective in the
infrared region of 400-100 cm.-1, which is not reached by
infrared absorption instruments, they should be very useful
in detecting carbon-halogen bonds. The determination of the
configurations of polyhalogenated aromatic and aliphatic
compounds and of axial and equatorial bromine in cyclohexane
systems should be especially valuable.
In addition to the detection of specific functional groups
for smaller molecules, or for molecules possessing a high
degree of symmetry a more definite and complete determination
of structure can usually be made. Structures are assumed and
the selection rules, which determine the number and
characteristics of the infrared and Raman bands, are predicted
for these structures by use of group theory. Observed Raman
and infrared bands are assigned to fundamental modes of
vibration of the molecule, or to their overtone or combination
frequencies. Agreement between the predicted and observed
bands is strong evidence that a particular assumed structure
is correct. For the complete determination of a structure,
the following data are essential:
1. Complete Raman and infrared spectra throughout the
region 100-4000 cm."1.
2. A reliable determination of which of the bands are
fundamentals.
3. Reliable, quantitative values of the depolarization
factors, in order to determine the number of
polarized and unpolarized frequencies of light.
-93-
Certain generalizations have been made10 from the
selection rules:
1. Totally symmetrical vibrations are always polarized
in the Raman, other vibrations are depolarized.
2. The greater the symmetry of the molecule, the greater
the number of forbidden fundamentals, combinations,
and overtones.
3. If a center of symmetry is present, no frequency
appears in both the Raman and infrared spectra.
4. The greater the symmetry, the greater the tendency
toward a small number of fundamental vibrations of a
particular type.
As an example of complete structure determination,11
consider the three possible structures for hexachloroethane .
CI
CI CI
1. staggered structure ^K CI
2. eclipsed structure
CI
CI
CI J
A^Cltl
01 CI
(D3d symmetry type)
^D3h symmetry type)
3. free rotation structure
(D3h' symmetry type
Selection rules predict three polarized lines for each
structure. Six depolarized lines are predicted for I^h and
Dah', three for D3d. The observed spectrum has only three
polarized and three depolarized lines; therefore, structure
D3d must be the correct one. D3d has a center of symmetry,
which is consistent with the fact that no coincident Raman
and infrared bands are observed.
BIBLIOGRAPHY
2,
3
5.
7
C. V. Raman and K. S.
C. V. Raman, ibid. , p
2, 387 (1928).
K. V7. P. Kohlrausch,
Arbor, Mich. ,
J. H. Hibben,
cations, A.C.S
New YorR,
Krishnan,
, 619; C.
Nature ,
V. Raman,
121, 501 (1928);
Indian J . Phys . ,
Edwards Bros
Ann
Ramanspektren ,
(19^5).
The Raman Effect and its Chemical Appli-
Monograph Series, Reinhold Publishing Co.
1939.
G. Herzberg, Infrared and Raman Spectra of Polyatomic
Molecules, 1st. ed., D. van Nostrand Co., New York, 19^5.
F. D. Rossini, American Petroleum Institute Catalog of
Raman Spectral Data, Department of Chemistry, Carnegie
Inst, of Tech., Pittsburg, Pa.
M. Magat, Numerical Data on the Raman Effect and Raman
Effect, vols. XI and XII of Annual Tables of Constants
and Numerical Data, McGraw-Hill Book Co., New York, 1936,
1937.
A. Dadieu and K. ¥. F. Kohlrausch, Monatsh. Chem. , 60,
221 (1932).
-94-
8. Herzberg,loc . cit., p. 329.
9. Hibben, loc. cit., p. 200-208.
10. P. F. Cleveland, Raman Spectra, ch. 6 in Determination of
Organic Structures by Physical Methods, Edited by E. A.
Braude and F. C. Nachod, Academic Press, Inc., New York,
1955.
11. R. A. Carney and F. F. Cleveland, Phys. Rev., 75, 333
(19^9); R. A. Carney, A. G. Meister and F. F. Cleveland,
Phys. Rev., 77, 7^0 (1950).
-95-
ANODIC SYNTHESIS OP LONG CHAIN UNSATURATED FATTY ACIDS
Reported by Thet San January 6, 1956
The long chain unsaturated fatty acids, in recent years,
have attracted much attention because of reports that a
number of them are growth promoting factors for various micro-
organisms. In his recent papers, Linstead has accomplished
the anodic synthesis of a number of naturally oc curing long
chain unsaturated fatty acids, and their stereoisomers. These
were obtained in high purity and with known configurations.
The electrolysis of a mixture of a monocarboxylic acid,
RCOOH, and a half ester of a dicarbcxylic acid R'OOC(CH2)nCOOH
is known to give rise to three main products: RR, R(CH2J COOR'
and R02C[CH2 32nC02R' as a result of symmetrical and crossed
coupling of the Kolbe type1. By a proper choice of the mono-
carboxylic acid and the dicartoxylic acid, these three products
can be made to have widely diff extent molecular weights, hence
they can easily be separated by distillation. This has
therefore been developed into a general method for the synthesi
of long chain fatty acids2. Many naturally occuring branched
chain fatty acids have been synthesised by this method. This
method however has a few limitations. Most a-alkyl substituted
carboxylic acids give extremely low yield of coupled products
on electrolysis. Also, when the a-position is substituted by
phenyl, hydroxy 1, halogen, etc., the Kolbe reaction is largely
suppressed. The Kolbe reaction is totally suppressed when
the acid used is a,|3 or p, f unsaturated acid.1
Normal anodic coupling of olefinic acids has been reported
in cases where the double bond is separated from the carboxyl
group by at least two carbon atoms . Linstead3 observed that
the configuration and position of the double bonds were pre-
served during the electrolysis. Anodic synthesis is therefore
found to be generally applicable to the synthesis of unsaturate'
acids. It has an advantage over many other methods, in that
it is stereospecific.
Other general methods for the synthesis of olefinic
acids are:- (l) method used by Noller and Bannerot4 (2) a
method in which a symmetrical acyloin is employed as an inter-
mediate5 (3) Ahmad and Strong6 developed a method based on
the semi-hydrogenation of the corresponding acetylenic acid.
(4) method developed by Bowman7 in which a methoxy ketone is
an intermediate.
Electrolysis of oleic and elaidic acids in the presence
of excess methyl hydrogen adipate gave in each case three
products, by symmetrical and unsymmetrical coupling of the
two components3. The three products were separated by
distillation and subsequent hydrolysis of the unsymmetrical
products gave erucic and brassidic acids respectively (30$).
-96-
-2e
CH3[CH23TCH:CH[CH2]7C00H + H02C [CH2]4C02Me > Me02C [CH2 ]8C02Me +
cis-cleic acid + [CH3[CH2]TCH: CH[CH2]7- 1 +
trans-elaidic acid
CH3[CH2]7CH=CH[CH2]i;LC02Me -> CH3 [CH2]7CH=CH[CH2]iiC02H
cis-erucic, trans-brassidic
This synthesis therefore confirms that erucic acid is a cis
acid and that brassidic acid is trans . Bowman7 synthesised
these two acids according to the following scheme:
CH30CHRC0C1 + (CH2Ph02C)2CNa(CH2)i0C02CH2Ph ->
CH3OCHRC=0
i
( CH2Ph02C ) 2-C- ( CH2 ) 10 -C02CH2Ph
(a) H2Pd-C
' CH3OCIiR-CO-CH2(CH2)i0C02H -» CH3OCHR-CHOH(CH2 ) nC02H
Al
(b) -C02 isopropoxide
HBr ^ RCHBr-CHBr(CH2)nC02H ^) RCH=CH- (CH2)nC02H
mixture of erucic and brassidic
R=CH3[CH2]7
Electrolysis of threp and erythro dihydroxystearic acids I,
with methyl hydrogen adipate, followed by distillation and
hydrolysis gave threo- and erythro- dihydroxybehenic acids II
in 30$ yield. 3 These were converted into brassidic and
erucic acids respectively by the standard bromination,
debromination procedure used by Bowman.
Me(CH2)7,CH0H,CH0H-(CH2)7C02H + H02C (CH2) 4 ' C02Me )
Me(CH2)7*CH0H-CH0H- (CH2)nC02H _-> Me (CH2)TCH=CH(CH2)11C02H
II
Erucic acid occurs in the seed fats of Cruciferae and
Tropacolacae.
When oleic acid cis III and elaidic acid trans III are
electrolysed in the presence of an excess of methyl hydrogen
suberate, and the resulting solution worked up as usual,
cis- and trans- tetracos-15-encic acids were isolated in
30 fo - 35% yield. 8 The cis acid has been shown to be identical
with nervonic acid, from the cerebrosides of cattle and man,
and selacholic acid from shark and ray liver oils. Both the
cis and trans acids have been synthesised by the malonate
chain extension of erucic acid5.
-97-
CH3[CH2]7*CH:CH[CH2]7'C02H + H02C (CH2) 6 ' C02Me
III ^
CH3 [ CH2 ]Y' CH: CH [ CH2 ] 1 3C02H
IV
In the latter method a mixture of the cis and trans forms
were obtained, and separation was effected by fractional
crystallization.
Both the cis and trans forms of octadec-11-enoic VI and IX
acid are found to occur in nature. The cis isomer was
identified with the haemolytic factor of horse brain. The
trans isomer was identified with 'vaccenic acid'. Until re-
cently it was the only natural monoethenoid acid known with a
trans configuration. Anodic synthesis of the cis isomer was
accomplished by the electrolysis of palmitoleic acid V in the
presence of a large excess of methyl hydrogen succinate.10
H. H H OH
SC=C^ ) CH3' (CH2)5-C— C-(CH2)7C02H
CH3(CH2)5 (CH2}TC02H
OH H
V VII
H OH
i i
H H CH3(CH2)5C— C-(CH2)9C02H
\k
xc=c" '
CH3(CH2)5^ N(CH2)9C02H
VI
i
VIII
CH3(CH2)5 H
h' ^(ch2)9*co2h
IX
Hydroxylation of palmitoleic acid by performic acid furnished
the threo-9:10 dihydroxypalmitic acid VII. Electrolysis of
this acid with excess of methyl hydrogen succinate gave
threo-ll:12 dihydroxy-stearlc acid VIII {2J>%) . The product
was converted into the trans -octadec-11-enoic acid IX (42$)
by the standard procedure of bromination and debromination.
Both of these acids have been syntheslsed by Strong et al11.
Half esters of the type H02C[CH2] C'CtCH^'CX^R12' 13
have been found to undergo the normal Kolbe reaction, provided
n)> 1. This then provides a flexible route to unsaturated
acids since by crossed coupling first at one end of the molecule
with a monocarboxylic acid and then, if desired, at the other
half with a half ester, acids of different length and with
different positions of unsaturation can be obtained. Partial
reduction of the acetylenic acid will give the olefinic acid.
Depending on the nature of the reducing agent used, the cis
or trans acid is obtained respectively^4 Synthesis of oleic
acid according to the following scheme has been accomplished
by this method.
-c^O-
CI- [CH2]4C:CH + Br[CH2]4Cl ---> CI [CH2]4C:* C[CH2]4C1
liq.NH3
NC- [CH2]4*C:C[CH2]4CN -> H02C[CH2]4C: C[CH2]4* C02H* ->
H02C[CH2]4C:'C[CH2]4'C02Me + CH3 [CH2]3 • C02H ->
CH3[CK2]yC:C[CH2]4'CC2H + H02C [CH2]3C02Me ->
CH3[CH2]7C:C(CH2)7C02Me ■* CH3 (CH2)yC: C[CH2]7 * C02H S2
H H
XC=C''
CH3' (CH2)7 ^[CH2]7'C02H
Oleic acid has been synthesised by many chemists. However,
all these syntheses with the exception of Hubers work and
the one given above give mixtures of oleic and elaidic acids
in which the latter predominates. Only the anodic synthesis
and that of Huber15 are substantially stereospecific.
In recent years it has been realized that during the
electrolysis of a fatty acid some esterificaticn with the
methanol used as solvent may accompany the coupling process.
This side reaction with the solvent may result in the
contamination of the product with the starting material in
cases where the carbon chain of the original acid is extended
by only a few carbon atoms. It has now been observed3^ that
this drawback may be avoided by the use of benzyl half esters
in place of methyl or ethyl half ester. After cross coupling
with a monocarboxylic acid the benzyl ester formed may either
be separated by distillation from any methyl ester of the
starting acid and be subsequently hydrolysed, or, alternately',
converted without isolation into the required acid by
hydrogenolysis .
BIBLIOGRAPHY
1. Weedon, Quarterly Rev. , 6, >cO, 1952.
2. John R. Demuth Seminar University of Illinois, March 15,
1953-
3. D. G. Bounds, R. P. Linstead and B. C. L. Weedon, J. Chem.
Soc, (1953) 2393.
4. C. R. Noller and R. A. Bannerot, J.A.C.S., 56, 1563, 1934.
5. Ruzicka, plattner and Widmer, Helv. Chim. Acta, 25, 604,
1036 (1942).
6. Ahmad and Strong, J.A.C.S., 70, I699, 1948.
7. R. S. Bowman, J.C.S. (1950), I?7.
8. D. G. Bounds, R. P. Linstead and B. C. L. Weedon, J.C.S.
(1954) 44b.
9. J. B. Hale, W. H. Lycan and Roger Adams, J.A.C.S., 52,
4536, 1930.
10. E>. G. Bounds, R. P. Linstead and B. C. L. Weedon, J.C.S.
(1954) 4210.
11. Ahmad, Bumpus and Strong, J. Am. Chem. Soc, 1948, 70,
3391.
12. B. W. Eaker, R. W. Kierstead, R. P. Linstead and B. C. L.
Weedon, J.C.S. (1954) 1804.
13. R. W. Baker, R. P. Linstead and B. C. L. Weedon, J.C.S.
(1955) 2218.
14. Crombe, Quart. Rev., 1952, 6, 128.
15. W. Frederic Huber, J.A.C.S. (1951) 73, 2730.
16. R. p. Linstead, B. C. L. Weedon and B. Wladislaw, J.C.S.
(1955) 1097.
-99-
POLYACETYLENIC COMPOUNDS PROM PLANTS
OF THE COMPOSITAE FAMILY
Reported by Philip N. James
January 13* 1956
The first acetylenic compound to be discovered in nature
was carlina oxide1, whose structure (I) was confirmed by
synthesis2. Later, from another source, a group of Russian
workers isolated the lachnophyllum ester3, whose structure (II)
and configuration were established by extensive degradative
studies.
C6H5CH2C=C
"No'
CH3CH2CH2C=CC=CCH=CHCOOCH3
I II
In 19^1* Sorensen and Stene4 isolated the matricaria ester
from the scentless mayweed, and from numerous degradation
studies assigned to this compound the structure III. They
noticed that this compound underwent rearrangement to an isomer
upon irradiation with ultraviolet light. A later study of the
compound by means of ultraviolet spectroscopy5 confirmed struct-
ure III. This compound was synthesized by Bruun10 using
Glaser's coupling reaction25. Both the 2-cis-6-trans and all
trans isomers were produced, but neither was identical with the
Cu2Cl2
— - — 4 CH3CH=CHC=CC=CCH=CHCH2OH
°2 V ,
|Cr03
CH3CH=CHC=CH + HC=CCH=CHCH20H
trans
jCH2N2
Cu2Cl2
CH3CH=CHC=CH + HC=CCH=CHC00CH3 * CH3CH=CHC=CC=CCH=CHCOOCH3
02 III
natural ester. The 2-cis-8-trans isomer, however, was identical
with the irradiation isomer of the natural ester, and, from
energy considerations, these workers selected the all cis
isomer for the natural product. In later work12, the 2-cis-8-
trans isomer was discovered in nature.
The starting materials in these reactions became
synthetically available largely through the work of Heilbron's
group24, and the ultraviolet data, which permit surprisingly
accurate deductions with respect to the structures of polyynes,
were accumulated from several sources4~24, 26~3i.
Bruun also synthesized the trans isomer of II by the
following schemes. This isomer was subsequently discovered in
nature18.
Cu2Cl2 Cr03 CH2N2
CH3CH2CH2C=CH + HC=CCH=CHCH2OH — > > > II
trans
0;
-100-
A hexair/dromatricaria ester apparently possessing a
cumulene structure has also been isolated7. On the basis of
spectral comparisons, the structure IX has been assigned to
this "composit cumulene I".
CH3CHaCH2CH2CH2CH=C=C=CHC00CH3 IX
A dehydromatricaria ester having the formula CnHs02 was
isolated and characterized by Sorensen's group8. From
preliminary investigations, only structures X and XI seemec"
plausible for the compound. Synthesis of the trans isomers of
CK3CH=CHC=CC=CC=CCOOCH3 X CH3C=CC=CC=CCH=CHCOOCH3 XI
both11'28 showed that neither was the natural ester, but
spectral comparisons of these and other related synthetic
compounds indicated that the natural ester possessed the
structure cis XI.
From the same source as above, a ketone with the formula
C14H14O was isolated8. Preliminary investigations and
spectral data8*29 ruled out many possible structures, XV and
XVI finally remaining. Bohlmann29 synthesized these and
determined that the natural ketone possessed structure XVI.
HC=-CCH2CH(C00H)2 ) NaNHj^ _CHaCH2COCl^
H2SO4
A
^HsCH-CHCj-CCfCH HC=CCH2CH2C0CH2CH3
j Cu2Cl2, 02
CH3CH=CHC=CC=CC=CCH2CH2C0CH2CK3
trans
XV A
NaOEt HC=CCH=CHCH2Br. KOH A
CH3CH2C0CH2C00R ^ ^ ~— 1
CH3C=CC=CH
I Cu2CI2, 0;
HC-CCH=CHCH2CH2COCK2CH3
CH3C=CC=CC=CCK=CHCH2CH2COCH2CH3
trans
XVI
Both isomers of a.fi-dihydromatricaria ester have been
prepared13, and the 8-cis isomer has oeen discovered in
nature12.
All trans matricarianol (V)14, its acetate17, and a cis
isomer of the acetate17 have also been isolated from Compositae
plants .
-101-
Prom another species of this family a series of compounds
have been isolated20 and structures tentatively assigned to
them:
ch3ch=chc=cc=cc=ccscch=Ch2 XIX
C6H5C=CC=CCH=CHCH20C0CH3 XX
CH3CH=CHC=CC=CCH=CHCH=CHCH=CH2 XXI
C6H5C=CC=CC=CCH=CHCH=CHCH3 XXIII
CH2=CHCH=CHC2CC=CC=CCH=CHCH20C0CH3 XXIV
Structure XIX was assigned on the basis of the comparison be-
tween the ultraviolet spectrum of the natural product and tho^e
of several closely related synthetic compounds20 * 23,30 #
Structure XX was confirmed by synthesis from phenylacetylene^i .
Structure XXI was also confirmed by synthesis and by comparison
of maleic anhydride adductsai.
(C6H5)3P + CH2=CHCH23r )i C6H5 )3PCH2CH=CH2 4"9-.
all trans V % CH3CH=CHC=CC=CCH=CHCHO ^ gsgs / 3P=CHCH=CH2 XXI
~~7
Structure XXIII was assigned on the basis of spectral comparisor
and hydrogenation studies2i as was structure XXIV22. Another
highly unstable substance has also been isolated, and structure
XXV, representing a tris-dehydro XXI, is consistent with the
limited data available23.
CH3C=CC=CC=-CC=CC=CCH=CH2 XXV
For .other studies related to naturally-occurring poly-
acetylene compounds, see references 32 and 33.
REFERENCES
1. F. Semmler, Chem. Ztg., 13, 158 (1889).
2. A. Pfau, J. Pictet, P. Plattner and B. Suoc, Helv. Chim.
Acta, 18, 935 (1935).
3- W. Wiljams, V. Smirnov and V. Goljmow, J. Gen. Chem.
(U.S.S.R.), 5, 1195 (1935).
4. N. A. Sorensen and J. Stene, Ann., 549, 80 (1941 ).
5. R. T. Holman and N. A. Sorensen, Acta Chem. Scand., 4,
416 (1950).
6. T. Bruun, C. M. Haug and N. A. Sorensen, Acta Chem. Scand..
ib 850 (1950).
7- N. A. Sorensen and K. Stavholt, Acta Chem. Scand., 4, I080
(1950).
8. K. Stavholt and N. A. Sorensen, Acta Chem. Scand., 4, TR67
(1950). "' ^ '
9- N. A. Sorensen and K. Stavholt, Acta Chem. Scand., 4, 1575
(1950).
10. T. Bruun, P. K. Christensen, C. M. Haug, J. Stene and N. A.
Sorensen, Acta Chem. Scand., 5, 1244 (1951).
11. P. K. Christensen and N. A. Sorensen, Acta Chem. Scand., 6,
602 (1952) . -'
12. K. K. Baalsrud, D. Holme, M. Nestvold, J. Pliva, J. S.
Sorensen and N. A. Sorensen, Acta Chem. Scand., 6, 883
(1952). —
13. P. K. Christensen and N. A. Sorensen, Acta Chem. Scand., 6,
893 (1952).
14. G. M. Tronvold, M. Nestvold, D. Holme, J. S. Sorensen and
N. A. Sorensen, Acta Chem. Scand., 7, 1375 '1953).
-102-
15. L. Skattebol and N. A. Sorensen, Acta Chem. Scand., 7,
1388 (1953).
16. J. S. Sorensen, T. Bruun, D. Holme and N. A. Sorensen,
Acta Chem. Scand., 8, 26 (1954).
17- D. Holme and N. A. Sorensen, Acta Chem. Scand., 8, 34
(195^).
18. D. Holme and N. A. Sorensen, Acta Chem. Scand., 8, 280
(1954).
19. J. S. Sorensen and N. A. Sorensen, Acta Chem. Scand., 8,
234 (1954).
20. J. S. Sorensen and N. A. Sorensen, Acta Chem. Scand., 8,
1/41 (1954).
21. T. Bruun, L. Skattebol and N. A. Sorensen, Acta Chem.
Scand., 8, 1757 (1954).
22. J. S. Sorensen and N. A. Sorensen, Acta Chem. Scand., 8,
1763 (1954).
23- J. S. Sorensen, D. Holme, E. T. Borlaug and N. A.
Sorensen, Acta Chem. Scand., 8, 1769 (1954).
24. Researches on Acetylene Compounds:
Paper I: K. Bowden, I. M. Heilbron, E. R. H. Jones and
B. C. L. Weedon, J. Chem. Soc, 39 (1946).
Paper XLVIII: E. R. H. Jones, 3. L. Shaw and M. C. Whiting
J. Chem. Soc, 3212 (1954;.
Studies in the Polyene Series:
Paper I: E. Barraclough, J. W . Batty, I. M. Heilbron and
W. E. Jones, J. Chem. Soc, 1549 (1939).
Paper LI: H. B. Henbest, E. R. H. Jones and T. C. Owen,
J. Chem. Soc, 2765 (1955).
See also: E. R. H. Jones, M. C. Whiting, J. B. Armitage,
C. L. Cook and N. Entwhistle, Nature, 168, 900 (1951).
25. C. Glaser, Ann., 154, 137 (1370).
26. E. F. L. J. Anet, B. Lythgoe, M. H. Silk and S. Trippett,
J. Chem. Soc, 309 (1953).
27. B. Lythgoe, Lecture: "Some Naturally Occurring Poly-
acetylenes," delivered at a joint meeting of the Royal
Institute of Chemistry and the Society of Chemistry and
Industry held at Ilarischal College at 7:30 P. M. , Friday,
January 13, 1956. Announced in Proc Chem. Soc, November
28. F. Bohlmann and H. J. Mannhardt, Chem. Ber., 88, 429 (1955)
29. F. Bohlmann, H. J. Mannhardt and H. G. Viehe, Chem. Ber.,
88, 361 (1955).
30. E. R. H. Jones, J. M. Thompson and M. C. Uniting, Acta
Chem. Scand., 8, 1944 (1954).
31. F. Bohlmann and H. J. Mannhardt, Chem. Ber., 88, 1330
(1955).
32. I. M. Heilbron, E. R. H. Jones, P. Smith and B. C. L.
Weedon, J. Chem. Soc, 5_4, (1946); I. M. Heilbron, E. R.
H. Jones and F. Sondheimer, J. Chem. Soc, 1586 (1947).
33- F. Bohlmann and H. G. Viehe, Chem. Ber., 88, 1245 (1955).
-103-
KINETIC CONFORMATIONAL ANALYSIS OF CYCLOHEXANE DERIVATIVES
Reported by Carol K. Sauers January 13, 1956
Introduction
The stereochemistry of substituents on six-meinbered saturated
rings was not generally understood until results of recent
work both theoretical and experimental became known. Hassel
and his coworkers2 have determined the conformations of cyclo-
hexane and many of its derivatives from analyses of x-ray and
electron diffraction data on Loth the solid and vapor states.
Pitzer, Beckett and Spitzer1 have elucidated the geometry of
cyclohexane from thermodynamic calculations. It has been
generally assumed and is borne out by the experimental
evidence mentioned above , that in polysubstituted cyclohexanes,
equatorial positions will be preferred by all substituents and
that the more bulky ones will occupy equatorial positions if
there is a competition for these positions.
Barton3 has pointed out that a small difference in the free
energy content (ca. 1 kcal./mole at room temperature) will
insure that a molecule appears by physical methods of
examination and by thermodynamic considerations to be sub-
stantially in only one conformation. But, because one con-
formation of a molecule is more stable does not mean that the
molecule is compelled to react as if it were in this conforma-
tion. In fact, Curtin has noted a number of depressed rates of
chemical reactions resulting from necessary conformation
changes from stable to less stable isomers during the rate
determining step and has labeled these cases "the axial effect".4
Conformation and Reactivity
In 1951* Birch remarked that conformation analysis for study
of the stability and reactivity of saturated or partly saturated
cyclic systems promises to have the same degree of importance
as the use of resonance in aromatic systems.5 The large
volume of research reported on conformation and reactivity,
especially in the steroid and terpene fields, verifies this
prediction. (Reviews in addition to the above are noted in
reference 6) .
For example, in the esterification of cyclohexanols and the
hydrolysis of these esters, equatorially oriented groups react
far more readily than the axial epimers. Vavon7 has shown that
trans 2- and trans h- alkyl cyclohexanols are more reactive than
the cis isomers. The rate ratio for basic hydrolysis of
2-isopropylcyclohexyl hydrogen succinates at 59° is trans : cis
= 6.0 : 0.15-
Moreover, in an interpretation of Read and Grubb ' s data8 on
the rates of esterification of the menthols with p_-nitrobenzoyl
chloride in pyridine at 25°, Eliel9 has attributed the
following differences in reactivity to the conversion of two of
the axial alcohols into less stable equatorial alcohol con-
formations for reaction.
-104-
Isomer
Rel. Rates
Me i-Pr
Isomer ~~ ' Ftel
i-Pr
i-Pr.
Rates
16.5
III
3.1
i-Pr
i-Pr
i-Pr-V'
II
12.3
1.0
Recently Winstein and Holness10 have placed conformational
analysis of cyclohexane derivatives on a quantitative basis
in a study of the 4-t-butyl and 3-t-butyl cyclohexanols . If
a free energy diagram applicable to the axial and equatorial
isomers of a cyclohexane compound is constructed, the following
facts become apparent:
*
bO
a
e
/
\
-
<•
a"
a
■'
V
e
•
A
1. That the relative amounts of reaction through e and a"* are
independent of A"'r. 2. But, the observed rates of reaction
are related to the conformational distribution of the ground
state; for we see that for unimolecular reactions:
ku
k'T
h
\¥
a
K
a"'s
I KIT
X h
where :
K@ and K^ are equil. const,
k is Boltzmann's const.
h is Planck's const.
* stands for Transition
State
e is equatorial
a is axial
products
The rate of formation of these products, dx/dt is given by:16
dx/dt = k'TKg/h [e] + k'TK^/h [a]
-105-
Which upon dividing by [e + a] gives:
dx/dt/ [e + a] = k'TKeA • Ne + k'TKa/h . Na
Or,
k = keNe + kaNa (1)
io>ii
Where k is the observed rate of reaction, ke and ka are the
rates for each conformation and N and Na are the mole
fractions.
It will also be seen that
- Fe = 2.303 RT log (Ne/Na)
A. (2)
If k and ka can be determined for "conformationally pure"
compounds, then using these values for the same reaction on
"conformationally mixed" compounds will lead to knowledge of
Ne and Na.
Curtin and Stolow have derived equation (l) without the use of
transition state theory from equilibrium considerations alone.12
For the purpose of obtaining the ke and ka values for various
reactions, Winstein and Holness prepared cis and trans 4-t-
butyl and 3-t-butyl cyclohexanols. They measured the rates
of saponification of the acid phthalates, chromic acid oxidation
and solvolysis of the p_-toluenesulfonates. These results
along with Vavon's13 work on the acid catalyzed dehydration
of the alcohols are reported in the following table.
Table I, Relative Rates
Compounds
OH
Sapn. Cr03
Acid Phth.
50° 25° 50° EtOH AcOH
Dehydr.l4o°
Solvolysis 50° 160° 13
0.11
2.97 2.55 3-90 3.24
HCOOH
3-58
3.5
t-Bu
1.00
1.00 1.00 1.00 1.00 1.00
1.0
t-Bu
1.02
1.03
t-Bu
-106-
1.24 1.4l 1.29 1-24 1.23 1.16
0.96
0.11
3.45
Applying theset results to those of other workers, notably
Vavon14 and Huckel,is Winstein and Holness were able to
construct the following table of "A values11.
Table II, Group A Values
Group
Solvent
Temp . , ° C
A,kcal.,
t-Bu
5.4
i-Pr
H20
39
3-3
n-Bu
n
ii
2.6
n-Pr
it
n
2.1
Ethyl
n
it
2.1
Methyl
1.8
OTs
Et0H,Ac0H,
,HC00H
50
1.7
0C0C6H4C00-
H20
39
1.2
OH
1% AcOH
4o
0.8
BIBLIOGRAPHY
1. C. W. Beckett, K. S. Pitzer, R. Spitzer, J. Am. Chem. Soc . ,
6£, 2488 (19^7).
2. 0. Hassel, B. Ottar, Acta. Chem. Scand. I, 929 (1947 h
0. Hassel, H. Viervoll, ibid., I, 149 (194?); 0. Hassel,
Research, 3, 504 (1950).
3. D. H. R. Barton, Experientia, 6, 316 (1950).
4. D. Y. Curtin, Rec. Chem. Prog., 15, 111 (1954) and
references contained therein.
5. A. J. Birch, Ann. Repts . , XLVIII, 192 (1951).
-107-
6. S. J. Angyal, J. A. Mills, Rev. Pure and Appl . Chem.
(Australia) 2, 185 (1952); 0. Hassel, Quart. Rev., 7,
221 (1953);. D. H. R. Barton, J. Chem. Soc, 1027 (1953);
H. D. Orloff, Chem. Rev., 54, 347 (1954); W. Klyne,
"Progress in Stereochemistry" Vol. I, Chapter 2, Academic
Press Inc., New York (1954) and reference 4.
7. G. Vavon, Bull. soc. chim. Pr., (4) 4£: 937 (1931).
8. J. Read, W. J. Grubb, J. Chem. Soc, 1779 (1934).
9. E. L. Eliel, Experientia, 9, 91 (1953).
10. S. Winstein, N. J. Holness, J. Am. Chem. Soc, 77,
5562 (1955).
11. E. L. Eliel, C. A. Lukack, R. S. Ro, Technical Report
from Notre Dame, p. 4 (1955).
12. D. Y. Curtin, R. Stolow, private communication.
13. G. Vavon, M. Barbier, Bull. soc. chim. Fr. (4) 4£:
567 (1931).
14. G. Vavon, Bull, soc chim. Fr. (4) 4£: 989 (1931).
15. W. Hu'ckel, et.al., Ann., 533, 128 (1937).
16. S. Glass tone, K. J. Laidler, H. Eyring, "The Theory of Rate
Processes" 1st ed., p. 14, McGraw Hill Book Co., Inc.,
New York (1941).
17. F. H. Westheimer, A. Novich, J. Chem. Phys., 11, 506
(1943). ~
18. M. L. Bender, J. Am. Chem. Soc, 73, 1626 (1951);
75, 5596 (1953); M. L. Bender, R. D. Ginger and K. C. Kemp,
J. Am. Chem. Soc, 76, 3350 (1954).
■■■
SEMINAR TOPICS
CHEMISTRY 435 II SEMESTER 1955 56
The Structure of Ajmaline
R. G. Schultz, February 10 1
The Alkylatlon of Mesomeric Anions
R. A. Scherrer, February 10 7
Conversion of Primary Amines to Alcohols
B. M. Vittimberga, February 17 11
Vapor Phase Chromatography
B. D. Wilson . February 17 15
The 1,4-Elimination Reaction With Cleavage
W. De Jarlais, February 24 19
The Absolute Configuration of Morphine
D. S. Matteson, March 2 23
Alkylations With Alcohols Under Basic Conditions
Joe A. Adamcik, March 2 27
Colchicine: Aspects of Structure and Synthesis
J. H. Rassweiler, March 9 31
Ferrocene as an Aromatic Nucleus
Kenneth Conrow, March 16 35
Application of Mass Spectrometry to Organic Chemistry
Philip N. James, March 16 39
The Unsaturation of Cyclopropane Rings
Norman Shachat, March 23 43
Aliphatic Hydroxy Sulfonic Acids and Sultcnes
J. S. Dix, March 23 47
Nucleophilic Substitution of Vinyl Halides
Willis E. Cupery, April 6 50
Non-Polymer-Forming Reactions of Vinyl Halides
H. Scott Killam, April 6 54
Alkaline Ferricyanide Oxidations
C. W. Schirnelpfenig, April 20 57
The Structure of Novobiocin
Kaye L. Motz, April 20 6l
Ozonation Studies of Aromatic Hydrocarbons and Heterocycles
M. S. Konecky, April 27 64
Isomer! zation in the Flavanoids
Jerome Gourse , May 4 71
--2
Vitamin B12
L. R. Haefele, May 11 7^
Reactions of Cyclooctatetraene and its Derivatives
W. A. Remers, May 11 78
Some Aspects of the Mechanisms of Catalytic Hydrogenation
C . K . Sauers , May 18 82
Organic Peroxides
J . C . Little , May 18 88
THE STRUCTURE OF AJMALINE
Reported by R. G. Schultz
February 10, 1956
Ajmaline is an alkaloid isolated from several species of
the Rauwolfia family of shrubs.1'2 The physiological effects
of crude extracts of the roots $f the Rauwolfia family have
been known in Europe since 17^1 > but until recently attracted
little attention. The pharmacology of ajmaline has been in-
vestigated,3 and it was found, in contrast to the related
reserpine, that ajmaline was an hypertensor and an intestinal
stimulant.
The molecular formula, C2CH26O2N2, was determined early
and some preliminary structural work done,1'4'5 but it remained
for Robinson and coworkers and Woodward and SchenKer to
elucidate the structure completely.6'7'8'9
Ajmaline takes up three moles of hydrogen over platinum
to give completely saturated hexahydroajmaline. Both nitrogens
are tertiary. The infra red and ultra violet spectra are
characteristic of dihydroindoies, and color reactions are
typical of N-alkyl substituted anilines. 0,0-Diacetyl and
dibenzoyl derivatives can be prepared showing that the oxygens
are present as hydroxyls. From this information it may be
concluded that ajmaline has six rings.
Ajmaline (I) on potassium hydroxide fusion yields indole-2-
carboxylic acid (II). On treatment with soda lime or
selenium N-methylharrnan 'III; is formed, and on zinc dust
distillation carbazole (IV) and N-methylharman are isolated.
Ajmaline then has a partial structure
r^t
\.
r
CH3 c
KOH
Ajmaline I soda_lime 2Q0°
or
Fusion C20H26O2N2
11 Hg/Pt/
K
hexahydroajmaline
C2q^3202N2
The "Herbarium Amboinense" of
that year stated that the
powdered root "valet contra
anxietatem. "
selenium 300
Zinc dust
distillation
+
III
-2-
Ajmaline may be converted to isoajmaline (VI)
or heat. Reduction of ajmaline (I) or isoajmaline
by alkali
(VI) by
the Huang-Minion modification of the Wolff -Kishner method
yields desoxydihydroajmaline (XII ) and desoxydihydroiso-
ajmaline (XIII ) respectively. Oxidation of either XII or XIII
yields methyl ethyl ketone. On oxime (VII ) can be prepared
from ajmaline and hydrcxylamine. This oxime can be converted
to the nitrile (VIII; by 'treatment with acetic anhydride, and
ajmaline regenerated by reduction of the nitrile with lithium
aluminum hydride. Reduction of ajmaline with sodium or
potassium borohydride affords dihydroajmaiine (IX) in which
N-, is secondary and two hydroxyls are present. Treatment of
IX with HBr at 300° yields desoxyajmaline (X) in which N- is
and only one hydroxy 1 is present. Finally
in boiling xylene decarbonylates ajmaline to
(XI) which contains one hydroxy 1 and a
again tertiary
Raney nickel
decarbonoajmaline
secondary amino group. This work can be rationalized if a
carbinol amine, -N-CH0H-, is postulated. (Schenker also found
that heating ajmaline monoacetate to 200° formed an N-acetyl
aldehyde. -N-CKOAc JPQPiL) -N-Ac 01IC-) The partial structure
of ajmaline (i) may now be extended as in the following scheme;
N OH
\ y heat
CH3 \\£ epimerization CH3
V Av
VI
H2NNH2
KOH
HOCH2CH2OH
k
H2NNH2
KOH
HOCHaCHsOH
/N
XII
— /\
r
v
^
XIII
r~
vn A K M U A k NH
V
/ X
CH3 !
VIII
CK3
1
CH3
CH3
X
\
\
\
Cr0;
- Cr03 \£
\ \
-W4
fl
CH3q.CH2CH3
-3-
NaBH,
^VIX_
_\
7
KX
CH3
NH
CK2OH
+ one OH
and two rings
\ Ni(R)
\ boiling xylene
\
^/
XI
+ CO
HBr/
/
/
300°
X
^\ A
vv
CH:
N
X
Robinson6' 7> 8 considers the second hydroxy 1 to be bridge-
head tertiary in ajmaline since it doesn't undergo displacement
reactions with several reagents including thionyl chloride,
and since it is not oxidized by Cr03. On the basis of this and
the other data, Robinson proposed two possible structures for
ajmaline, la and lb.
-v
\N
\
OH
Vi
I \ N
CH3
OH
la
However the second hydroxyl might be secondary, since
is easily acetylated and benzoylated and indeed, Schenker9
has been able to oxidj.se desoxyajmaline (X) with potassium
t-butoxide and benzophenone to yield a ketone (XIV ) in 85$
yield which has an infra red spectrum characteristic of a
it
-4-
cyclopentanone
for ajmaline.
(1745 cm."1).
He then proposed the structure Ic
IN
ahA/n
OH-
X
KO t-Bu
0
XIV
\
\ I lN OH
The dehydrogenation studies of Robinson on desoxydihydro-
ajmaline were also explained by Schenker. It was postulated
that desoxydihydroajmaline (XII ) on treatment with palladium
on carbon rearranged to the intermediate aldehyde (XV) and
thence by cleavage at a and d to N-methyl harman (III) {6$),
by cleavage at a to CaoH26Na (XVI ) (7$), by cleavage at c to
C2CH24N2 (XVTl) (15$), and by cleavage at b to C20H24N2 IxviII )
Schenker9 has treated dihydroajmaline (IX ) with lead
tetraacetate and alkaline silver oxide to obtain a lactone of
postulated structure XIX, and with lead tetraacetate to obtain
an hemiacetal (XX) which can then be dehydrated to an enol
ether (XXI ) with acetic anhydride and heat. The structure of
Woodward and Schenker (Ic) appears to be the best of those
postulated.
-D-
Pd/C .
240° /
XII
CH3 CH3
III {&fo)
a,d
/
^
^
X
CHO
\k
\ /\
^N'V
"1
CH3
XVI (7#)
/
^ : !
i
XVII (15$)
./
CH:
XVIII
(1*)
Cs
OH
//
y
VSA*
CH3
IX
i NH
CH2OH
<^—y
%
N-.
V" w
NH /
CK
XIX
-6-
Pb(OAc)4
CHO
/
Ag20/'
/oh
CHpOH
/£
,0
\
y\
OH
I
A.
L
/
V^nA/
NH
'0
i
CH;
XX
r
ac2o
200c
1
/\
^N^V
CH3
XXI
BIBLIOGRAPHY
NH
/
0
/
\
1.
2.
3.
4.
5.
6.
7.
8.
9.
S. Siddiqui and R. H. Siddiqui, J. Indian Chem. Soc . , 8,
667 (1931). ~~
C. Dj eras si, et.al., J. Am. Chem. Soc, 76, 4463 (1954);
77, 6687 (1955). "~
R. N. Chopra et.al., Indian J. Med. Research, 21, 261 (1933);
24, 1125 (1937) 5 29, 763 (19^1); 30, 319 (1942T7
S. Siddiqui and R. H. Siddiqui, J. Indian Chem. Soc, 9, 539
(1932); 12, 37 (1935); 16, 421 (1939).
A. Chatter jee and S. Bose, Experientia, 9, 254 (1953);
J. Indian Chem. Soc, 31, 17 (1954).
P. A. L. Anet, D. Chakravarti, R. Robinson and E. Schlittler,
J. Chem. Soc, 1242 (1954).
R. Robinson, Chem. and Ind., 235 (1955).
F. C. Pinch, J. D. Hobson, R. Robinson, Chem. and Ind.,
653 (1955).
K. A. Schenker, 7th Summer Seminar in the Chemistry of
Natural Products, Univ. of New Brunswick, 1955.
-7-
THE ALKYLATION OP MESOMERIC ANIONS
Reported by R. A. Seherrer February 10, 1956
This seminar concerns the prediction of products from
the reactions of mesomeric anions. The problem exists for
such cases because two or more structural isomeric products
can be formed, depending on which atom of the anion is
attacked. It is well known that the relative stability of
the various products cannot always be used to predict their
relative rates of formation; at times the less stable isomer
is formed and at other times the more stable isomer results.
In addition, for a given reaction, a change of reaction
conditions or reagents may bring about a change in product
ratio to favor the more or the less stable product.
A rigorous solution to the problem depends on the
ability to estimate the structure and stability of the transit-
ion states leading to the various products. The product ratio
of two products formed competitively will depend only on
their relative rates of formation, and hence on the difference
in free energy of the transition states ( ^ <ii*F* ) leading
to these products. Hammond1 has proposed a method of
establishing the structure of the transition state from the
overall thermodynamics of the reaction. For a highly exothermic
reaction, the transition state has a structure closely re-
sembling that of the starting material. For a highly
endothermic reaction the transition state will resemble the
product. This correlation is valid if the free energy of
activation is not high for the exothermic reaction or for the
reverse of the endothermic reaction. The assumption is also
made that the more nearly alike two structures are, the closer
their energies will be.
Another method of estimating transition state structure
is from reaction theory derived from kinetic data, steric
data, structure-medium-reactivity relationships and the like.
Thus, for example, from all the data on displacement re-
actions of alkyl halides we can draw with fair certainty
the structure of the transition state for the reaction of
hydroxide ion with methyl bromide .
These principles can be applied to rationalize the data
on product composition and rates for several reactions re-
cently reported by Kornblum2.
Nitrite ion reacts with alkyl halides to give a mixture
of nitrite ester and nitroalkane. In the reaction of
2-iodooctane with silver nitrite it has been shown that both
products are produced with inversion of configuration3.
With this same reagent, the order of reactivity of alkyl halides
is 3° "> 2° >- 1°. The tertiary halides give mostly alkyl
nitrite while primary halides give mostly nitroalkane
(Table I).
The study of substituted benzyl bromides in which
electrical effects may be varied with a constant steric effect
provides further data on product composition. As one goes
from p-N02- to p_-Me0- benzyl bromide and as the carbon atom
-8-
undergoing valence change becomes more cationic, the yield
of nitrite ester relative to nitroalkane increases and the
relative rates are again characteristic of an ionization
process induced by an electrophilic attack of silver ion on
halogen. (Table I)
Table I
Reaction of alkyl halides with AgNOp
compound
1-bromobutane (1-iodo)
2-bromobutane (2-iodo)
_t -butyl bromide
£-N02 -benzyl bromide
benzyl bromide
P-CH3 -benzyl bromide
p-CH3Obenzyl bromide
relative
% yield
rates
RNO2/RONO
1 (1)
73/13
^ (9)
1500
19-25/27-37
0-5/65
.09
1
16
>16
84/16
70/30
52/48
39/61
reference
h.
5
5
From the above data we can postulate a transition
for the reaction of silver nitrite with alkyl halides.
are two variables in the transition state which must be
considered: a) the degree of ionization of the C-X bond,
(or the degree of silver to halogen bond formation) and b)
degree of bonding of nitrite to carbon.
state
There
the
Let us consider first the case in which a) (above) is
small. This corresponds to the situation with primary alkyl
halides and p_-N02-benzyl bromide. This is so because the
positive charge that would be induced on formation of a silver-
halogen bond could not be stabilized to a great extent.
Nitrite ion is needed as a nucleophilic agent to complete the
reaction. A high degree of bond formation between nitrite
ion and carbon is needed in the transition state to displace
the halogen. There are two transition states which can be
drawn for this displacement of halogen:
,/:N <5(-)\/
0-^ xo - - c -
- X -
- Ag
(leading to alkyl nitrite)
II
0
0^
N -
\ /
- C -
X
6(+)
■ Ag
(leading to nitroalkane)
in free energy of these transit-
The relative differences
ion states will determine the relative rate of formation of
each product. The main factors contributing to the difference
in free energies of these transition states are l) the
difference in energy of the C--N and C--0 bonds 2) the
difference in resonance energy of the nitro group and the
nitrite ester group 3) differences in solvation energy, 4)
steric hindrance, and 5) electrostatic forces. One and two,
-9-
above, are reflections of the stability of the products.
Since^-nitroalkane is"3 Kcal. more stable than an alkyl
nitrite ref (6), and assuming the other differences are
small in comparison, the free energy of the transition state
II will be lower than I, and nitroalkane will be formed
predominately .
Now let us consider the case in which the carbon-halogen
bond is broken to a considerable degree in the transition
state, as with tertiary halides and p_-MeO-benzyl bromide.
Bond formation of nitrite ion to carbon is less important
here, since the carbonium ion being formed is stabilized by
resonance or hyperconjugation. We can draw two transition
states for this reaction:
in /N-cr~' V ^ - - x - Ag
ox © \ 4 (+) $(+)
IV \N__._C----X-Ag
0^
The main factors determining difference in free energy
of these transition states are the solvation energies and
electrostatic forces. Exact calculation of these energies is
not now possible, and therefore no prediction of the relative
amounts of alkyl nitrite and nitroalkane can be made. Note
that there is no direct relation between the stabilities of
the products and the relative stabilities of the transition
states.
It is observed that for the reaction just described, the
yield of alkyl nitrite is much higher than nitroalkane. We
can then say that III must have a lower free energy than IV.
Two generalizations concerning the reactions of mesomeric
anions can now be made. If the transition state involves
a high degree of bonding betxveen the anion and the alkylating
group, as in I and II, the stability of the products will
determine how the reaction proceeds. If the transition state
has a high degree of cationic character, as in III and IV, the
product cannot be predicted.
Silver salts of mesomeric anions will tend to react via
a transition state resembling III and IV, and alkali metal
salts will, in general, tend to react via a transition state
resembling I and II. This explains the sometimes observed
differences in product. (Table II)
-10-
Table II
Anion Cation Alkyl halide Yield Ref .
Ag+ C2H5I 80$ 0-R 0<fo N-R 7
K+ C2H5I 0% 0-R 70$ N-R
Ag+ CH3I 50$ N-R
CN ~ Ag 2Me-l-iodobutane 60$ N-R 8a
Ag+ (CH3)3SiI 80$ N-R b
Na+ n-C4H9Br 80$ C-R 1$ N-R c
(-) 11 4.
C6H5N; CH Ag C2H5I 1H 0-R 9
p-N02C6H5NCCH3 K+ C2H5I 84$ N-R 10
N02 ® Ag+ 2-icdooctane 17-25$ 0-R 15-20$ N-R 3
■ it
Na 2-iodooctane 30$ 0-R 53$ N-R 6
References
1. G. S. Hammond, J. Am. Chem. Soc, 77, 334 (1955).
2. N. Kornblum et.al., ibid., 77, 6269~(1955) .
3. N. Kornblum, L. Fishbein and R. A. Smiley, ibid. , 77, 6261,
6266 (1955).
4. N. Kornblum, B. Taub and H. E. Ungnade, ibid., 76, 3209
(1954).
5. N. Kornblum et.al . , ibid., 77, 5528 (1955).
6. Calculated from heats of combustion.
7- H. von Pechmann and 0. Baltzer, Ber., £4, 31 48 (1891)
C. Rath, P^nn. , 489, 107 1931).
8. a) H. Rupe and K. Glenz, Ann, 436, 184 (1929).
b) J. J. McBride, Jr. and H. C. Beachell, J. Am. Chem. Soc,
74, 5247 (1952).
c) R. Adams and C. S. Marvel, ibid. , 42, 310 (1920).
9- J. L. Simonsen and R. Storey, J. Chem. Soc, 95, 2106 (1909)
10. M. A. Sattar, J. Indian Chem. Soc, 32, 489 (1955).
-11-
CONVERSION OF PRIMARY AMINES TO ALCOHOLS
Reported by B. M. Vittimberga February 17, 1956
For many years, the only available method for the con-
version of primary amines to the corresponding alcohols
involved a reaction with nitrous acid. This method was not a
good preparative procedure; low yields and mixtures of isomers
were often obtained.1' 2' 3
It had been reported4'5 that when N-alkyl-N-nitrosoamides
were heated, they decomposed to form esters. Since that time,
little work has been done to investigate this reaction
further. Recent6'7'8'9'10 investigations on this decomposition
have shown it to be a convenient means of transforming amines,
in good yields, to corresponding esters, relatively free of
isomers.
The N-alkyl-N-nitrosoamides were found to undergo de-
composition with the elimination of nitrogen by the paths A and
B,
A
0=N Q . .) R'C02R + N2
I II '
R-N-C-R'
}.R'C02H + N2 + olefins corresponding
to R
the relative importance of which depends on the reaction
conditions.
The thermal stabitity of different N-nitrosoamides was
found to vary as follows:
Temp, of N2
Type of Compound elimination
Nitrosoamides of primary carbinamines 60-80°
Nitrosoamides of aliphatic secondary carbinamines 20-30°
Nitrosoamides of tertiary carbinamines about -10°
*
The term carbinamine refers to the C-NH2 grouping as compared
to the C-OH of carbinols. Primary etc. refer to the carbon
atom.
Nitrosoamides of primary carbinamines produce the highest
yields of the corresponding esters. An example of this is
the decomposition of N-(n-butyl )-N-nitroso-3,5-dinitrobenzamide
in hexane.
0=N n N02
! ft ^— < 69° 8
CH3CH2CH2CH2-N-C-<^ ^> Hexane CH3CH2CH2CH20C
N02 Q
XN02 15 hrs* 81-8^
<^ \_C-0H + CH3CH2CH=CH2 + N2 (1 mole)
N°2 16-18*
■ !
1 .:
'J. .'■'/
. Kf;
-12-
Other examples are
R-N-C-R*
Isomers
Yield Butyl ester
R R1 Solvent Temp. Ester Acid n iso sec ter
n-Butyl Methyl Heptane 77° 67 IS 99 l
Isobutyl 3,5-Dinitro- Hexane 690 66 33 95.5 3.5 1
phenyl
sec -Butyl Phenyl Pentane 25° 23 64 100
Nitrosoamides of aliphatic secondary carbinamines follow
path B more closely and give lower yields of ester and
proportionately higher yields of olefin and acid. Tertiary
carbinamines give the lowest yields of esters.
Variation of the acyl group has little effect on this
decomposition reaction. Essentially the same results were
obtained with nitroacetamides, benzamides, and dinitro-
benzamides.
The first step in the mechanism of this decomposition is
thought to be the formation of a diazo ester as was shown to
be the case in the aryl series. u'12 In the aliphatic series
this diazo ester is very unstable and decomposes.
N==0 0
•4/
r-N_C_rt > [R-N=N-0-C-R»] ) Products
0
The nitrogen elimination step can proceed by a uni-
molecular or bimolecular mechanism with retention or inversion
of configuration at R depending on the reaction conditions.
In order to explain the experimental observations the
following mechanisms have been proposed:
\ ^N-
C. ^ ) R'COaR (Retention)
A. Unimolecular elimination
Et
1 H 0^
0=C-R'
B. Bimolecular elimination
0 Et ^_ ^ 0
Ri-C-0— > C-^N=N-0-C-R' (Inversion) r1=r« or R"
n Me H
-13-
C. Acyl transfer followed by elimination
Et Et + R'C02H
R"C02H + .C'^ ^„ C^Vv^
.'I XN ) .•|f\SxN R"C02R (Retention)
MS H 0^ Me ' H \^
0=C-R' 0=C-R"
D. Solvolysis- Unimolecular elimination
E? Et , a
Me.-"-r N N -) Solvent) AC ~f^ X^N "^ R'C02R (Inversion)
H / Me o* c< .
0=C-R' a ' "-) — J R'C02R (Retention)
R'°
E. Acyl transfer-Sol volysis-Unimolecular elimination
0 0
R-N=N-0-C-R + R"C0aH-> [R-N=N-0-C-R" ] + R'C02H
%. -J
Et
Solven
t) .f\^'l * R"C02R (Inversion)
7 Me ) H\ Vg
' " \ ■ f
0 i •'
e -V.-r.O' •' R"C02R (Retention)
■c:
I
The following mechanism is postulated for olefin
formation: . A
• /
y(T ^N -.c/> + R.C02H + N2
HK7ie > I
0=C-R'
The decomposition of N-(n-butyl )-N-nitroacetamide, N-
vn-butyl)-N-nitroso-p-toluenesulfonamide, and N-cyclohexyl-N-
nitrosourethan is thought to proceed by a similar elimination
reaction. a
-14-
BIBLIOGRAPHY
1. F. C. Whitmore and D. P. Langlois, J. Am. Chem. Soc, 54,
3441 il932).
2. F. C. Whitmore and R. S. Thorpe, Ibid., 63, 1118 (194l).
3. D. W. Adamson and J. Kenner, J. Chem. Soc, 838 (1934).
4. H. V. Pechmann, Ber., 31, 2640 (1898).
5- M. F. Chancel, Bull. soc. chim. France, (3) 13, 125 (1895).
6. K. Heyns and W. v. Bebenburg, Ber., 86, 278 TT953).
7- E. H. White, J. Am. Chem. Soc, 76, "PF97 (1954).
8. E. H. White, ibid., 77, 6008 (1955).
9. E. H. White, ibid., TJ_, 6011 (1955).
10. E. H. White, ibid., 77, 6014 (1955).
11. R. Huisgen, Ann., 5747 184 (1951) and preceding papers.
12. D. H. Hey, J. Stuart-Webb and G. H. Williams, J. Chem. Soc.
4657 (1952) and preceding papers.
-15-
VAPOR PHASE CHROMATOGRAPHY
Reported by B. D. Wilson 17 February 1956
Vapor phase chromatography (VPC) differs from conventional
types 01 cnromatography only in that the mobile fluids are
volatilized under the conditions used. For this reason, the
tool largely has developed in the realm of organic chemistry,
to^be found6^ the larsest number of volatile compounds are
<amo-nThe mftno<* is fast, generally reproducible, requires only
small samples (5-100 jul. of liquid; 1-10 ml. of gas), and as
many as lb components are reported1 as having been separated
in one analysis. Azeotrope formation does not interfere as
it does in distillation. Accuracy is on the order of 1%
£™f^trani0n£Vas low as k ppnu have been accurately measured.2
However 1 part per 5,000 is more common with the detector
generally employed.3
*rt<,nJ^ith Jlqui?Phase chromatography, VPC is of two classes:
adsorption and partition. «.oo^o,
Adsorption gas chromatography. This is a process of adsorbing
the vapor on some solid surface and then selectively desorbins
haveCb°eePn0nLnvise? Ire! "^ The desorptl- -*thoJa which
(1) Fractional desorption by heat.4"6
(2) Elution from the adsorbent by a carrier gas.7"9
(3) Displacement by a more strongly adsorbed vapor.3'10**12
coal ^hfuSf n?\???d iS ?lm°f excl^ively activated char-
Z«*h v, k silica gel, alumina, zeolite, sand, or glass
beads has been reported. BldbS
Methods (2) and (3) require a carrier gas. Carbon dioxide
or nitrogen is most often used for this purpose. Air hvdSen
or helium sometimes is used. ' nyarogen,
The detector device is a thermal conductivity cell.
Method (1) was the earliest developed Tt pntai^ Qlnir1„
procesf "as we^L^-* m°Xle ^te^it is Trathlr3 1°^
process, as well as having all the limitations of method (2).
Method (2) gives asymmetric peaks, with freoueni- i-a-m™
making resolution difficult. This is traced hill t«\H g'
sis sts^-sks sasrtsst.'-s "aft..
' 1-
n-<
. .. r ■, r ■ r ■: . '4
-16-
having been superseded by method (3). This is because the dis-
placement technique is ideally applicable to the Langmuir type
adsorption isotherms obtained.12'14
P.,*!?6 disPlacement technique, the adsorbed vapors are
desorbed by a more strongly adsorbed vapor in the carrier gas.
Ethyl ace, ate, diethyl malonate, or brompbenzene is most com-
monly used. Displacement does not give the characteristic
peaKs of the elution methods, but rather gives a stepwise
graph. The height of the step is a characteristic of the com-
pound; the width is a measure of the amount present. The order
ointsP^°emeni: iS aPProximately that of the relative boiling
The displacement technique, though useful, suffers from
two serious drawbacks: (a) The column packing is not re -usable-
the™*! T rP^°^.aft?r eaCh rUn* {h) Compounds with simtlar'
h^H? conductJvities (e.g. isomers) give identical step
heights, and, if displaced one after the other, while being
separated, are indistinguishable on the graph. ^ Deing
Gas-Liquid partition chromatography* Suggested in lQln in
Mart inland Synge ' s classic paper?* introducing par^ion
STjS^SS'i*11?"^ ™s introduced by the work of Martin
pti0n7???,i8 in 1951-2. Theory was developed on three assum-
(a) The partition coefficient between two phases is a
constant.
(b) ?H^5l02 ?£ SaSeS Wlthin a single Phase alonS the
length of the column is negligible.
(c) The partial pressures of substances to be separated
are negligible compared to that of the carrier gas.
^ Gas-liQuid partition theory differs from liquid-liquid
theory only in that the mobile phase is compressible Sn,
.Lower viscosity of the mobile phase, relatively loneer col-
umns can be used, with a corresponding gain i e c e„ v
Won 'of tVt ±S thS advantaSe «»t »tho3« for the determina-
ble^ ?hana?hSosenformriSS steam^ ""■» ™ ■—«*
f;: •'
' . ->' ■.
-17-
In partition work, the gas phase (M or He), carrying the
vapors, flows over an inert solid (celite) coated with the
liquid (static) phase. While somewhat limited by theoretical
considerations, the choice of a proper liquid ohase is mostly
empirical.19 A whole host of substances have been used.
Di-(3,5,5-trimethylhexyl) phthalate ("dinonyl phthalate" of
the trade) seems to be used more often than the others.
The order of elution depends on the Henry coefficient of
the substance.19
Temperature must be controlled, although the operating
range is 0-230° C. The boiling point of the liquid phase
ought to be at least 100 degrees greater than the column
temperature. A general rule is to keep the column tempera-
ture 40 degrees above the boiling point of the most volatile
component.5 Pressures as low as 20 mm. have been used.
For qualitative analysis, the retention volume (that
volume of the mobile phase that must be passed before the
particular elution peak is reached) is used, since it is a
characteristic of the compound. Using a constant rate flow
of carrier gas, the retention time is generally the parameter
measured. This retention time (volume) is analogous to
Rf values of liquid-liquid partition chromatography.
For quantitative analysis, one measures the area under
each peak. Accuracy can be greatly improved by the use of
an internal standard.20
Partition chromatography gives linear isotherms, which
are ideally suited to the elution technique involved.12'14
The reason for various types of isotherms is that in parti-
tion chromatography, vapor distribution depends only on solu-
tion effects (ideal at these low concentrations), while
adsorption chromatography deals with the interface effects
of adsorption.21
The limit of VPC methods lies in the detection device.
While thermal conductivity is now most often used, there are
several other promising techniques: (a) surface potential
method J (b) gas density balance method.22
VPC (usually partition) has been used in the separation
of permanent gases, hydrocarbons (aliphatic, cycloaliphatic ,
and aromatic), fatty acids through Ci2, fatty acid methyl
esters Ci2-C22, amines, aromatic bases, halides, alcoho1 s
esters, aldehydes, ketones, and ethers.
To date, no separation of optical isomers has been suc-
cessful.^2 VPC is applicable to such things as:
'}„■
-18-
I. Control
A. Purity of gaseous anesthetics.
B. Perfume industry.
C. Petroleum industry.
II. Check raw materials and solvents for impurities.
III. Preparation of pure substances in small amount.
In theory, this can be scaled up.
IV. Analysis of intermediate and final products in
gaseous reactions.23*24
V. Identification of volatile oils, perfumes, plas-
ticizers, etc. in commercial products.
BIBLIOGRAPHY
1. D. H. Lichtenfels, S. A. Fleck and P. H. Burow, Anal.
Chem., 27, 1510 (1955).
2. J. H. Griffiths and C. S. G. Phillips, J. Chem. Soc . ,
3446 (1954).
3- J. Griffiths, D. James and C. Phillips, Analyst, 77, 897
(1952).
4. N. M. Turkel'taub, J. Anal. Chem. U.S.S.R., 5, 200 (1950).
5. N. H. Ray, J. App. Chem. (London), 4, 21 (1954).
6. N. C. Turner, Petroleum Refiner, 22, 140 (1943).
7. G. Hesse and B. Tschachotin, Naturwissenschaf ten, 30, 387
(1942).
8. N. H. Ray, J. App. Chem. (London), 4, 82 (1954).
9. J. Janak, Chem. Listy, 47, 464 (1953); cf. C.A. 48, 3196h
(1954). This is paper no. 1 in a series of 12. For no. 12,
see C.A. 50, 104b (1956).
10. S. Claesson, Arkiv. Kemi . Min. Geol., 23A, No. 1 (1946).
11. C. S. G. Phillips, Dis. Far. Soc, 7, 2TI (1949).
12. D. H. James and C. S. G. Phillips, J. Chem. Soc, 1600
(1953).
13« H. W. Patton, J. S. Lewis and W. I. Kaye, Anal. Chem., 27,
170 (1955).
14. D. Harvey and D. E. Chalkey, Fuel, 34, 191 (1955).
15. A. J. P. Martin and R. L. M. Synge, Biochem. J., 35, 1359
(1941). —
16. A. T. Jamesand A. J. P. Martin, ibid., 48, vii (1951).
17. A. T. James and A. J. P. Martin, ibid., 50, 679 (1952).
18. A. T. James and A. J. P. Martin, Analyst, 77, 915 (1952).
19. A. I. M. Keulemans, A. Kuantes and P. Zaal, Anal. Chim.
Acta, 13, 357 (1955).
20. A. B. Littlewood, C. S. G. Phillips and D. T. Price, J.
Chem. Soc, 1480 (1955).
21. B. W. Bradford, D. Harvey and D. E. Chalkey, J. Inst.
Petroleum, 4l, 80 (1955).
22. A. J. P. Martin, Kolloid Zeitschrift, 136, 5 (1954).
23. C. J. Hardy, Analyst, 79, 726 (1954).
24. J. H. Knox, Chem. and Ind., 1631 (1955).
25. M. I. T. Org. Chem. Sem. Abst., II Sem. 1954-5, p. 342.
■::.
-19-
THE 1,4-ELIMINATION REACTION WITH CLEAVAGE
Reported by W. De Jarlais February 24, 1956
A considerable number of reactions, when examined
closely, fit the mechanistic picture formulated as follows:
0o
A-B-C-D-X
■> A=B
C=D
X
©
The atom A must of course be capable of forming a double bond
with B. By far the greater number of reactions of this type
involve an anionic oxygen as atom A. An additional require-
ment is that the anion expelled be a relatively weak base.
Steric factors such as increased substitution on the atoms
B and C aid the reaction.
Familiar examples of reactions fitting this mechanism are,
the reverse Michael,
Claisen reactions as
acids. These may be
OH. 0
|i I I l 11
-C-C-C-C-C-
0H 0
I I 11
•C-C-C-
I I
Base=B
B
the reverse aldol and the reverse
well as the decarboxylation of glycidic
formulated:
0 ^~, 0
-c-c-c-c-c-
0Ct Of
-c-c-c-
I I
.A
0
ll /
-C-C=C +
I x
8
-c- + c=
©0
/ I
©
O^C-C _C —
CO;
c
e
+ c=c-
0H
co2 + c=c-
Perhaps somewhat less familiar is the decarboxylation of
the anions of certain P-bromoacids. For example, a successful
method for the preparation of ^-bromostyrene depends upon the
elimination of carbon dioxide and bromide ion from the anion
of a,£-dibromohydrocinnaralc acid. This reaction has been
shown to be stereospecific and shows a rate dependent on the
concentration of the anion. 1,z
The importance of a relatively weak base as the anion X"
is shown by the fact that the £-toluenesulfonate of a-hydroxy-
£, ^-dimethyl- y -butyrolactone is cleaved to the sodium
salt of P,&-dimethylacrylic acid, formaldehyde and sodium
£-toluenesulfonate by treatment with two equivalents of sodium
hydroxde at 90°, while the unesterified lactone under the same
conditions does not yield any formaldehyde.3
An attempt to prepare 2,2-dimethyltrimethylene oxide
form 2,2-dimethyl-3-bromo-l-propanol by a potassium hydroxide
catalyzed Williamson reaction gave only formaldehyde and
:»;.'
. ''<"' l"< I "
n ■
i i
-20-
isobutylene. 4 Similarly, it was found that the methiodide of
the Mannich base of isobutyrophenone on treatment with alkali
gave isobutylene, benzoic acid and trimethylamine.5
Many of the reactions for the formation of diazomethane
are of this type. For example, diazomethane may be prepared
by the action of potassium hydroxide on nitrosomethylurethane
or N-nitroso-N-methylurea or by the reaction of alkoxide ion
with N-nitroso-f3-methylaminoisobutyl methyl ketone.6 It may
also be prepared by the reaction of N-nitroso-N-methyl-
acetamide with potassium hydroxide solution; the yield is
lltfo 1 A reaction which might be considered to be ,;pseudo"
of this type is the recently revealed preparation of diazo-
methane from the corresponding N-nitroso-N-methyl-p-toluene-
sulfonamides. 8 The yields are good (usually from o0-90$).
The reaction is carried out in the usual manner. The
nitrosocompound, dissolved in ether is added to a solution of
potassium hydroxide in alcohol or, if alcohol free diazo-
methane is desired, carbitol is used instead of alcohol and
the diazomethane codis tilled with ether. The real advantage
in this method lies in the fact that the nitrosocompound is
in this case, stable, and may be stored in stoppered brown
bottles for long periods of time without decomposition.
An
action w
chain fa
the dete
one carb
for this
degradat
labelled
only 9%
method g
activity
used but
Schmidt
dioxide
results.
interesting application of the 1,4-elimination re-
ith cleavage is a method for the degradation of long
tty acids.9 The method was specifically designed for
rmination of radioactive carbon by degrading the acid
on at a time
purpose but
io
An iron pyrolytic method has been used
the product is not suitable for further
ion.*" In addition, an experiment with carboxyl
octanoic acid led to a specific activity that was
of theory for the carboxyl group. The Barbier-Wieland
ave only average yields and led to a dilution of the
of 13 to 1. A bromine-silver salt method has been
again a lower than expected activity was found. The
degradation gives good yields but extraneous carbon
causes difficulties. The following method gave good
R-CH2C02H
SCC1,
HO-N 0
(i M
-) R-CH2C0C1 CgH*^ R-CH2C0$ R~0N9 R-C-C-0
A1C1«
R-CN + 0CO2H
TsOH <-
r
TsO-N 0
ii 1 1
R-C-C-0
L
OH
TsCl
The yields ran about 75$ overall.
The compound I (see below) when treated with kofo aqueous
potassium hydroxide gave 5-methyl-5-hexenoic acid (II ) in 82$
yield.11 The infrared spectrum shows the bands of the
methylene double bond (893 cm.-i, 1655 cm.-i). Upon catalytic
hydrogenation (platinum-glacial acetic acid) a mole of hydrogen
-21
was taken up. The resulting dihydro acid was identified
by the melting point of its benzyl thiouronium salt as
5-methylhexanoic acid. Ozonolysis of the product from the
treatment of I with alkali gave formaldehyde and a 70$ yield
of 5-ketohexanoic acid. There can be little doubt that the
reaction product is II.
- CHaOSOaMe „n„ /
— 0 ■ KQH >
U
COaH
II
Treatment of the methane sulfonate of 2-hydroxymethyl-2-methyl-
cyclopentanone (i) with methyl magnesium iodide gave a
compound CgHxaO which on the basis of its origin and
properties is assigned the structure III below. The compound
assigned structure III snows the band of the hydroxyl
(3^50 cm.-i) group and the two bands of the methylene double
bond in the infrared as well as an atom of active hydrogen
by a Zerevitinov determination. This compound takes up a
mole of hydrogen on catalytic hydrogenation and an atom of
oxygen when treated with perbenzoic acid. Here, again then,
the reaction involves a 1, ^--elimination with cleavage
of the carbocyclic system.
Ill
The reaction of I with lithium aluminum hydride gave an 85$
yield of 2,2-dimethylcyclopent^4e^e*'and therefore is not
analogous to the above two reactions of I.
It has been reported that the debromination of dibromides
can proceed by a reaction of 1, 4 -elimination with cleavage.
For example, Vogel12 reported that debromination with zinc
dust of l,2-dibromocyclobutane-3,4-dicarboxylic acid gave
muconic acid. Much more extensive investigations of this type
of dehalogenation reaction have been made by Grob and Baumj&n.13
The^< prepared the "cis" and "trans" 1,4-dibromo and diiodo-
cyclohexanes and treated them with solutions of sodium metal
in decalin. They obtained benzene and cyclohexene plus an
8$ yield of biallyl. Furthermore, small amounts of 2,4-
hexadiene and 1,3-cyclohexadiene were found. Mo indication of
the presence of bicyclo-[2. 2. 0]-hexane could be found.
Conditions were then sought in which the yield of biallyl
would be increased. If the dibromide was treated with
magnesium in ether only traces of biallyl were formed. With
zinc dust in alcohol 20 to 40% dialiyl was obtained. The best
yields were obtained by the use of dioxane and zinc dust.
The yield of biallyl from either of the two iodides was 90$ and
from the dibromides 70$. This reaction is remarkable in that
-22-
steric effects do not seem to play an important role. This
is in contrast to the case of loss of carbon dioxide and
bromide ion from the anions of the dibromodihydrocinnamic
acids. It is, however, not so unreasonable, if one makes
the assumption that the compound IV is an intermediate. The
condition then for the smooth coupling of two trans -eliminations
is that the molecule be able to arrange itself so that the four
carbon atoms involved lie in the same plane. This is obviously
impossible no matter whether one has the "cis" or "trans"
dihalide. It should, hov/ever, be possible in the open chain
1, 4-dibromobutane. Consequently, it might be expected that
this dibromide would react more rapidly than the cyclic
dibromides. However, 1, 4-dibromobutane gave only a 10$
yield of ethylene after 20 hours of reaction time. Much of the
dibromide is recovered and butyl bromide and 1-butene are
found. This can be rationalized by the cyclic intermediate,
V\ below
IV
BrZn
<z>
Br
-HBr
CH2
Br
Zn
I
CH2
\
CH2— CH2
//
CH2
H20
CH3(CH2)3Br
BIBLIOGRAPHY
CH3CH2CH=CH2 fJ
HBr
1. E. Grovenstein and D. E. Lee, J. Am. Chem. Soc, 75 »
2639 (1953).
2. S. J. Cristol and VJ. P. Norris, ibid., 75, 2645 (1953).
3. H. Bretschneider and H. Hass, Monatsh. ,~3l, 954 (1950).
4. S. Searles and M. J. Gortatowski, J. Am. Chem. Soc, 75,
3030 (1953).
5. H. R. Snyder and J. H. Brewster, ibid., 71, 1061 (1949).
6. "Organic Synthesis", Coll. Vol. Ill, J. Wiley and Sons, Inc.
New York, N. Y.
7. K. Heyns and 0. F. Wayrsch, Ber., 86, 76 (1953).
8. J. De Boer and H. J. Backer, Rec. Trav. Chim. , 73, 229,
682 (1954).
9. W. G. Dauben, E. Hoerger and J. W. Petersen, J. Am. Chem.
Soc, 75, 2347 (1953).
10. A. Zabin, J. Biol. Chem., 189, 355 (1951).
11. A. Eschenmoser and A. Prey, Helv. Chim. Acta, 35, 1660
(1952).
12. E. Vogel, Angew. Chem. 66, 305 (1954).
13. C. A. Grob, W. Bauraan, Helv. Chim. Acta, 38, 594 (1955).
-23-
THE ABSOLUTE CONFIGURATION OF MORPHINE
Reported by D. S. Matteson
March 2, 1956
A knowledge of the relationship
of natural products is useful to tho
on biosynthetic pathways. Emil Fisc
aldehyde as a standard to which othe
referred. That the Fischer conventi
aldehyde is actually correct1'2 has
and physical measurements, including
the absolute configurations of all c
related to this standard are known.
s between configurations
se who like to speculate
her adopted D-glycer-
r configurations were
on for writing D-glycer-
been shown by calculations
X-ray diffraction. Thus
ompounds which have been
Morphine alkaloids have recently been degraded to simple
compounds of known absolute configuration by two independent
methods.3'4 The method of Kalvoda, Buchschacher and Jeger3
is outlined below.
HO
v^
morphine
CH3O
H2,Pd
5> 6
thebaine
OCH3
CH3O >c
Hofmann
degradation
CH3O
7,8,5 !
OCH:
R= -CH=CH2
OCH3
HOCH2CH2OH
p-TsOH
3 /
OCH:
OsOa
3
R= -CH=CH2
R= -CH=CH2
-2k-
R= -CHOHCH2OH Pb(OAc)4 R=
n-urs W. K. Or _,
-CHO i, R= -CH^
(l)HSCHaCHsSH
(2) Ni
HC1
^
OCHr
Al(Hg)
(l)Me2S04
(2}HSCH2CH2SH
(3)N1
>
OCH3
CH3O
\
CH3i
CH30
OCH<
Cr03
HOAc (H20)
~>
(1) 03
(2) HCO3H
(3) purification
CH3
COOH
.COOH
(-)-£is-[2-methyl-2-carboxvcyclohexyl-(l) 1-
acetic acid
The stereoisomeric [2-methyl-2-carboxycvclohexyl-(l) ]-
acetic acids have also been used in the proofs of the absolute
configurations of abietic acid,10 cevine (veratrum alkaloids) lx
ergosterolirf and (3-eudesmol (a bicyclic sesquiterpene).13
S"rSSS^tffifSSJSS.?f.SSee aclds have been •»**""*«
HOOC. CHX " CH*
H N
HOOC
V
f
0
mirror image of morphine
degradation product
T Pd/C
-25-
HOOC
HOOC
Js
/
-1
synthesis of steroids
The absolute configuration of the steroid series has been
established by several methods. 14>15> i6>i7, is. 19*20
Corrodi and Hardegger have proved the absolute
configuration of morphine by a much simpler degradation.4
OCH3
HO
OCH3
(l)acetylate
(2)BrCN
(3)deacetylate
(4)H00CC00H,m.p.
/
(1)03
(2)HC03H
COOH
-}
HOOC
HOOC
J
H
NH
COOH
H-C-NH2
CH2
COOH
D-aspartic acid21
.NH
nor-apocodeine
COOH
H-C-NH-CH2CH2COOH
CH2
COOH
(1) CH2=CHCN (2) HC1
-26-
It should be noted that the morphine alkaloids,
triterpenes, steroids and veratrum alkaloids all contain a
common structural element.
1.
2.
3-
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19-
20.
21.
J. van Bommel,
58,
REFERENCES
W. Kuhn, Z. El. Chem. 56, 506 (1952).
J. H. Bijvoet, A. F. Peerdeman and A.
Nature 168, 271 (1951).
Actaa38°di847*(iQ?^ChaCher and °* Jegsr' Helv" Chim*
?" £S?Fodi and E* Hardegger, Helv. Chim. Acta 38, 2038
(1955). —
H. Wieland and M. Kotake, Ann. _444, 69 (1925)
h£' '^r\' H* M* Fitch and W' e7 Smith, J.a!c.S.
1457 U936).
L. J. Sargent and L. F. Small, J. Org. Chem. 16, 103 (1951).
H. Wieland and M. Kotake, Ber. 58, 2009 (1925J7
H. Rapoport and G. B. Payne, J.A.CS. 74, 2630*(1952)
Heivyih?m: ActaaM:di85?- (?o^r^ °- Jeser and L- Ruzicka'
Ll^G^'A2taJM:W(1955)? "" *' B* W0°dWard'
Sli,HeUrSer' E*\BQlrSe*> g- Anllker, 0. Jeger and L. Ruzicka,
Helv. Chim. Acta 36, 1918 (1953).
?" 2inik?^ J; Kalvoda' D- Arigoni, A. Furst, 0. Jeger,
A. M. Gold and R. B. Woodward, J.A.CS. 76, 313 (1Q54)
W. G. Dauben, D. F. Dickel, 0. Jeger and"v. Prelog^
Helv. Chim. Acta 36, 325 (1953).
J. A. Mills, J.C.S. 4976 (1952).
?4 *£!£*/?**? \ AriS°ni and 0. Jeger, Helv. Chim. Acta
J. W. Cornforth, I. Youhotsky and G.
536 (1954).
Helv. Chim. Acta 32, 3
A. Lardon
(1949).
and P. Miglioretto,
S. Bergs tr^m,
S. Bergstrom,
Acta 32, 1617
M. Viscontini
930 (1955).
P. Brewster, E. D. Hughes,
Nature 166, 178 (1950).
Popjak, Nature 173,
(1949).
and J. Reichstein, Helv. Chim.
Helv. Chim. Acta 38,
C. K. Ingold and P. A. D. S.
Rao,
-27-
ALKYLATIONS WITH ALCOHOLS UNDER BASIC CONDITIONS
Reported by Joe A. Adamcik March 2, 1956
Examples of the use of alcohols as alkylating agents under
basic conditions have long been known. Haller's alkylation
of camphor1, for example, dates from 1891. Unfortunately
many of the older methods are not of great preparative use
because of the low yields and mixtures of products obtained.
Haller and Minguin1'2 observed the alkylation of camphor
by the action of an alcohol and its alkoxide. Cyclohexanone
has also been alkylated by n-butyl alcohol and sodium butoxide
to produce a low yield of 2-butyl cyclohexanone3.
Another example of the alkylation of active methylene
compounds is the observation of Carroll4'5'6 that the re-
action of £, ^-unsaturated alcohols and ethyl acetoacetate
in the presence of a basic catalyst such as sodium acetate
produced, among other products, alkenylacetones. An allylic
shift was usually, but not always, involved in the reaction.
An example is the reaction of cinnamyl alcohol with ethyl
acetoacetate6:
PhCH=CH-CH2OH + CH3COCH2COOEt > Ph-CH-CH=CH2 (33#)
CH2COCH3
The yields of ketone were generally poor however. A similar
alkylation of ethyl malonate yielded unsaturated acids. In
the case of cinnamyl alcohol the yield of acid was 66%.
Saturated alcohols did not alkylate.
The Guerbet reaction7, conducted by heating a primary
alcohol with its alkoxide gives as the major products the salt
of the acid corresponding to the original alcohol, hydrogen,
and the condensation product in approximate accordance with
the following equation:
RCHCH2ONa
I
2 RCH2CH2OH + RCH2CH2ONa — > RCH2CH2 + RCH2COONa + 2H2
With secondary alcohols, cleavage products are produced instead
of the acid. The use of a copper vessel or copper bronze as
a catalyst is helpful.3 It has recently been shown8'9'10 that
the use of nickel rather than copper and removal of water
from the reaction mixture leads to a higher yield with less
formation of the undesired acid. In this manner, alcohols as
low boiling as n-butyl have been successfully condensed at
atmospheric pressure in yields of about 70$. 9 n-Propyl
alcohol has also been condensed10, but the yield is not stated.
Mixed condensations have also been successful. The mechanism
of the Guerbet reaction has been discussed9'11. The major
route to the main products seems to be:
-28-
-§Ha v ppptr Pun Cannizzaro , RCH2CH2OH
2RCH2CHaOH -55?^ 2RCH2CH0 ^ RCH2COONa
aldol
RCHCHO -£ ^ RCCHO „„„ nu -„
I U A || RCH2CH20H
RCH2CHOH ,ngu ) RCH2CH alkoxide RCH2CHO + RCCH2OH
RCCH2OH RCHCHO RCH2CH
RCH2CH _NL RCH2CH2 RCHaCHs0H> RCHCH2OH , Rrw rwn
alkoxide RCH2 I H2 + RCH8CHO
Pyrroles12'13'14'15 and indoles16 and some of their
derivatives have also been alkylated by alcohols under basic
conditions. Examples are the formation of 2,4-dimethyl-5,5-
diethylpyrrole by reaction of 2,4-dimethylpyrrole with sodium
ethoxide in ethanol in a sealed tube at 220° and the formation
of skatole by treatment of indole with methanolic sodium
methoxide at 210-220°.
Certain phenols are methylated in low yield by treatment
with methanolic sodium methoxide at high temperature. Beta-
naphthol, for example, gives 1 -methyl -2 -naphthol. 17
As one would expect, an alcohol which is branched in the
2-position cannot be condensed in the Guerbet manner. However,
reaction of 2-ethylhexanol with its alkoxide at 300° in the
presence of copper bronze has been reported to give
approximately equimolar amounts of 2-ethylhexanoic acid and
bis- (2-ethylhexyl) -ether.18 A similar observation has been
made in the case of cinnamyl alcohol.3 These interesting
O-alkylations find analogy in the observation of Lund19 that
isopropyl ethers are sometimes produced in the Meerwein-
Ponndorf-Verley reduction of a,0-unsaturated ketones.
Nef20 early reported N-ethylation of aniline by treatment
with sodium ethoxide at high temperature. The yield was poor
however and the reaction was of little preparative use.
Recently Pratt and Frazza21 have reported the N-alkylation of
anilines with certain primary alcohols in high yields. Benzyl
alcohols gave yields in the range of 30-90^, and n-hexyl and
n-decyl alcohols gave yields only slightly lower. Aliphatic
amines did not undergo the reaction. The procedure involved
refluxlng with Universal Oil Products Company (U. 0. P.)
nickel a xylene solution of excess alcohol", the aniline, and
potassium alkoxide. Water was continuously removed by means
of a Dean-Stark apparatus. It was observed that the presence
of nickel was unnecessary at high temperatures, as refluxlng
a mixture of benzyl alcohol, aniline, and potassium benzoxide
gave a Q4% yield of N-benzyl aniline. The course of the re-
action was represented as follows:
(1) PhCH20H — Ni7N PhCHO + H2
(2) PhCHO + Ph-NH2 -) Ph-CH=NPh + H20
(3) PhCH=N-Ph + PhCH20H _?2E2Sl PhCHaNHPh + PhCHO
-29-
The effect of substituents on the rate of the reaction were
consistent with the assumption that step (3) was rate con-
trolling and that its mechanism was similar to that proposed
for the Meerwein-Ponndorf-Verley reduction.22
It should be noted that F.ice and Kohn23 have described
a method for N-alkylation of aniline and benzidine in high
yield by refluxing an alcohol with the amine in the presence
of a large amount of Raney nickel catalyst. This procedure
is successful for many lower aliphatic primary alcohols as well
as for benzyl alcohol. They write a mechanism somewhat
similar to the above except that the reduction step involves
catalytic hydrogenation of the intermediate. It is of interest
that U. 0. P. nickel is not sufficiently active to cause
this reaction to proceed. Other examples of N-alkylation with
alcohols in the presence of Raney nickel have been reported,
for example, the work of Clapp and coworkers24'25 in the
alkylation of piperazines.
The first base-catalyzed alkylation of a hydrocarbon with
an alcohol was reported by Becker and coworkers23 in 1953 •
The reaction of 2,3, 4,5-tetraphenylcyclcpentadiene with
ethanolic sodium ethoxide at high temperature gave an 84$
yield of l-ethyl-2, 3> 4,5-tetraphenylcyclopentadiene . The
alkylation of fluorene has been reported by Schoen and Becker27
and Sprinzak28. For example, ethanolic sodium ethoxide and
fluorene give 9-ethyl fluorene in 83$ yield. Benzyl alcohol,
the normal primary alcohols from d to C7 inclusive and also
C18 have been condensed to give the corresponding 9-alkyl-
fluorenes in 58-99$ yields. The mechanism proposed is similar
to that proposed for the N-alkylation of amines, with a
fulvene intermediate rather than an anil.
BIBLIOGRAPHY
1. A. Haller, Compt. rend. 112, 1490 (1891).
2. A. Haller and P. Minguin, Compt. rend. 142, 1309 (1906).
3- C. Weizmann, E. Ber^mann and L. Haskelberg, Chemistry and
Industry 56, 53? (1937).
4. M. F. Carroll, J. Chem. Soc. 1266 (194o).
5. M. F. Carroll, J. Chem. Soc. 70 4 (19^0).
6. M. F. Carroll, J. Chem. Soc. 507 (194l).
7. M. Guerbet, Compt. rend. 128, 511 (1899)-
8. Clare A. Carter, U. S. Patent 2,457, 866, Jan. 24, 1949;
Chem. Abstr. 43, 3437i (1949).
9. E. F. Pratt and D. G. Kubler, J. Am. Chem. Soc. 76, 52
(1954).
10. J. Bolle and L. Burgeois, Comot. rend. 233, 1466 (1951).
J. Bolle, Compt. rend. 233, 1628 (1951).
11. H. Machemer, Angew. Chem. 54, 213 (1952).
12. H. Fischer and E. Bartholomaus, Z. physiol. Chem. 77 , 185
(1911).
13« H. Fischer and E. Bartholomaus, Z. physiol. Chem. 80, 6
(1912).
14. H. Fischer and H. Rose, Z. physiol. Chem. 87, 38 (1913).
15. U. Colociachi and C. Bertoni, Atti accad. Lincei 21, I,
653; ibid. 21, II, 450, 518; G. Plancher and T. Zambonini,
ibid. 21, I, 598; Chem. Abstr. 7, H83 (1913).
-50-
16. R. H. Cornforth and R. Robinson, J. Chem. Soc . 680 (1942).
17. J. W. Cornforth, R. H. Cornforth and R. Robinson, J. Chem.
Soc. 683 (1942).
18. C. Weizmann, E. Bergmann and M. Sulzbacher, J. Org. Chem.
15, 54 (1950).
19- H. Lund, Ber. 70, 1520 (1937).
20. J. U. Nef, Ann. j*l8, l4o (1901).
21. E. F. Pratt and E. J. Frazza, J. Am. Chem. Soc. 76, 6174
(1954).
22. W. von E. Doering and T. C. Aschner, J. Am. Chem. Soc. 75,
393 (1953).
23. R. G. Rice and E. J. Kohn, J. Am. Chem. Soc. 77, 4052
(1955).
24. L. T. Plante and L. B. Clapp, J. Org. Chem. 21, 86 (1956).
25. L. T. Plante, VJ. G. Lloyd, C. E. Schilling and L. B. Clapp,
J. Org. Chem. 21, 82 (1956).
26. S. M. Linder, E. I. Becker and P. E. Spoerri, J. Am. Chem.
Soc. 75, 5972 (1953).
27. K. L. Schoen and E. I. Becker. J. Am. Chem. Soc. 77, 6030
(1955).
28. Y. Sprinzak, J. Am. Chem. Soc. 78, 466 (1956).
-31-
COLCHICINE: ASPECTS OF STRUCTURE AND SYNTHESIS
Reported by J . H. Rassweiler
March 9, 1956
The alkaloid colchicine is an important tool in
physiological research1. It was isolated in crystalline
form in 1884, but the first postulated structure was that of
Windaus in 19247. In 1945, Dewar3 proposed what is now
considered the correct structure (I). The final problem, the
relative location of the methoxy and carbonyl groups in ring C,
NHCOCH3
J-
VN
II
7
-OCH3
b
0
in
was reported by Rapoport last summer5,
has not been a complete synthesis of I.
To date, however, there
Most of the structural information has been obtained from
degradation work. I, on hydrolysis, yields colchiceine III
which, on treatment with diazome thane, gives two isomeric
methyl ethers, I and isocolchicine II1. Windaus7 treated I
with hot alkaline permanganate to obtain 3,4,5-trimethoxy-
phthalic acid, proving the benzenoid character of ring A.
Degradation of III to the deaminocolchinol methyl ethers8*9
VI, VII; the oxidation of VI to the quinone4 VIII; and the
independent synthesis of these compounds proved the bridged
biphenyl system of ring B and the positions of the ring A
methoxyl groups. The three carbon bridge of VI was proved
by treatment with 0s04 then lead tetraacetate with the
isolation of X, an internal condensation product of the
dialdehyde10. Two other series of colchicine degradation
products7'11'12 giving N-benzoylcolchinic anhydride XI and
some substituted phenanthrene ring systems conclusively proved
the 7-membered character of ring B.
Ring C in Dewar ' s formula I is a tropolone. This was
established in several ways. N-Acetylcolchinols IV and
allocolchicine13'14 XII were obtained by the expected ring
contraction. Finally, Rapoport' s5 work and many others
observed similarities of the C ring reactions to those of
"— ••
'
Ill
OH"
T->
B
c
-32-
1) Zn,HAc
OH 2) CH2N2
^T
NHAc
/
V
OCH?
Xylene
P2O5
IV
VT
OCH-
VII
-OCH3
B VIII
CHO
X
V
XI
2> 15U6> 17j 18
tropolones
structure of ring C.
indicated the 7-membered aromatic
There are also several other important degradations which
should be mentioned, though they were not important in the
structure proof. Hydrogenation gives a complicated reaction6'18
as in most tropolones, but Rapoport5'19 has established
several important structures. The structure of the ketone A
was proved5 thus establishing the methoxy, carbonyl positions in
1)(CH3)2NH CH3°f
2)H2
)
CH3O
NHCOCH3 i)ZnCl2,CH3SH
-NHCOCH3
P20s
Xylene
XIII
2)Ni
:■ Ji ;,. :
.!". : '<;//;;
■• ; r ■
-33-
I. I also undergoes photoisomerism to a,&,)P lumicolchicines
one of whose structure is postulated as XX.
20
Although less important, some mention must be made of the
principle synthetic work to date. The synthesis of colchinol
methyl ether V and its identification with the degradation
B
NH2
V
-Y-NHCOCH3
XII
■ C02Me
XX
OCH3
OCH:
product was basic to the structure proof. Two somewhat similar
methods were used4'21; the best probably was Cook's4.
Synthesis of the deaminocolchinic anhydride also was success-
ful26.
1.0s04
.Pb(Ac)i
OCH3
cyclization
_
Pd
H2
1 ) oxime
2)H2Fd
dl-
V
The skelation of I was prepared by Gutsche22, but this
could not be converted to the actual alkaloid. TheA-B23 and
OCH3
0CH3
CH3O--./X
CH3O -^ >
A,
l.perbenzoic acid
CH3O
2.H2S04, <^
'CH30
V
V
l.Zn,Et Bromo-
acetate
2.S0C12
__
4. Saponification
>
CH30
CH3O-,
n/ cooh
CH2
-34-
l.Newman-Beal
->
2 . polyphosphoric
acid
OCH:
H02C
the A-C ring24 systems have been synthesized, coumarin
derivatives acting as intermediates25, but again the complete
molecule has not been obtained.
OCH:
A-C
BIBLIOGRAPHY
1.
0.
Pr
2.
H.
3-
M.
4.
J.
5.
H.
U.
6.
V.
7.
A.
8.
J.
9-
J.
10.
J.
11.
J.
12.
J.
13.
P.
14.
H.
15.
J.
16.
A.
17.
F.
18.
0.
19.
H.
20.
E.
21.
H.
22.
G.
23.
J.
24.
J.
i5.
V.
26.
J.
I. Eigsti, P. Dustin. Colchicine, Iowa State College
ess 1955-
Fernholz, Ann. 576, 131 (1952).
J. S. Dewar, Nature, 155, l4l (1945).
Cook, J. Chem. Soc, 1951, 1397 (1951).
Rapoport, 7th Summer Seminar on Chem. Natural Products,
of New Brunswick, Aug. 16-19, 1955.
Bursian, Ber, 71, 245 (1938).
Windaus, Ann, TjQ, 59 (1924).
Cech et.al., Coll. Czech. Chem. Comm., Ik, 532 (1949).
Cook, J. D. London, J. Chem. Soc . , 1945, 176 (1945).
D. Loudon, J. Chem. Soc, 1947, 746 (1947).
Koo, G. E. Ullyot, J. Am. Chem. Soc. 72, 4840 (1950).
Cook, J. Chem. Soc, 1950, 537 (1950).
Santavy, Helv. Chim. Acta, 31, 821 (1948).
Fernholz, Angew Chim., 59A, 218 (1947).
Loudon, Quart. Revs., 5, 99 (1951).
Uffer, Helv. Chim. Acta, 35, 2135 (1952).
Santavy, Coll. Czech. Chim. Comm., 14, 145 (1949).
S. Tarbell, J. Am. Chem. Soc, 72, "^O (1950 ).
Rapoport, J. Am. Chem. Soc, 7673693 (1954).
J. Forbes, J. Chem. Soc, 1955, 3864 (1955).
Rapoport, J. Am. Chem. Soc, 73, l4l4 (1951 )•
D. Gutsche, J. Am. Chem. Soc, 76, 1771 (1954).
Koo, J. Am. Chem. Soc, 75, 1625 (1953).
E. Loewenshal, J. Chem. Soc, 1953, 3962 (1953).
Boekelheide, J. Am. Chem. Soc, 74, 1558 (1952).
Koo, J. Am. Chem. Soc, 75, 720 "(T953).
-35-
FERROCENE AS AN AROMATIC NUCLEUS
Reported by Kenneth Conrow March 16, 1956
Since the original demonstration that ferrocene is an
unusual aromatic system, a great deal of work has been done to
investigate its chemistry. The simplest demonstration of the
aromatic character of the cyclopentadiene rings of the
ferrocene molecule is found in their non-reactivity toward
maleic anhydride and toward hydrogen over Adams' catalyst.1
A convincing example of the resistance of the ferrocene system
to catalytic reduction is found in the preferential reduction
of the benzene rings in bis-indenyl iron to bis-( tetramethylene-
cyclopentadienyl) iron.2
The simplest aromatic substitution reactions are not ob-
served with ferrocene because of its ready oxidation to the
ferricinium ion. Thus nitration, halogenation and sulfonation
under the usual conditions lead to the destruction of the
molecule. However, a dilute solution of 100$ sulfuric acid in
acetic anhydride3 or sulfur trioxide in pyridine4 have served
to sulfonate ferrocene without concurrent oxidation.
Friedel-Crafts acylations are quite successful in the
ferrocene series and have led to the majority of the reported
types of derivatives of ferrocene. With acetic anhydride in
anhydrous hydrogen fluoride an 87$ yield of monoacetyl
ferrocene is obtained.3 With excess aluminum chloride and
acetyl chloride in methylene chloride, a 71$ yield of diacetyl
ferrocene is obtained.5 Phthalic anhydride similarly gives
o-carboxybenzoyl-ferrocene, and 0-chloropropionyl chloride gives
{3-chloropropionylferrocene. x Competition experiments between
anisole and ferrocene with aluminum chloride and acetyl chloride
give acetyl ferrocene exclusively.6
In view of the ease of most acylations it is surprising to
find that oxalyl chloride fails to acylate ferrocene.^ >7
Friedel-Crafts alkylations are reported not to occur with
propylene or isobutylene in anhydrous hydrogen fluoride
(conditions which alkylate benzene). However, cyclopentenyl
ferrocene is formed under these conditions. This reaction may
be formally regarded as the degradation of the ferrocene
molecule followed by alkylation of another molecule by the
cyclopentadiene produced.3 It is also reported that isopropyl
chloride, ethyl bromide and benzyl chloride fail to alkylate
ferrocene with aluminum chloride in carbon disulfide.17
Ferrocene also reacts with aldehydes in anhydrous hydrogen
fluoride. Formaldehyde gives a product whose molecular weight
and analysis agree with the binuclear (C6H4)2Fe(CH2)2Fe(C5H4 )2.3
Attempts at chloromethylation of ferrocene have given only
polymethyleneferrocene. 6
Mercuration of ferrocene proceeds smoothly at room
temperature with mercuric acetate to give mixtures of starting
material, mono-mercurated and di-mercurated ferrocene in
approximately equal amounts.4'7 Reduction of monochloro-
mercuriferrocene with thiosulfate gives the interesting
diferrocenyl mercury. 4'7 Reaction of these mercuri derivatives
-36-
with halogens give haloferrocenes, otherwise unobtainable.4'9
Ferrocene reacts with butyl lithium to form mono and di-
lithium derivatives of ferrocene. 4'7' 14 The acids formed on
carbonation are identical with those from hypohalite oxidation
of the acetyl ferrocenes.7 Triphenylsilyl ferrocenes have
also been prepared from these lithium intermediates.14 With
Q-benzyl hydroxylamine , aminoferrocene is obtained.4'10
Another very successful reaction has been the arylation
of ferrocene with aromatic diazonium salts.7'8'12'13 A large
variety of substituted phenyl ferrocenes have been prepared
in this way, though once again the generality is limited
by the ease of oxidation of ferrocene. Thus 2,4-dinitrophenyl
diazonium salt is reduced to dinitrobenzene and no arylated
ferrocene is obtained.12 This reaction is enjoyed by neutral
ferrocene as well as ferricinium ion and has been done under
a variety of conditions, so that there is some doubt about
the mechanistic analogy with the free radical Gomberg-Bachmann
reaction.
The above reactions almost invariably give mixtures of
mono-, di- and sometimes poly- substituted ferrocenes. Di-
substituted ferrocenes are usually assumed to be hetero-
annular. The first reported proof of this is the identity
of the bis-benzhydryi ferrocene from dibenzoyl ferrocene (by
reaction with phenyl lithium followed by reduction with
titanous sulfate) with the bis-benzhydryl ferrocene from
benzhydryl cyclopentadiene. 15 Similarly diphenyl ferrocene
from aniline diazonium salt and ferrocene is identical with
diphenyl ferrocene from phenyl cyclopentadiene. l2 Infra-red
evidence for heteroannular substitution in the disubstituted
derivatives is based on the observation that bands at 9 and
l0y<7 seem to be characteristic of an unsubstituted cyclo-
pentadlenyl ring in the molecule.5
Many transformations in the side chain of ferrocene have
been accomplished to yield a variety of derivatives not
available by direct substitution. Several of these have
already been mentioned. Oxidation of the acetyl substituent
to the acid has been accomplished by hypohalite5 and by
iodine in pyridine.18 Amino ferrocene can be obtained from
ferrocene carboxylic acid via the Curtius rearrangement,
though the Hofmann rearrangement of the amide and the Beckmann
rearrangement of the oxime of acetyl ferrocene both failed
to give this product.16 Reduction of acetyl ferrocene with
L1AIH4. gives 89$ of the corresponding carbinol, whose acetate
may be pyrolysed to give vinyl ferrocene. Various copolymers
of vinyl ferrocene have been prepared.16 Reduction of the
acetyl group to the ethyl group has been accomplished with
zinc amalgam and hydrochloric acid16 and with hydrogen over
Pt.5
Reaction of 1,1 ' -diacetyl ferrocene with ethyl magnesium
bromide yields a di-tertiary carbinol, each carbinol carbon
being asymmetric.17 Two isomers (assumed to be 1) meso (DL)
and 2) racemic (DD + LL)) were obtained but the latter has not
been resolved. Since use of methyl magnesium iodide yields
but one isomer, belief that isomerism is indeed of the type
■■•'■' •:.;
-37-
indicated is substantiated. Dehydration of bis-(2-hydroxy-2-
butyl) ferrocene gives a mixture of isomers also,
formulated on the basis of cis-trans asymmetry.17
These are
A different sort of isomerism should also offer interest
in the ferrocene system. Compounds of type I are not
superimposable on their mirror images and should be re-
solvable. Compounds of type II should also be distinguishable
"cis" form a is a meso form, while "trans" form b is a
racemate. s
Ha
lib
That ferrocene has a higher electron density than has
benzene is evident from chemical evidence of the comparitive
ease of attack on ferrocene by electrophilic substituents.
A more elegant demonstration of this comes from a comparison
of the pK's of corresponding phenyl and ferrocenyl anilines
and phenols.11
pKb PKa
1.
2.
3-
4.
5-
6.
7.
8.
p-ferrocenyl aniline
m-ferrocenyl aniline
p-amino biphenyl
amino ferrocene
aniline
p_-ferrocenyl phenol
p-phenyl phenol
phenol
9.66
9-85
10.89
8.81
10.14
11.79
11.04
11-33
BIBLIOGRAPHY
R. B. Woodward, M. Rosenblum and M. C. VJhiting, J.A.C.S.
74, 3^58 (1952;.
E. 0. Fischer and D. Seus, Z. Naturforsch. 9b, 386 (1954).
V. Weinmayr, J.A.C.S. 77, 3009 (1955).
A. N. Nesmeyanov, Abstract XlVth IUPAC, Zurich, p. 193,
1955.
M. Rosenblum, Thesis, Harvard Univ., 1953-
P. L. Pauson, unpublished work; c.f. P. L. Pauson, Quart.
Revs., 9, 391 (1955).
A. N. Nesmeyanov, E. G. Perevalova, R. V. Golovnya and
0. A. Nesmeyanova, Doklady Akad. Nauk. USSR 97, 459 (195*0;
C.A. 49, 9633f. —
A. N. Nesmeyanov, E. G. Perevalova, R. V. Golovnya, ibid.
99, 539 (195*0; C.A. 49, 15918c. *
'):•
■• :;
S* '•■:. !
J /'.
i ::•■■• •" j i. .■•'■.
.' • ) ::'
■j
-J , 4 ,
■ '
-38-
9- A. N. Nesmeyanov, E. G. Perevalova, 0. A. Nesmeyanova,
ibid. 100, 1099 (1955).
10. A. N. Nesmeyanov, E. G. Perevalova, R. V. Golovnya and
L. S. Shilovtawa, ibid. 102. 531 (1955).
11. A. N. Nesmeyanov, E. G. Perevalova and R. V. Golovnya,
ibid. 103, 81 (1955).
12. G. D. Broadhead and P. L. Pauson, J. Chem. Soc . , 367 (1955).
13- V. Weinmayr, J.A.C.S. 77, 3012 (1955).
14. R. A. Benkeser, D. Goggin and G. Scholl, J.A.C.S. 76, 4025
(1954).
15. P. L. Pauson, J.A.C.S. 76, 2187 (1954).
16. F. S. Arimoto and A. C. Haven, Jr., J.A.C.S. 77, 6295 (1955).
17- R- Riemschneider and D. Helm, Ber. 89, 155 (1956).
18. V. Weinmayr, U.S. 2,683,157; C.A. 49, 10364a (1954).
'U
-39-
APPLICATIONS OP MASS SPECTROMETRY TO ORGANIC CHEMISTRY
Reported by Philip N. James
March 16, 1956
Positive rays were first discovered by Goldstein in 1886,
and J. J. Thomson developed the first machine for their
analysis. Since these investigations, the field of positive
ray analysis has developed along two different lines1. The
first, pioneered by Aston and called mass spectrography, uses
photographic recording for the accurate determination of
isotopic masses. It is the second branch, called mass
spectrometry, which is of primary interest to the organic
chemist. In this branch, pioneered by Dempster, an ion current
recording device is used for the accurate measurement of the
relative abundances of the ions present in the positive ray.
A mass spectrometer consists of the following parts2: 1.)
sample handling and introduction system, 2. ) ion source, 3- )
mass analyzer, and 4. ) ion current detector. Only the first
of these need concern us, since the remaining parts are
standard for most chemical work. The problem in the design of
the sample handling system is the production and introduction
of a vapor characteristic of the sample, but this is essentially
a problem in vacuum technique. Thus, it is obvious that gases
and low-boiling liquids are easily analyzed by the spectrometer,
while high-boiling liquids, solids, and mixtures present
difficult problems.
Undoubtedly the most
mass spectrometer has bee
mixtures3'4. Such analys
molecule rarely yields a
methane can give rise to
CH3+, CH2+, CH+, C+, and
to hydrocarbons of higher
usefulness of the machine
produces a characteristic
mportant industrial application of the
n the analysis of hydrocarbon
es are complicated by the fact that a
simple mass spectrum. For example,
all of the following species: CH4 ,
H+. The extension of this complication
molecular weight is obvious. The
resides in the fact that each compound
fragmentation ("cracking") pattern.
o
o
O
a
<
>
•H
-P
cd
iH
<D
100
90
80
70
60
50
40
30
20
10
10 0
Jk.
II „ li A
90
80
70
60
50
40
30
20
10
26 27 28 29' '39 40 41 42 43
i — i.
), V ' ■•_£» — JLl
26 27 28 29 39 40 41 42 43
Atomic Mass Units
-40-
Figure 1: Comparison of Portions of the Mass Spectra of iso-
Butane ^left) and n-Butane (right). (See p. 39, bottom.)
Typical examples are the partial spectra of n-butane and iso-
butane shewn in Fig. I5. In the complete specta, it can be
seen that the most abundant species for each compound lies
not at mass 58 (C4Hio+), but at mass 43, equivalent to C3H7+,
indicating that the easiest path for both molecules on electron
bombardment is the rupture of a CH3-C bond. The band at mass
29 in the i so -butane spectrum could correspond to a rearrange-
ment peak6, an isotope effect peak, or a peak due to doubly-
charged C4H1o++ ions. There is also a weak band at mass 31-9
corresponding to a metastable ion transition.
From the spectra, it is obvious that a mixture of the two
isomers could be quantitatively analyzed by a measurement
of, for example, the ratio of the relative intensities at masses
Table I: Compounds Successfully Analyzed by the Mass
Spectrometer
Oxygen Compounds
Aldehydes C1-C5
Ketones C2-C3
Esters C2-C4
Acids C2
Lactones
Alcohols Ci-C4
Ethers C2-C4
Sulfur Compounds
Mercaptans Ci-C4
Sulfides Ci-C4
Disulfides CJ.-C3
Thiophene
2 and 3-Methylthiophenes
Hydrocarbons
Paraffins
Ci -Cg
Olefins
C2-C5
Diolefins
C3-C5
Naphthenes
C5-C7
Aromatics
C6~CiO
Acetylenes
C2-C4
Alkyl Halides
Alkyl Chlorides
C1-C4
Alkyl Iodides
C1-C4
Freon
Dichlorodifluorome thane
42 and 43. A similar technique has been applied to much more
complex hydrocarbon mixtures. By a combination of mass
spectrometry with infrared spectroscopy, the time required for
the quantitative analysis of typical refinery samples has
been reduced from about 10 days (for a low-temperature
fractionation method) to 4-5 hours, and the accuracy compares
favorably with that obtained using more tedious methods.
With high molecular weight and highly complex mixtures, the
calculations become so complicated that data are usually re-
ported as compound types rather than specific compounds.
Table I gives a partial list of the types of compounds which
have been successfully analyzed by mass spectrometry7.
Mass spectrometry is a natural medium for the use of tracer
techniques8' 9,1° using stable isotopes, such as C13, N15, 018,
H2, and S34. The main consideration is that, for ease of
analysis, the labelled atom must be converted to a gaseous
molecule. The usual gases for the elements mentioned are,
respectively, C02, N2, C02, H2, and S02, although in some
applications, it may be easier or more convenient to use other
gases containing the required element10 .
-41-
The ions which are measured in the mass spectrometer are
produced by bombarding the neutral vapor with electrons.
If the energy of the electrons is gradually increased from
zero, it is noted that ions do not appear until a certain
electron energy is reached. This electron energy is called the
appearance potential, and is characteristic for the particular
ionic species being measured4'7'9' 11 ' l2. The magnitude of
the appearance potential is related both to the ionization
potential of the neutral fragment and to the dissociation
energy of the bond whose rupture led to the neutral fragment.
Thus, both ionization potentials and bond energies may be
obtained from mass spectral data. The results check closely
with those obtained by other methods.
A few instances of the analysis of solids have been reported,
but the data are not extensive enough at this time to permit
an evaluation of the method. The use of high resolution mass
spectrometers for this purpose, however, promises to have
wide application in the fields of natural products, polymers,
and biochemistry-14.
In gas phase reactions, particularly those involving free
radicals, the mass spectrometer may be used to follow the
fate of short-lived intermediates, giving an insight into the
mechanism of the reaction which is difficult to obtain in any
other way4'7'9'11'12. The particular advantage in using this
technique for free radicals lies in the fact that radicals
generally have much lower ionization potentials than molecules,
and lower electron energies may be used for the ionization.
The machine has also been used industrially as a process
monitoring device3. A sample may be piped continuously from
a vapor phase reaction mixture into the mass spectrometer,
thus providing a continuous check on the progress of the re-
action.
The mass spectrometer provides an excellent method for the
detection of leaks in vacuum systems9'11, having the advantage
over other methods that leaks in metal systems may be found
in this way. The system is connected to a mass spectrometer,
and a test probe of helium is applied along the exterior of
the system. A leak is indicated by the appearance of helium
peaks in the spectrum.
The instrument provides a useful method for the measurement
of low vapor pressures13 since determinations are rapid and
convenient, and the results are not affected by traces of
volatile impurities in the sample. The method has been used
for a number of hydrocarbons with vapor pressures in the
range 10" to 10 mm. of mercury.
REFERENCES
1. F. W. Aston, Mass Spectra and Isotopes, Second Ed.,
Longmans, Green and Co., New York, 1942.
2. M. G. Ingraham and R. J. Hayden, Mass Spectroscopy, Nat.
Res. Council, Nat. Acad. Sci. (U.S.), Nucl. Sci. Ser.
Rept. No. 14, 1954.
3. C. E. Berry and J. K. Walker, Ann. Rev. Nucl. Sci., 5, 197,
(1955).
■ ,-'.;• I
-42-
4. G. P. Barnard, Modern Mass Spectrometry, Institute of
Physics, London, 1953-
5- Catalog of Mass Spectral Data, Am. Pet. Inst. Res. Pro j .
44, Nat. Bur. Stds., Washington 25, D.C.
6. This is a common phenomenon in mass spectra. For an
example with aliphatic acids, see G. P. Happ and
D. W. Stewart, J. Am. Chem. Soc . , 74, 44o4 (1952).
7- H. W. Washburn in W. G. Berl (ed. ), ^Physical Methods in
Chemical Analysis, Vol. I, pp. 587-639 > Academic Press,
Inc., New York, 1950.
8. R. F. Glascock, Isotopic Gas Analysis for Biochemists,
Academic Press, Inc., New York, 1954.
9- D. W. Stewart in A. Weissberger (ed.), Technique of Organic
Chemistry, Second Edition, Vol. I, Part II, pp. 1991-2058,
Interscience Publishers, Inc., New York, 1949«
10. W. E. Coleman, B.S. Thesis, Coll. Lib. Arts and Sci.,
University of Illinois, Urbana, Illinois, 1956.
11. W. J. Dunning, quart. Revs., £, 23 (1955).
12. M. Krauss, A. L. Wahrhaftig and H. Eyring, Ann. Rev.
Nucl. Sci., 5, 241 (1955).
13 . W. A. Sheppard, MIT Seminar in Organic Chemistry, March 12,
1952.
14. Chem. and Eng. News, 33, 3988 (1955).
-43-
THE UNSATURATION OF CYCLOPROPANE RINGS
Reported by Norman Shachat
March 23, 1956
The cyclopropane ring exhibits many of the properties
associated with an ethylenic linkage. Much chemical and
physical evidence relating to this phenomenon has been compiled
On the basis of this evidence, two reasonable molecular orbital
pictures have been postulated for cyclopropane.
Chemically, many similarities exist between cyclopropyl
and ethylenic compounds. Cyclopropane can be hydrogenated
catalytically under slightly more vigorous conditions than are
required for an ordinary double bond.1'2 Addition of hydrogen
halides, which results in ring opening, occurs in accordance
with the Markovnikov rule.3'4'5
C6H5
V
H H
CH3
HBr
CeHs — CH — CH
i ^
Br
CH:
CH3
Furthermore j
propane s has
the addition of halogens to yield 1,3-dihalo-
been observed.5'6'7
In contrast to propylene, which generally gives rise to
isopropyl products as a result of ionic reactions, cyclopropane
yields only n-propyl compounds under similar conditions. ,9
The most striking chemical difference between cyclopropane rings
and unsaturated compounds is observed in their behavior toward
oxidizing agents, as is concisely illustrated by the following
reactions of vinylcyclopropane: 10 ' xx>xz
KMnO.
CH=CH2
03
CHO + HCHO
Although vinylcycloporpane does not form an adduct with maleic
anhydride at 100°C, it does polymerize readily in the presence
of benzoyl peroxide and ultra-violet light.10
The ability of unsaturated cyclopropyl compounds to undergo
conjugate addition has been demonstrated in a variety of
cases
2 , 12, 13, 14
following reaction:15
(C02C2H5)2 + NaCH(C02C2Hs)a
For example, Bone and Perkin observed the
CH2-CH-(C02C2H5)2
/ CH2-CH-(,C02C2H5)2
Although benzene condenses with cyclopropyl mesityl ketone in a
conjugate manner in the presence of aluminum chloride, the
Grignard reagent or ethyl malonate did not combine with the
ketone.16
-44-
Cu+,
Olefins are known to form 7f-electron coordination
complexes with a variety of substances, including Ag
platinous salts, iodine, and tetranitrome thane. Similarly
cyclopropane forms complexes with chloroplatinic acid,17
iodine,1® and tetranitrome thane.19
Hg++,
Physical measurements and especially spectral data have
supplied much significant information concerning the unsaturated
character of cyclopropyl compounds. Ultra-violet absorption
studies on a large number of systems containing a cyclopropane
ring adjacent to a double bond indicate a conjugative
effect. °~26 However, the bathochromic shift is less in the
case of a cyclopropyl conjugated system than for a fully un-
saturated one. Recently, it has been demonstrated that a chain
of conjugation cannot be transmitted through a cyclopropane
ring
27~30
Infrared spectra, mainly of cyclopropyl ketones,
also indicate that the conjugative effect of the cyclopropyl
group is less pronounced than that of an ethylenic
bond.16'28'31'33 In addition, it is significant that cyclo-
propyl compounds exhibit C-H stretching frequencies at
3010 cm."1 and 3090__crn. -1, since ethylenic hydrogens also absc
in this region. "
33-35
Other physical measurements such as molecular refrac-
tion, 36,37,3e dipole moment, 23' 39' 40 quenching cross-section
of cadmium resonance radiation,41 and electron diffraction42 '43
have also supplied much important data relating to the
TT-electron character of cyclopropane rings.
On the basis of the available evidence, Walsh has suggested
the following orbital pictures for cyclopropane:44
CAO
MO
More detailed calculations led Coulson and Moffit to
propose the following "bent bond" structure:45
-45-
OAO
BIBLIOGRAPHY
1. R. Willstatter, J. Bruce, Ber., 40, 4456 (1907).
2. R. Van Volkenburgh et al., J.A.C.S., 71, 172 U9^9)»
3. N. Kishner, Chem. Abst., 6, 2915 (1912 J.
4. D. Davidson, J. Feldman, J.A.C.S., 66, 488 (1944).
5. M. S. Kharasch et al . , ibid., 6l, 2139 (1939 J •
6. R. A. Ogg, Jr., W. J. Priest, ibid., 60, 217 (1938).
7. G. Gustavson, J. Prakt. Chem., [2], 627 270 (1900 ).
8. T. B. Dorris, F. J. Sowa, J.A.C.S., bO, 358 (1938).
9. C. D. Lawrence, C.F.H. Tipper, J. Chem. Soc, 713 (1955).
10. R. Van Volkenburgh et al . , J.A.C.3., 71, 3595 (1949).
11. N. J. Demjanov, M. Dojarenko, Ber., 55, 2718 (1922).
12. E. P. Kohler, J. B. Conant, J.A.C.S., 39, l4o4,l699 (1917)
13- R. W. Kierstead et al., J. Chem. Soc, 3^10 (1952).
14. R. W. Kierstead et al., ibid., 1799 (1953).
15- W. A. Bone, W. H. Perkin, ibid., 67, 108 (1895).
16. R. C. Fuson, F. N. Baumgartner. J.A.C.S., 70, 3255 (1948).
17. C.F.H. Tipper, J. Chem. Soc, 2045 (1Q55).
18. S. Freed, K. M. Sancier, J.A.C.S., 74, 1273 (1952).
19- 0. Filipov, Chem. Zentb., [I], 1057 (1915).
20. R. P. Mariella et al., J.A.C.S., 70, 1494 (1948).
21. R. P. Mariella, R. R. Raube, ibid., 2±, 518,521 (1952).
22. A. E. Gillam, T. F. West, J. Chem. Soc, 95 (1945).
23. M. T. Rogers, J.A.C.S., 69, 2544 (1947).
24. E. P. Carr, C. P. Burt, ibid., 40, 1590 (1918).
25. I. M. Klotz, ibid., 66, 88 (194TJ\
26. J. D. Roberts, C. Green, ibid., 68, 214 (1946).
27. L. I. Smith, E. R. Rogier, ibid., 73, 3840 (1951).
28. R. H. Eastman, ibid., 76, 4115 (1954).
29. R. H. Eastman, J. C. Selover, ibid., J6, 4ll8 (1954).
30. R. H. Eastman, S. K. Freeman, ibid., 77, 6642 (1955).
31. N. Fuson et al . , ibid., 76, 2526 (195TTJ.
32. N. Fuson, M. L. Josien, Compt.Rend., 231, 131,1511 (1950).
33. H. Hart, 0. E. Curtis, Jr., J.A.C.S. ,~T8, 112 (1956).
34. S. E. Wiberley, S. C. Bunce, Anal. Chem., 24, 623 (1952).
35-
V.
36.
V.
37.
G.
38.
L.
39-
M.
4o.
B.
41.
W.
42.
J.
43.
L.
44.
A.
45.
C.
-46-
A. Slabey, J.A.C.S., 76, 36o4 (1954).
A. Slabey, ibid., 7j4,~¥928 (1952).
J. Ostling, J. Chem. Soc . , 101, 457 (1912).
Tschugaeff, Ber., 33, 3118 J1900).
T. Rogers, J. D. Roberts, J.A.C.S., 68, 84} (1946).
I. Spinrad, ibid., 68, 617 (1946).
R. Steacie, D. J. Le Roy, J. Chem. Phys., 11, 164 (1943)
Donohue et al . , J.A.C.S., 67, 332 (1945).
Pauling, L. 0. Brockway, ibid., 59, 1223 (1937).
D. Walsh, Trans. Far. Soc, 45, 179 (1949).
A. Coulson, VI. E. Moffitt, Phil. Mag., 40, 1 (1947).
-47-
ALIPHATIC HYDROXY SULFONIC ACIDS AND SULTONES
Reported by J. S. Dix March 2J>, 1956
Reactions of Sultones
The preparation of aliphatic sultones was first fully re-
ported by Helberger in 1949. x He and other workers have
described many of their varied reactions:
1. With salts2
CH2CH2CH2CH2 CH2CH2CH2CH2-X
I I + KX » I
(I) S02 0 SO3K
X = halogen, cyanide, carboxylate, phthalimide
2. With ammonia and amines2
(I) + RNH2 > CH2CH2CH2CH2NH2R
so,<->
R = phenyl, alkyl, H
3- With alcohols3
(I) + ROH > CH2CH2CH2CH2OR
I
R = alkyl S°3H
4. With aromatic hydrocarbons4
(I) + ArH ^iCl3_^ CH2CH2CH2CH2-Ar
i
SO3H
ArH = benzene, p_-xylene, p_-dichlorobenzene
5. With organometallic compounds
(a) Grignard reagents5
(I) + Et-MgBr > CH2CH2CH2CH2-Et
I
, x SO3H
(b) Alkali metals6
CH3-CH-CK2CH2 + RM CH3CHCH2CH2-R
(II) S02 0 SO3M
R = Butyl, M = Li
R = phenyl, 9-fluorenyl, M = Na
Preparations of Sultones
1. Helberger employed the Reed chlorosulfonation reaction with
alkyl halides:
C1-CH2CH2CH2CH3 + S02 + Cl2 *L^ C1CH2CH2CHCH3
(I) + (II) /vac. H20 ^<h S02C1
^ e— C1CH2CH2CH2CH2-S02C1
-48-
Disadvantages are:
(a) Low yields
(b) The sultone isomers are not readily separable
(c) Decomposition of higher molecular weight acids
often occurs before sultone formation.
2. Helberger noted that the sultones could be regenerated
after hydrolysis to their acids by the vacuum distillation
technique used for the halo sulphonic acids, with water
being eliminated rather than hydrogen chloride. Previous
attempts to prepare aliphatic sultones from their hydroxy
acids had failed.7'8 Helberger 's method often causes
decomposition of the higher molecular weight acids, however,
and is not general.
Very recently a diluting agent technique has been
found to be more general and to give higher yields.9 The
diluting agent must fulfill three requirements:
(a) Its boiling point must correspond to the dehydration
temperature of about 150°.
(b) It must be miscible with the sultone formed.
(c) It must form an azeotropic mixture with the water
which is eliminated.
Xylene has proved most successful thus far.
With this method, # -and 6 -sultones have been
formed, as well as the c -sultone of 5-hydroxypentane-l-
sulfonic acid, but attempted elimination of water from
11-undecane-l-sulfonic acid failed. No |3-sultone has been
formed in this manner, although an unstable intermediate
in the sulfonation of styrene by dioxane-sulfur trioxide
is thought to be a P-sultone.10
Preparations of the acids
No general method is available, but four modes of
preparation have been developed:
1. Bisulfite addition to an olefinic alcohol.
A free radical addition,11 this method is restricted
to terminal double bonds:
CH3(CH2)7CH-CH=CH2 + NaHS03 ^ CH3 (CH2)7CHCH2CH2-S03Na
t ' !
OH OH
t -butyl
perbenzoate
2. Reduction of keto sulfonic acids
These acids can be formed in two ways:
(a) From a,£-unsaturated aldehydes or ketones and sodium
bisulfite9'12 Q
CH3(CH2)13CH=CHCCH3^S-°3-) CH3 (CH2)13CHCH2CCH3
S03Na
i. s ,;
-49-
(b) Prom acetoacetic ester, an aldehyde, and sodium
bisulfite9'13
0 0 0
CH3CCH2C00Et + HCCH2CH2CH3 ^U CH3C-C=CHCH2CH2CH3
Na
0
COOEt
(III)
• HSO3— > ~^±^ CH3CCH2CHCH2CH2CH3
SO3H
The carbonyl group is best reduced with Raney nickel
catalyst.
3. The Strecker synthesis of alkyl sulfonates
Disadvantages:
(a) Starting materials are often difficult to obtain
(b) Higher molecular weight halides are less reactive
A special case:4'14
+ CH3COCI ^i2-} CH3C00(CH2)4C1 Nl£?°3 5_> H0(CH2)£O3H
H20
4. Oxidation of hydroxyalkyl mercaptans
Again starting materials represent a disadvantage, but
in this case the halides are more reactive toward the
reagent.
HO-R-X + NaSH > HO-R-SH I5523-) HO-R-SO3H
BIBLIOGRAPHY
1. Helberger, Manecke and Fisher, Ann. 562, 23 (1949).
2. Helberger, Manecke and Heyden, ibid. , 565, 22 (1949).
3. Helberger, Heyden and Winter, ibid., 5Bo7 147 (195M-
4. Truce and Hoerger, J. Am. Chem. Soc , "75, 5357 (1954).
5- Willems, Bull. soc. chim. Belg., 64, 7W (1955).
6. German patent 894,116 to Bohme Fettchemie (Helberger and
Heyden); C.A., 48, 4234e (1954).
7. Marckwald and Frahne, Ber., 31, 1854 (1898).
8. Shriner, Rendleman and Berger, J. Org. Chem. h, 103 (1939).
9- Willems, Bull. soc. chim. Belg., 64, 409 (1955).
10. Bordwell, Peterson and Rondestvedt, J. Am. Chem. Soc, 76,
39^5 (1954); and preceeding papers.
11. Karasch, May and Mayo, J. Org. Chem., 3, 175 (1938).
12. Smith, Norton and Ballard, J. Am. Chem. Soc, 75, 7^8
(1953). ~"
13- Rashig and Prahl, Ann., 448, 265 (1926).
14. Helberger and Lantermann, ibid. , 586, 158 (1954).
' ": : ■ J ■■
f i
NUCLEOPHILIC SUBSTITUTION OF VINYL HALIDES
Reported by Willis E. Cupery April 6, 1956
The inertness of vinyl halides toward nucleophilic
substitution can be explained in several ways. The carbon atom
at which substitution would occur is shielded by TT electrons1,
and resonance forms of the type,
/
.h e ^h
/x
R-CH=C t ) R-CH-C rr,
^^Cl " *C1©
should strengthen the C-Cl bond2 and would result in prohibitive
loss of resonance energy in the transition state.3 When a
carbonyl group is introduced at the {3-position to the halogen.,
greatly increased reactivity is observed. In resonance
terminology, additional resonance forms more inviting to the
nucleophile are possible.4
R-C-CH=C $ > R-C-CH=C 4- > R-C=CH-C
0 01 oe o<c; L
Or, in terms of a transition state, charge is better dispersed.
R CI R ,C1
XCX Y © xc'
11 x n .IX j-
^C /0 > d,C. ..0°
R' C'' R' SCX
V' XR"
The latter transition state followed by elimination repre-
sents a mechanism which is reminiscent of Taf t ' s work on the
halogenation of double bonds where addition or substitution
may occur.5 The mechanism together with an assumption that
elimination occurs before rotation is used by Jones and Vernon
to explain substitution of halogen by thioethanolate in the
ethyl (3-chloro crotonates with retention of configuration.6
In models, a slight steric hindrance to rotation appears with
thioethanolate which is not present with ethanolate. Only one
product is formed with ethanolate.
The other extreme transition state, leading to inversion,
involves a tendency toward sp_ hybridization rather than sp3.
One of the two p orbitals takes part in the C-C bond, and the
other forms half bonds to the nucleophile and the leaving group.
This would explain the reported inversion of P-chloroacrylate
during sulfonic acid formation with ammonium sulfite.8 The work
itself is far from clear, so final judgment is best reserved.
There are many very early reports, mainly due to Autenreith
concerning substitution of P-halo-a.^-unsaturated acids, esters,
and salts, sometimes under rather strenuous conditions, with
benzene sulfinic acid9, thiophenolate, thioethanolate,
phenolate10, benzyl alcoholate11 , and benzyl and allyl
mercaptides . 12 Fritsch in lo97 reported that ethyl trichloro-
acrylate reacted with two moles of sodium ethoxide with the
7
-51-
displacement of both P-halogen atoms.
13
Two syntheses indicative of the usefulness of this grouping
are shown below:
CH3-C-CI
II
HC
\
C-OH
CH3-C-CI
HC ,0
vC-OH
CH3
C6H5NHNH2
CeHs
>
AICI3, <^»
CH3-C-
li
-> HC-
HC1
>
■NH
CH3-C=
=N
N-C6H5
^0
CH3
C6H5-C-C6H5
CH2
^C-OH
0*
H2C C
/
N-C6H5 14)
^r
PCI5 N AICI3 v
^
In this case, the reactivity of the
P-halide allov/s more direct
preparation of 3>5-diphenyl butyric
acid.15
Although
camphor exist
ketones been
formed with a
with free ale
have treated
solution with
in yields of
tained.18
early reports of substituti
, 16 only recently have P-hal
extensively studied. Vinyl
Ikoxides, although under too
ohol, addition also occurs.1
phenol, p_-cresol, and a- and
methyl, propyl and isobutyl
30-87$. With P-naphthol two
0-CH=CH-C-CH3
l!
0
on in chloromethylene
o - a, {3 -unsaturated
ethers are easily
vigorous conditions
The Russian workers
(3-naphthol in basic
halovinyl ketones,
products were ob-
CH=CH-C-CH3
6
-V-ONa
VV
Where the para position in aromatic
systems is blocked, the migration
proceeds with FeCl3 to give products
of the type shown to the right.19
FeCl.
<T>
In cyclizations, groups other than halogen have been
displaced. I, above, when allowed to react with phenyl-
hydrazine forms P-naphthol and 1 -phenyl -3-methyl pyrazole.
the reaction below, a diethylamino group is displaced by an
active methylene group:20
In
Hv ^N(Et),
R
CH2-CN
I
C=0
->
H2N
-52-
Much of the study on substitution with amines has been
carried out on highly halogenated compounds.4 When two
P-chlorine atoms are present, usually they are both displaced,
although perchloropenta-l,4-diene-3-one lost only two chlorine
atoms and oxidation of the product did not give symmetrical
diphenyl urea. The product is probably
CI CI 0 CI CI
C6H5NH-C=C — C— C=C— NH-C6H5 .
The £,£-dianilino-derivatives can be converted to
substituted pyrazoles by the action of phenyl hydrazine, e.g.,
Cl-C-
M
C6H5NH-C
C6H5-NH
•C-CHCI2
II
0
C6H5NHNH2
->
CI
C6H5NH
11
N
1
C6H5
-CHC1;
as can the original halogen compounds:
R"-C C-R
R'-C
v
0
CI
C6H5NHNH2
~>
R".
R'.
R
N
C6H5
The reaction is poor when R=H or C6Hs. The dependence on R'
and R" is less clear at present. The only unexpected re-
action from a series of eight highly halogenated compounds
was found with perchloro-l-pentene-3-one, supposedly by the
following route:
Cl-C C-C2CI.
|) 11
Cl-C 0
XC1
n „ ..„.„ Cl-C C-NHNH-C6H5 CI
C6H5NHNH2 v !i || v
^ci-c 0 > C1
\C1 01.
^=0
NH
C6H5
The dianilino derivative of trichloro acrolein is easily
formed, but a Skraup-type ring closure was less successful.
Even so, a fair yield of 2-hydroxy-3-chloroquinoline resulted
H-C=0
V,
C-Cl
H2SO4
^^
P-NH-CeHs
//
H-C=0
XC-C1
> >■>
C-OH
N
H
.- ;"l"l
-53-
BIBLIOGRAPHY
1. A. G. Catchpole, E. D. Hughes, C. K. Ingold, J.C.S., 19^8,
10.
2. E. D. Hughes, Trans. Farraday Soc . , 37, 627 (1941).
3. G. W. Wheland, Theory of Resonance, John Wiley and Sons,
Inc., New York (1944): p. 272.
4. A. Roedig, H. J. Becker, Ann. 597, 21 4 (1955).
5. R. W. Taft, Jr., J.A.C.S., 70, 3364 (1949).
6. D. E. Jones, C. A. Vernon, Nature 176, 791 (1955).
7. V. Gold, J.C.S., 1951, 1431.
8. H. J. Becker, A. E. Beute, Rec. Trav . Chim. 5jf, 523 (1935).
9. W. Autenreith, Ann. 259, 335 (1890).
10. W. Autenreith, Ann. 255 > 222 (1889).
11. W. Autenreith, Ber. 2£, 1646 (1896).
12. H. Scheibler, J. Voss, Ber., 53, 379 (1920).
13. P. Pritsch, Ann. 297, 312 (1897).
14. W. Autentreith, Ber., 2£, 1653 (1896).
15- C. F. Koelsch, H. Hochmann, C. D. LeClaire, J.A.C.S., 65,
59 (19^3).
16. A. W. Bishop, L. Claisen, W. Sinclair, Ann. 23l, 36l (1894)
H. Rupe, M. Iselin. Ber. 49, 29 (1916).
17. M. Julia. Annales de Chimie (12) 5, 595-640 (1950).
18. N. K. Kotchetkov, M. I. Rybinskaya, A. N. Nesmeyanov.
Dok. Akad. Nauk, S.S.S.R. 79, 798-802 (1951); C.A. 46,
6102 (1952).
19. A. N. Nesmeyanov, N. K. Kotchetkov, M. I. Rybinskaya,
Izvest. Akad. Nauk, S.S.S.R., Odtel. Khim. Nauk 1954,
418-26; C.A. 49, 9634a (1955).
20. N. K. Kochetkov. Izvest. Akad. Nauk, S.S.S.R., Odtel.
Khim. Nauk 1954, 47-55; C.A. 49, 6090i (1955).
.i)
-54-
NON- POLYMER -FORMING REACTIONS OP VINYL HALIDES
Reported by H. Scott Killam April 6, 1956
The use of vinyl halides in polymer chemistry is
profusely illustrated in the current literature. Of importance
also are those reactions of vinyl halides which do not involve
the double bond directly. It is the purpose of this discussion
to indicate the manner in which these halides may be prepared
and utilized in synthetic work.
Preparation:
1.
Ar
Ar^
Ar"
C=CH
+ Br«
^
Ar Ar"
:C=<T (1,2,3,4)
Ar
\
Br
Ar=Ar'-(CH3)2N-, CH3O-, (CH3)3CO-, I, CI, Br, OH, C6H5CH20-
Ar"=Br, H-, CH3-,
2.
Ar
Ar
:C=CH2
S0C1;
^ (Ar)2C=CHCl
(5,6)
Ar
"V
C=CH2
Ar
+
Br;
^ (Ar)2C=CHBr
(7,8,9)
3.
2 X-C6H5
+
OEt
CHC12CH
OEt
X = H, CH3, C2H5, CH30
R R
R-C-C-C02H
i \
Br Br
Pyridine or
^ (X-C6H5)2-CHCHC1;
Na2C03
v
DH (18,19)
(X-C6H5)2C=CHC1
R R
1 1
J^ R-C=C-Br
(10,11)
R=Alkyl
Reactions:
1. Grignard Formation. Until recently, employment of vinyl
halides for the preparation of Grignard reagents has been
limited to the use of the more highly substituted halides
shown by formula I where R, R', and R" are aryl or R" is
hydrogen.
R ^R"
><
R1 NX
+
Mg
R
.R"
MgX
55-
A survey of the literature indicates that the frequency
of application of vinyl Grignard reagents to synthetic problems
is determined by the ease of preparation of the reagent. Until
1954, the more highly substituted vinyl Grignard reagents had
been obtained with facility (21,22) while reports concerning
the formation of vinyl magnesium bromide or chloride had not
been adequately substantiated (23). This situation has been
altered somewhat by the recent work of Normant (12). By
utilizing solvents differing from those usually associated
with the preparation of Grignard reagents he was able to
apply to synthetic procedures even the simplest vinyl organo
magnesium compounds.
2.
CF2=CHC1
CH3OH
-7
CH3OCP2CH2CI
(13)
3.
RCH=CHC1
CH2=CHC1
Me
Me-C-Cl ^ CHC12CHC(CH3)3 (I2*)
Me R
Me
Me-CH > CHC12CHC(CH3)3 (15, 16)
Me
4.
Ar
Ar
C=CHC1
KNHj
Ar xAr
(17,18,19)
5.
ArMgX
+
R
R
>
C=CHC1
C0C12
->
ArCH=CR2
(20)
1.
2.
3-
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
BIBLIOGRAPHY
W. Tadros and A. Latif, J. Chem. Soc . , 3823(1952).
W. Tadros, Y. Akhnookh and G. Aziz, ibid. , 186 (1953).
A. Schonberg, J. M. Robson, W. Tadros and H. A. Zahim,
ibid., 1327 (1940).
Aziz, ibid., 2553 (1951).
Am. Chem. Soc, 72, 1034
Tadros and G
wT
S. Patai and F. Bergmann, J
(1950).
F. Bergmann and J. Szmuszkowicz, ibid. , 72, 1035 (1950);
ibid., 69, 1777 (19^7).
P. Lipp, Ber., 56, 567 (1923).
P. Pfeiffer and R. Wisinger, Ann., 46l, 132 (1928).
E. Bergmann, L. Engel and H. Meyer, Ber., 65, 446 (1932)
J. Farrell and G. Bachman, J. Am. Chem. Soc, 57, 128l
(1935). —
A. Kirrmann, Bull, soc chim. France, 4l, 316 (1927).
H. Normant, Compt. rend., 239, 1510, loTl (1954); ibid.,
24o, 314,440, 631 (1955).
P. Tarrant and H. C. Brown, J. Am. Chem. Soc, 73, 1781
(1951). —
-56-
2235 (19^7).
J . Am . Chem .
Soc
14. K. Detling, C. Crawford, D. Yabroff and W. Peterson,
Brit. Patent, 591,632, Aug. 25, 1947; Chem. Abs. 42, 91 9
(1948).
15. L. Schmerling, J. Am. Chem. Soc, 68, 1650 (1946): ibid.
67, 14^8 (1945).
16. M. S. Malenovskii, J. Gen. Chem., 17,
17. G. Coleman, W. Hoist and R. Maxewell,
58, 2310 (1936).
18. G. Coleman and R. Maxewell, ibid., 56, 132 (1934).
19. W. Buttenberg, Ann., 279, 32TTT8947T
20. M. S. Kharasch, J. Am. Chem. Soc, 65, 504 (1943).
21. W. Krestinsky, Ber., 55B, 2770 (1922~7.
22. C. F. Koelsch, J. Am. Chem. Soc, 54, 2045 (1932).
23. M. S. Kharasch and 0. Reinmuth, "Grignard Reactions of
Non-metallic Substances", Prentice-Hall, Inc. New York,
1954, p. 36.
•;■ il .
-57-
ALKALINE FERRICYANIDE OXIDATIONS
Reported by C. W. Schimelpfenig April 20, 1956
There have been a few recent reports dealing with the
oxidation of simple molecules by alkaline ferricyanide. The
fact that these recent reports invalidate structures assumed
for years prompts this review of oxidations using potassium
ferricyanide in alkaline media.
Waters1 considers ferricyanide to be a reagent in which
one electron is removed from its substrate, producing ferro-
cyanide . The "substrate minus 1 e" then reacts by decomposition
and/or rearrangement to give the oxidized product. An example
is the oxidation of P-naphthol to give P-dinaphthol and
a-(f3-naphthoxy)-P-naphthol as main products. These products
indicate the mesomeric nature of the radical. This type of
reaction, oxidation produced by electron-abstracting agents,
includes those of eerie and ferric ions in acidic media and
of ammoniacal silver nitrate. It is reminiscent of some
biological oxidation systems, notably those linked with the
cytochrome system.
1. Kieffer2 oxidized the phenol, morphine. However, it
was only following the work of Goldschmidt and Pummerer that
Small postulated the structure of pseudomorphine.
Goldschmidt3 treated phenanthrene hydroquinone monoethyl
ether and obtained "ethoxyphenanthroxyl" (I) whose molecular
weight was intermediate between this monomer and the dimer.
Pummerer4 reported his oxidation of p_-cresol to a "dimer
minus 2H". On the basis of acid hydrolysis, hydrogenation,
and other chemical studies, he suggested that the dimeric
product was (II ). Later work by Westerfield and Lowe5 showed
that the diphenol from acid hydrolysis was 2,3' -bi-p_-cresol
and they proved the structure of ring C.
CH3
CH3
II
III
-58-
These data, together with his own observations, have led
Small6 to postulate that pseudomorphine is the 2,2' derivative
(III).
Although the ideas of Pummerer led to the structure of
pseudomorphine, his structure requires modification. Last
year Barton7 reported that the dimeric p_-cresol had structure
(IV) based on his degradation to ring A. This led him to the
first total synthesis of usnic acid (diacetate, V).
CH:
CH3
Ac
AcO I £ yv 0
CH3
IV
CH3,;
OAc 0
V
H
Another reaction involving a phenolic starting material
is the synthesis of selected indoles, adrenochromes, from
noradrenaline, adrenaline, and N-alkylated noradrenalines. 8' 9
2. Chronologically, the next application of ferricyanide
oxidations is that to carbohydrates and glycols. The oxidation
has been applied to a number of sugars; however, no products
have been isolated and the reaction is still an empirical
quantitative method.10
In the case of a glycol, the product of osmium tetroxide
oxidation of anthracene was oxidized further to napthalene-
2,3-dicarboxylic acid.11
3« Acid hydrazides and hydrazine have been oxidized.
12
RCONHNH2'
-^> RCHO + N2 + H20
_^ RCONHNHCOR + N2 + H20
(R = 0» 6k<fo 0CHO)
If R is aromatic or heterocyclic, the aldehyde is the
product. If R is alkyl or aromatic with a m-directing group
in the o- or p_-position, then the sym-diacylhydrazid is ob-
tained.
4. A reaction which has been extensively used is the
oxidation of N-substituted pyridinium compounds to the
corresponding a-pyridones. It has been postulated13 that the
reaction proceeds by dehydrogenating the pseudo-base.
The structure of reduced diphosphopyridine nucleotide
was proved14 by determining that reduction of DPN with
1,1-dideuteroethanol followed by chemical oxidation,
hydrolysis, methylation, and alkaline ferricyanide oxidation
-59-
produced the 2-pyridone and the 6-pyridone which contained
equal amounts of deuterium.
5- Alkaline ferricyanide has been applied to a few
amines. dl-Oxy sparteine was obtained (35%) from dl -sparteine15
and oxo-P-isosparteine was obtained (25$) from p-isosparteine .^
Perrine17, trying to prepare tropinone from tropine, obtained
nortropine (87$). He found that whenever an N-methyl
tertiary amine, where N is attached to a secondary or tertiary
C atom, is treated with alkaline ferricyanide, demethylation
occurs.
6. Toluene, xylene, and some of their derivatives were
oxidized by Noyes18 to the corresponding benzoic and phthalic
acids by boiling with alkaline ferricyanide.
7. Furan derivatives have been oxidized19 to the
corresponding furoic or dehydromucic acids, also in boiling
oxidizing media.
8. Thiophenol is quantitatively oxidized to diphenyl-
disulfide.20 Cysteine has been determined potentiometrically
with neutral ferricyanide indicating the mercaptan-disulfide,
ferricyanide-ferrocyanide equilibrium is reversible. 2l
A synthetic rubber polymerization catalyst includes
neutral ferricyanide and a mercaptan such as n-dodecyl-
mercaptan.22 The proposed mechanism involves generation of
a thioalkyl free radical which serves both as initiator and
as chain transfer agent.
RSH + Fe(CN)63" > RS* + H ^ + Fe(CN)64~
9. Among reactions which have not been fully investigated
is the conversion of hydroxy lamines to N-substituted oximes.
Grammaticakis23 reported the oxidation of N,N-di-(l-phenyl-
propyl )-hydroxylamine to the corresponding N-substituted
ketoxime.
10. Another synthetic method not fully explored is
exemplified by the synthesis of 2-methylbenzothiazole from
thioacetanilide . 24
In retrospect, ferricyanide has been used in systems
obviously favored for oxidation in this manner, that is,
extraction of an electron from an electron-rich site. The
reagent has also been utilized with some success where its
capability was not originally apparent. It is likely that
the potentiality of alkaline ferricyanide as an oxidizing
agent has not been exhausted.
-60-
BIBLIOGRAPHY
1. W. A. Waters in Gilman, Organic Chemistry, vol. IV, p. 1214;
Abstracts of 1955 IUPAC Meeting, 112.
2. L. Kieffer, Ann. Chem. Pharra. , 103, 271 (1857).
3. S. Goldschmidt and W. Schnidt, Ber., 55, 3197 (1922).
4. R. Pummerer, D. Melamed and H. Puttfarcken, Ber., 58,
1808 (1925) and previous papers in the series.
5. W. W. Westerfield and C. Lowe, J. Biol. Chem., 145, 463
(19^2).
6. L. F. Small and S. G. Turnbull, J. Am. Chem. Soc, 59,
1541 (1937).
7. D. H. R. Barton, A. M. Deflorin and 0. E. Edwards,
Chemistry and Industry, 1955, 1039; J« Chem. Soc, 1956,
530.
8. J. D. Bu'Lock and J. Harkey-Mason, J. Chem. Soc, 1951,
712, 2243.
9. P. Chaix and C. Pallaget, Biochim. et Biophys. Acta, 10,
462 (1953).
10. H. C. Becker, Thesis, Univ. of Illinois (194o) and
references therein.
11. J. W. Cook and R. Schoental, Nature, l6l, 237 (1948).
12. S. J. Angyal in Adams, Organic Reactions, vol. VIII,
p. 233, and references therein.
13« H. L. Brc:dlow and C. A. Vanderwerf, J. Org. Chem., 16,
73 (1951).
14. M. E. Pu.'Mman, A. San Pietro and S. P. Colowick, J.
Biol. Chem., 206, 129 (1954).
15- C. G. Cl?rmo, W. M. Morgan and R. Raper, J. Chem. Soc,
1936, 10:25.
16. B. "p. Moore and L. Marion, Can. J. Chem., 31, 187 (1953).
17. T. D. Perrine, J. Org. Chem., 16, 1303 (1951).
18. W. A. Noyes and W. B.Wiley, Am. Chem. J., 11, l6l (I889),
and previous papers in the series.
19. E. V. Brown, Iowa State College J. Sci., 11, 227 (1937).
20. V. 0. Lukashevich and M. M. Sergeveva, J. Gen. Chem.,
USSR, 19, 1493 (19^9).
21. G. 0-orin\. Abstracts of ACS meeting, April 1956, p. 1C.
22. W. Kern, Makromol. Chem., 1, 199 (1948).
23. P. C-ramiratica.kis, Compt. rend., 224, 1066 (1947).
24. p. Jacobson, Ber., 19, 1067 (188FJ7
-61-
THE STRUCTURE OP NOVOBIOCIN
Reported by Kaye L. Motz
April 20, 1956
Novobiocin has been isolated from fermentation broths by
both solvent extraction and by acid precipitation. Two
crystalline forms have been isolated, one with a melting point
of 152-1560 and the other melting at 17^-178°. Both forms
are optically active ([a]g4 -650 1$ in EtOH). Rast determina-
tions indicate a molecular weight of about 610, while X-ray
crystallographic studies show 618 as the molecular weight. ,s
Cryoscopic determinations show a molecular weight of 695 - 25?
Since several bases form neutral and acid salts with novobiocin,
the presence of a dibasic acid might well be suspected, and
indeed, the ultraviolet spectrum indicates this to be true.1'5
Potentiometric titration substantiates this and establishes
pK' values of 4. 3 and 9*1 in water and gives 636 as a value
for the equivalent weight. It has also been established by
Kuhn-Roth determination that there are two C-methyl groups
and one 0-methyl group in the molecule*1
Recent microanalysis2 shows the composition of
novobiocin (I) to be C31H36N2O11. On treatment of I with
hydrogen in the presence of platinum or Raney nickel the
dihydro-derivative II is formed. The optical activity and
pK' values of II are close to those found for I. The
infrared spectrum shows little change in the conjugated system
or in the carbonyl region.
The following degradation was used to identify one part of
the molecule.1
II
(CH3C0)20
HOOC
->
H2
CH2CH2CH
OCOCH3
VT
CH3
-CH3
+ V
PT
or
Ni(R)
T
H2 Cat.
(CH3C0)20
CH2CH=C
■>
HC1
,CH3
-CH3
+ V
ETOH (60$)
4N HC1
\l/
ETOH {10%)
\k
Optically
inactive acid
III
(CH3C0)20 H00C|^
optically active x
neutral compound
VII
+ neutral
/CH3 compound
v XT NCH3
VIII
-62-
The first compound definitely identified was (VII)
2,2-dimethyl-6-carboxy chroman. This was identified by its
£-bromophenacyl ester with the aid of infrared and ultra-
violet spectra.
Since the acetic anhydride treatment always gives the same
fragment of the molecule and no nitrogen is present in this
portion it seems quite likely that an amide linkage has been
broken in the process. The hydrogen chloride treatment may
well have broken a glycosidic linkage since this treatment
gives an optically active substance and an inactive acid. It
is apparent that the identified portion of the molecule is
linked to the rest of the molecule through its carboxyl group.
The unidentified part of the molecule must then all be
contained in V.2 ~ „ ~TI
U 0-Un3
il
NaOMe ^ Y n>
>
Deacetylation
C9H15N050l
XI
CH3
HC1
Boiling
Me OH
XII
VIII
MeOH
/^y
,0H
XIII
HO
v
Ov
■NHp'HCI
0^0
neutral
compound
CH3
The lactone ring of the substituted coumarin was
identified by direct comparison with known compounds. The
spectrum of the compound differed from model compounds only
in a manner which would be predicted by the presence of the
substituents on the benzene ring. The benzene ring sub-
stitution was determined as follows.
XII
XII
KOH
fusion
1 N NaOH
•>
^
several days
or
10
Benidict 's
solution
il
CH3
V J i
■Ik
-63-
The compound X (CnH2iN06) appears to be an ethyl
glycoside of a methoxy sugar and XIII the corresponding methyl
glycoside.2 The presence of infrared bands at 1702 + 1625
indicate a urethan grouping. The infrared spectrum and the
liberation of NH^Cl on methanolic HC1 treatment indicates
the presence of a cyclic carbonate ester. Barium hydroxide
treatment gives the theoretical amount of barium carbonate
which indicates the presence of nitrogen as a carbamate. The
methoxyl group found tob'e present and the bridge oxygen account
for all of the functionality of XIII.
Using the information presented above the following
partial structure for novobiocin has been proposed.2
OH
H2NCOO-
-0-
H0-
CH3O-
CH3-
C6H70
NHCO ,, ^CH3
X^X-CHsCP^C
I NCH3
0' *0 xAoH
CH3
RSPERENCES
1. H. Hoeksema, J. Johnson, J. Hinman, J. Am. Chem. Soc . ,
77, 6710 (1955).
2. J. Hinman, H. Hoeksema, E. Caron, W. Jackson, J. Am.
Chem. Soc, 78, 1072 (1956).
3- E. Kaczka, F. Wolf, F. Rathe, K. Folkers, J. Am. Chem.
Soc, 77, 64o4 (1955).
k. C. G. Smith, A. Dietz, W. T. Sokolski and G. M. Savage
Antibiotics and Chemotherapy, 6, 135 (1956).
5. H. Hoeksema et.al., Antibiotics and Chemotherapy 6,
1^3 (1956).
6. J. R. Wilkins, C. Lewis, A. R. Barbiers, Antibiotics
and Chemotherapy 6, 149 (1956).
7. R. M. Taylor et.al., Antibiotics and Chemotherapy 6,
157 (1956).
8. R. M. Taylor et.al., Antibiotics and Chemotherapy 6,
162 (1956).
9. W. J. Martin et.al., Proc Staff Meet. Mayo Clinic 30,
5^0 (1955).
10. E. T. Jones and A. Robertson, J. Chem. Soc, 1690 (1932).
11. R. C. Shah and M. C. Laiwalla, J. Chem. Soc, 1828 (1938).
• / > :.
■',-'• J.
-64-
OZONATION STUDIES OP AROMATIC HYDROCARBONS AND rfETEROCYCLES
Reported by M. S. Konecky
April 27, 1956
Since Kekule proposed his hexagonal alternating single and
double bonded structure for benzene in 1865, chemists have been
interested in the elucidation of the internal bond structure of
aromatic compounds. Although many structures for benzene and
naphthalene were postulated, none of the classical representa-
tions satisfactorily explained the chemical reactivity and
physical characteristics of these type compounds.1
Today, the ground state, aromatic molecule is considered a
resonance hybrid of various contributing classical structural
forms, and, due to resonance stabilization, exhibits properties
which are distinct from those expected for any of the contribut-
ing forms. Thus, application of the theory of resonance to
aromatic structure leads to a distinction between the free
molecule in the ground state and the reacting molecule in some
excited state.
This seminar is concerned with the use of ozone in elucida-
tion of the reacting structure of aromatic compounds.
I - Benzene and Derivatives; The ozonolysis products obtained
from o-xylene by Leviie and Cole2 first demonstrated the appli-
cability of ozonation to aromatic structure studies. Haayman
and Wibaut's3 semi-quantitative isolation of the products from
the ozonolysis of o-xylene chemically verified the resonance
concept of the equivalence of the carbon-carbon bonds in the
benzene nucleus. The products, glyoxal, methylglyoxal, and
dimethylglyoxal were isolated in a molar ratio of 3:2:1,
respectively, as shown in reaction scheme (A):
(A)
/V.CH3
\^Ach3
ground state
1 OHCCHO + 2 CH3COCHO
— > 2 OHCCHO + 1 CH3COCOCH3
Boer
4,5
designed an improved ozonator which enabled
accurate rate studies to be made during the ozonation of benzene
and derivatives. These rate studies6'^ showed that this
ozonation is a bimolecular reaction, is catalyzed by A1C13,
and involves the absorption of 3 moles of ozone per mole of
hydrocarbon. Furthermore, nuclear substituted halogen and
carbonyl decrease the rate of ozonation, while alkyl sub-
stitution increases the rate. Since these effects parallel
effects observed in electrophilie substitution, a related re-
action mechanism for ozonation was postulated, as follows:
ft f-.
'* '". "~j
-65-
(B)
X? ©JO©Vt
y^o-oe
+ Q
./
N)©Va
molozonide
The unstable molozonide is rapidly transformed into a stable
iso-ozonide via the mechanism for aliphatic ozonides proposed
by Criegee:
s
cc
■0
o o: jo ffio o o.-'
^o-b/
Molozonide
x0 0'
Iso-ozonide
The stable mono-ozonide now contains two aliphatic double bonds
and rapidly adds two additional moles of ozone to form the
triozonide, i.e.
(D)
+ 2 0:
Q3.
V
J.
0:
:.T0:
The rate determining step is the mono-ozonide formation.
II - Naphthalene and Derivatives: 8 Here, ozone preferentially
reacts with an a-carbon atom since the energy required to
localize a pair of electrons to an a-carbon is less than to a
P-carbon.9,1° Subsequently, only the a-(3 bond is polarized
since any other polarization would destroy the aromaticity of
both benzenoid nucleii--an improbable alternative from energy
considerations, i.e.
SO eOj
^ i
• •Q3
•0-
A CHO
H20 < o [ + OHCCHO
The decomposition products in the case of 2,3-dimethyl-
naphthalene indicate a main reaction in which the methylated
ring is attacked and a side reaction with attack on the
non-methylated ring, i.e.
66-
(P)
Main Reaction *- 80$
CHO
H20
+ CH3COCOCH3
CHO
03..,
H20
<x
CHO
CHO
+ OHCCHO
Side Reaction /v 20$
The small amount of methylglyoxal isolated was accounted for
by the decomposition of the small amount of pentozonide
originating from the side reaction:11
03--.
(G)
■.. o3--
30;
H2° x CH3COCHO
o3-^o
The predominant ozone attack of the methylated ring agrees with
the benzene rate data which showed that methyl substitution in-
creases the reactivity of the aromatic nucleus toward ozone.
Ill - Pyridine and Derivatives: The azomethine linkage in
pyridine is not attacked by ozone; however, treatment of the
ozonolysis mixture with base liberates NH3. A reaction scheme12
was proposed in which the -C=N- linkage is split during
hydrolysis, giving rise to an amide, i.e.
(H)
20-
O'
Q3
20HCCH0 +
^N-
HCONH2
|base
NH3 + HCOOH
This reaction is also bimolecular. The quantitatively determined
2:1 ratio of ozone -absorbed to ammonia -produced verified the
formation of a diozonide. The rates with 3-picoline, 2,6-di-
methylpyridine, and 2,4, 6-trimethylpyridine were faster and
increased in the order named. A higher activation energy for
pyridine in this reaction is indicated since the temperature
coefficient is 3-8 as compared to 3.0 for benzene and 2.7 for
toluene. Because of the electrophilic nature of this mechanism,
these data support the concept of the diminished reactivity
of the pyridine nucleus to electrophilic reactions as compared
to the benzene nucleus.
IV - Quinoline and Isoquinoline: Reaction scheme (J) was
proposed for the course of the ozonation of quinoline and its
-67-
Reaction
The isolated decomposition products, derived from the diozonide
bv the ?™wti0r\' are indicated for the quinolines studied
Dy the general formulas in equation (X .
Ri
Ri
(K)
R2-C=0
I
R3-C=0
+
i
o=c
o=c
I
R4
o
where, R!,R2>R3,R4 = h or CH3
A small amount of ammonia, which can only be produced bv
reacted'w^r °f °™es in which the pyridine nucleuses
reacted with ozone, also is isolated. Quantitative evaluation
of the ammonia produced and the total ozone absorbed verified
indicatS"?hrlde4%the S°UrCe °f the ^onia. Rate stales
nt 6d ^e.rapid fo^ation of the diozonide and slow
formation of the tetra-ozonide of the main reaction. Initial
or at ?hei 2 TV* *£ 5"6 °r ?"8 b°nd in the benzene" ™"eU8
hLft *r\2 u°nd ^ the Wldine nucleus is postulated on the
basis of the charge distribution in the quinoline nucleus and
the energy barrier to subsequent polarization o^the bonding so
as to destroy the aromaticity of both rings, as was shown'in
to form" the te?rf o^h ^J*8* WMtiMl of the ^ono-ozonide
bSt n™ n«??«n 5 arozon^de in the side reaction was unexpected,
presen? in ?he°lnnnZal V^ JeVealed that the anil Structure
present m the mono -ozonide can be rapidlv attacked bv ozone
with accompanying breakdown of the aromatic nucleus.
aftP^h? raC\tion late with isoquinoline decreases greatly
after -1.4 moles of ozone has been absorbed
quinoline An unexpectedly large amount of
decomposition. A mono-ozonide was shown to
the ammonia. After absorption of 1.4 moles
andJn/n?^! f^sists of 60* of the pyridinic monolozonide
and 40% of the benzenoid diozonide, as in (L).
per mole of iso-
NH3 is obtained on
be the source of
of ozone, the re-
■68-
(L)
9r
Thus, the pyridine nucleus reacts about 1-1/2 times as fast as
the benzene nucleus. The isoquinoline mono-ozonide reacts
slowly with additional ozone since there is no anil structure
present.
V - ?T -Pyrones : 14 Atypical carbonyl reactivity, oxonium salt
formation, and unusually high dipole moment are properties
of (f-pyrones which disagree with the classical representation,
illustrated in (M) for 2, 6- dimethyl- cf -pyrone . The actual
structure is considered to be a resonance hybrid of contributing
forms, some of which are shown below:
A
o (-
OO
(->
A0A^ A0/\
(M)
(N)
(0)
15
All the pyrones investigated1 * absorbed 2 moles of ozone per
mole of pyrone at a rate faster than for benzene or toluene but
slower than for a compound possessing 2 isolated double bonds
such as in the classical structure (M). The decomposition
products isolated (p) indicated reaction with ozone according
to the canonical forms shown; no distinction can be made between
(N) and (0) by the ozonation technique.
(P)
9£>
0
203 (,..-■/ N...n H20
0HCC0CH0
7X0X
0 6
^ +
2CH3C00H
O3-,
20:
CH3COCHO + 0HCC0OH
y ^ (x C°3 pk°_4 + CH3COOH
®
Other <T-pyrones gave comparable results
-69-
VI - Pyrroles:14 Ozonolysis of pyrrole, 2, 4-dimethylpyrrole ,
N-phenylpyrrole, and N-phenyl-2, 5-dimethylpyrrole yields products
which are explained by reaction of the pyrrole as if it were
the classical imine structure (Q) in reaction scheme (R):16
(R)
0 0
KjK
I,
0
°3v 0£] r>;03 2H2°v [CH3-C-N-C-CH3]+OHCCHO
/ (Q)
i
0
±
H20
mA
C6H5NHCCK3 + CH3COOH
11
0
2 c
dime thy lpyrrole and 1 ,2, 5-trimethylpyrrole give
However.
ozonolysis products which are not
structure. Reaction according to
plain the small amount of glyoxal
the large amount of methyigiyoxal
based upon a pola r f orm of the pyrrole nucleus and utilizing the
electrophilic initial step, rationalizes the methyigiyoxal
formation.
explained
the imine
produced,
isolated.
by the imine
structure can ex-
but cannot explain
A proposed mechanism,
(S)
JCk~^&
R
°3 v J'— 1
R 0
s
r
[ch3-c
(Og) x N
C-CH3]
0
R
03
.0-
H
RNH2 + 2CH3C0CH0
where, R = H or CH3
H20
NL
H
— V*
CH3-C
tl
N
l
C-CH3
li
0
Simultaneous reaction via the imine structure is also
postulated. The rate of ozonation is too fast for measurement.
The ratio of ozone absorbed to NH3 or CH3NH2 produced is 2:1
which is in agreement with reaction via the imine and polar
structures.
VII - Furans:14 Furan reacts rapidly with ozone to form an
ozonide which on decomposition produces glyoxal, a product
which agrees with reaction via the classical structure. Methyl
glyoxal is a product of the ozonolysis of 2-methylfuran and
2, 5 -dimethyl furan. This product cannot be explained by the
classical structure, but can be explained by reaction via a
polar structure. The mechanism is best illustrated with 2,3-di-
methylfuran which gives glyoxal, methyigiyoxal, and dimethyl -
glyoxal as ozonolysis products. These products and the absorp-
tion of 1.5 to 1.6 moles of ozone per mole of furan agree with
the postulated simultaneous reaction via the classical and
■■'
-70-
polar structures, as in scheme (T).
(T)
|f jt^ 203 . CH3COCHO + HCOOH + CH3COOH
' classical
*.
r^1"^ ( ) 1 ~" C °3 ) CH3COCOCH3 + OHCCHO
#) polar 9
BIBLIOGRAPHY
1. Gilman, Organic Chemistry, vol I, chapter 3 (Fieser), J.
Wiley and Sons, N.Y., 1942.
2. Levine and Cole, J. Am. Chem. Soc . , 54, 333 (1932).
3. Haayman and Wibaut, Rec. Trav. Chim . , 60, 842 (1941).
4. Boer, ibid. , 6j_, 217"7Tc4'5r]T~
5- Boer, ibid. , 70, 1020 (1951); Boer and Sixma, ibid. , 70,
997 (1951;.
6. Sixma, Boer, and Wibaut, ibid. , 70, 1005 (1951); Wibaut
and Sixma, ibid. , 71, 76l~7l952).
7- E. R. Lovejoy, Organic Seminar, Univ. of Illinois,
May 11, 1951.
8. Kampschmidt and Wibaut, Rec. Trav. Chim. , 73, 431 (1954);
Wibaut and Van Dijk, ibid. , 65, 413~Ti9^6).
9. Sixma, ibid., 68, 915~Tl949).
10. Suyver and Wibaut, ibid. , 64, 65 (1945).
11. Kooyman, ibid. , 66, 201 (19^7).
12. Sixma, ibid., 71, 1124 (1952).
13. Boer, Sixma, and Wibaut, ibid. , 70, 509 (1951).
14. Wibaut, J. Chim. Phys. , 53, 143 TT956).
15- Wibaut and Herzber^ Proc. Kon. Nederl. Akad. Wentensch. , 56,
333 (1953). ^?
16. Wibaut and Gulje, ibid. , 54, 330 (1951).
-71
ISOMERIZATION IN THE FLAVANOIDS
Reported by Jerome Gourse May 4, 1956
In the synthesis of flavones, demethylation is an essential
step and hydriodic acid is a favored reagent. No complications
were reported until 1930 when Wessely and Moser1 observed that
5,8,4' -trimethoxy-7-hydroxyflavone yielded 5,6,7, 4' -tetra-
hydroxyflavone on demethylation.
CH30
OCH3O
OCH3
OH 0
Wessely and Kallab1 confirmed this isomerization by using
the tetramethyl ether. This was also found to be true in the
case of the 8-methoxy-5,7-dihydroxy2 and the 5,7,8-trimethoxy
compounds. Sastri and Seshadri3 proved that the resultant
5,6,7-trihydroxy compounds do not undergo this isomerization
and are therefore the stable forms.
A similar observation was made by Baker4 in the demethyla^
tion of the 5,8-dihydroxy series of flavones yielding the
corresponding 5,6-dihydroxy flavones.
In the above cases, there is no substitution in the
3-position. None of the flavanols (3-hydroxy compounds) with
the 5,7,8 arrangement of hydroxy groups have been known to
isomerize except under drastic demethylation conditions.
Studying appropriate isoflavones, it has been shown5 that a
phenyl group in the 3-position also inhibits this change. A
methyl group does not seem to prevent this isomerization6,
Mukerjee, Seshadri and Varadarajan7 have proposed the
following mechanism for this reaction:
/y^/ co
V^
CH
CO
/
-?2-
The presence of hydroxyl or phenyl groups in the 3-position
seems to inhibit ring opening. This is attributed to their
ability to reduce the electrophilic character of the 2-position.
Gallagher8 has shown a similar rearrangement involving the
2 ' -hydroxy compounds .
/?W
Hr
R" 0
A similar isomerization is found in 8- and 6-methyl-
chromones, flavones, and flavanols. In these cases the
6-methyl compound is isomerized to the 8-methyl compounds. 7 ' 10
CH30 . 0 CH3
CH30'
^
ht
ch3
HO i 0 CH3
OR 0
In this case also, the presence of a phenyl group in the
3-position, inhibits the isomerization.
In the furanochrome series, an isomerization has been
found that involves the rearrangement of the furan ring.9
Hr
MeOH
,0 CH3
v
These isomerizations have been of great assistance in
synthesizing the compounds resulting from the rearrangements.
In view of the relative ease of preparation of the 5,7,8-
trimethoxy compounds, their conversion to the 5,6,7-trihydroxy
compounds offers a distinct advantage over direct synthesis
of the latter.
-73-
Another type cf rearrangement has been utilized in the
synthesis of flavanones and flavanols. In certain cases 2-
benzylidene coumaran-3-ones (aurones) can be treated with
alcoholic potassium cyanide to give flavanones.12
OCH<
OCH:
These same compounds, when treated with alkaline hydrogen
peroxide, yield a mixture of flavanols as well as the aurome
epoxides.13
Not only has isomer! zation been brought about in acid
solution but also in basic solution. It has been reported14
that when 5-hydroxy-7,8-dimethoxy-isoflavone is boiled with
2% absolute alcoholic potassium hydroxide for 15 minutes,
the isomeric 5-hydroxy-6,7-dimethoxy isoflavone is produced
in 60<?o yield.
OCH3
CH3O
CH3O
CHaO^A^
OH 0
r <:
BIBLIOGRAPHY
1. S. K. Mukerjee and T. R. Seshadri, Chem. and Ind., 271
March (1955).
2. R. C. Shah, C. R. Mehta and T. S. Wheeler, J .Chem.Soc . ,
1555 (1938).
3- V. D. N. Sastri and T. R. Seshadri, Proc .Ind. Acad. Sci. ,
24a, 243 (1946).
4. W. Baker, J. Chem.Soc, 1922 (1939).
5. S. K. Mukerjee et.al., Proc . Ind. Acad. Sci . , 35A, 46 (1952).
6. S. K. Mukerjee, T. R. Seshadri and S. Varadarajam, ibid. ,
35A, 82 (1952).
7- S. K. Mukerjee, T. R. Seshadri and S. Varadarajam, ibid. ,
37A, 127 (1953).
8. K. M. Gallagher, A. L. Hughes, M. D'Donnell, E. M. Philbin
and T. S. Wheeler, J. Chem.Soc, 3770 (1953).
9. J- R. Clarke, G. Glaser and A. Robertson, J. Chem.Soc,
2260 (19^8).
10. W. B. Whalley, Chem. and Ind., 1230 (1954).
11. K. V. Rao, T. R. Seshadri and N. Viswanadham, Proc Ind.
Acad, Sci., 2£A, 72 (1949).
12. D. M. Fitzgerald. E. M. Philbin and T. S. Wheeler, Chem.
and Ind., 130 (1952).
13. W. E. Pitzmaurice, W. I. 0' Sullivan, E. M. Philbin and
T. S. Wheeler, Chem. and Ind., 652 (1955).
14. V. B. Mahesh and T. R. Seshadri, J. Sci. Ind. Res., 14B,
671 (1955).
-74-
VITAMIN Bi2
Reported by L. R. Haefele May 11, 1956
The isolation of vitamin B12 from liver extracts by
Smith1'2 and Folkers3 in 1948 marked the beginning of a series
of investigations leading to the complete elucidation of the
structure of one of the most complex molecules known.
The vitamin is an odorless, tasteless, red, crystalline
compound with the rather formidable empirical formula
C63H90N14O14PC0. It is active in microgram quantities against
pernicious anemia and is a growth factor for several micro-
organisms .
Prom the beginning, there were indications that the
structure of Bx2 differs greatly from that of any other
substance known. Thus the discovery that the molecule contains
cobalt4'5 was somewhat surprising, since, although cobalt was
recognized as an essential trace element in nutrition, no
biochemical role had been assigned to it. Further, the cobalt
atom was found to be complexed with a cyanide ion6; until this
time, most cyano compounds had been considered to be highly
toxic .
A great deal of information concerning the structure of
the vitamin was obtained by a study of the products of acid
hydrolysis, which gave rise to large amounts of ammonia
(5-6 moles) and a red, acidic cobalt-containing gum, as well
as a number of other products, depending upon the conditions
employed.
Heating with 20 per-cent hydrochloric acid followed by
paper chromatography produced a compound which gave a purple
color with ninhydrin7. After some confusion7' 8, this was shown
to be D-l-amino-2-propanol9.
Hydrolysis of vitamin B12 with 6N hydrochloric acid at
150° for sixteen hours gave rise to a basic compound with a
characteristic ultraviolet spectrum, which suggested that it
might be a substituted benziminazole10"12. By degradation and
synthesis, it was shown to be 5,6-dimethylbenziminazole (I).
Milder conditions (6N hydrochloric acid at 100° for 48 hours)
led to the corresponding 1-a-D -ribofuranoside (II)13, while
IN acid at 100c for one hour gave the 3' -phosphate derivative
(III)14'15, the alternative 2' -phosphate structure being
eliminated by X-ray methods later on. The structures of II and
III were confirmed by degradation and synthesis.
Acid hydrolysis under still milder conditions, using
paper electrophoresis, led to the conclusion16 that the vitamin
contains at least four and probably six primary amide groups,
and also that the propanolamine residue was present as a
phosphate ester on the hydroxyl, and as an amide on the amino
end.
-75-
N H H
! H h J CH2OH
B12
6N HC1; 100°; 48 hrs.
CH3\An^
CH3
CH3-
II
CH20H
PO3H2
III
Spectroscopic studies17 showed that the benziminazole
ring is co-ordinated directly to the cobalt atom. This led to
the proposal9 of the partial structure IV for the vitamin.
6 H2NCO
LI CN
C38H54N4
Until late, in 195^, little was known about the nature of
the groups surrounding the cobalt atom. Some confusion re-
sulted when Karrer18 isolated succinic, methylsuccinic and
dimethylmalonic acids from permanganate oxidation of the red
gum obtained on acid hydrolysis of Bi2- He suggested that there
might be a terpene type of structure present in the molecule.
The first real break in this phase of the work came when
Todd19 was able to isolate a crystalline hexacarboxylic acid
from a red gum obtained by hydrolysis with 30 per-cent sodium
hydroxide at 150° for one hour.
-76-
Hodgkin and co-workers20 had begun X-ray studies on the
vitamin shortly after its discovery. They were able to confirm
the structure of the nucleotide portion of the molecule and
to place the phosphate definitely in the 3' -position of the
ribose. Furthermore, the structure about the cobalt seemed to
be similar to that of the porphyrins, but with one carbon
missing. This was so unusual that they were hesitant to accept
it. However, when this same pattern showed up on X ray analysis
of Todd's hexacarboxyiic acid, it appeared certain that the
atoms were, in fact, arranged in this way. Further refinements
in the procedure finally led to the placementof all of the
atoms in the molecule, giving the structure21 23 shown below.
The only part of the structure which was in the least doubtful
was the placement of the conjugated double bond system.
Todd has assigned this on the basis of both_the X-ray
data and on the results of chlorination studies22 24.
VITAMIN B12
CONH;
CH2
i
CH2 H CH CH3 CHsCONH2
H2NCOCH2
CH
CH2CH2CONH2
CH3
I
CH2CH2CONH2
HOCH2
-77-
BIBLIOGRAPHY
1. E. L. Smith and L. F. J. Parker, Biochem. J., 43, viii
(1948). —
2. E. L. Smith, Nature, 161, 638 (1948).
3- E. L. Rickes, N. G. Brink, p. R. Koniuszy, T. R. Wood and
K. Folkers, Science, 107, 936 (1948).
4. E. L. Smith, Nature, 152, 144 (1948).
5- E. L. Rickes, N. G. Brink, F. R. Koniuszy, T. R. Wood and
K. Folkers, Science, 108, 134 (1948).
6. N. G. Brink, F. A. Kuehl and K. Folkers, Science, 112,
354 (1950).
7- B. Ellis, V. Petrow and G. F. Snook, J. Pharm. Pharmacol.
1, 60, 950 (1949).
S' C28ley' B; Ellis and V. Petrow, J. Pharm. Pharmacol.,
2, 128 (1950).
9. D. E. Wolf, W. H. Jones, J. Valiant and K. Folkers, J. Am.
Chem. Soc, 72, 2820 (1950).
10. E. R. Holiday arid V. Petrow, J. Pharm. Pharmacol., 1, 734
11. G. R. Beaven, E. R. Holiday, E. A. Johnson, B. Ellis,
P. Mamalis V. Petrow and B. Sturgeon, J. Pharm. Pharmacol.,
A, 957 11949).
12 ' ?' ?^Brink and K- Folkers, J. Am. Chem. Soc, 71, 2951
13. N. G. Brink, F. W. Holly, C. H. Shunk, E. W. Peel J J
-,), ?ahii:L and K* Folkers, J. Am. Chem. Soc, 72, i860 (1950)
14. J. 0. Buchanin, A. W. Johnson, J. A. Mills~and A. R. Todd,
J. Chem. Soc, 2845 (1950). *«*«*,
15. E. A. Kaczka, D. Heyl, W. H. Jones and K. Folkers, J. Am
Chem. Soc, 74, 5549 (1952).
lo. J. B. Armatage, J. R. Cannon, A. W. Johnson, L. F. J. Parker
^hS'mJS^?' M' H* Sfcafford and A. R. Todd, J. Chem. Soc,
3o49 (1953).
17. G. R. Beaven, E. R. Holiday, A. W. Johnson, B. Ellis
l9 Y* JeJrovf and G* Cooley, J. Pharm. Pharmacol., 2, 733 (1950).
id. H. Schmid, A. Ebnother and P. Karrer, Helv., 367 65 (1953)
^V§\?2?^n' A* w' Johnson and A. R. Todd, Nature, 174,
iloo (195^).
C. Brink, D. C. Hodgkin, J. Lindsey, J. Pickworth, J. H.
Robertson and J. G. White, Nature, 174, 1169 (1954)
21. D. C. Hodgkin, J. Pickworth, J. H. Robertson, K. N. Trueblood
R. J. Prosen and J. G. White, Nature, 176, 325 (1955).
D. C. Hodgkin, A. W. Johnson and A. R. Todd, "Recent Work
on Naturally Occurring Nitrogen Heterocyclic Compounds",
(I955! Publication no' 3> The Chemical Society, London,
23. A. W. Johnson and A. R. Todd, Endeavor, 15, 29 (1956)
a 5°n£eh J' R' Cannon, A. W. Johnson, I. Sutherland and
A. R. Todd, Nature, 176, 328 (1955).
19
20
21
22
-78-
REACTIONS OF CYCLOOCTATETRAENE AND ITS DERIVATIVES
Reported by W. A. Remers May 11, 1956
Reactions of Cyclooctatetraene : In Diels-Alder reactions, cyclo-
octatetraene reacts as a diene in the form of its valence
tautomer, bicyclo (4.2.0) octa-2,4,7-triene, with maleic
anhydride or acrylic acid.1'12
r
M.A.
COOH
0
//
'J /
w
0
/£>y
COOH
Catalytic hydrogenation gives cyclooctane. No difference
in the reactivity of individual double bonds is observed.1
With lithium in liquid ammonia, 1,2- and 1 , 4-dilithium
salts are formed. The lithium atoms may be displaced by protons
to yield a mixture of cyclooctatrienes or may be displaced by
carbon dioxide to form a dicarboxylic acid.1'2
V
S
2Li
NH3
(liq.)
->
ROH
/
/
A
^~N
<N
+
CO:
COOH
->
(?)
COOH
A similar mixture of cyclooctatrienes is obtained with
sodium in liquid ammonia.3
Phenyllithium adds to give phenylcyclooctatetraene and the
mixture of cyclooctatrienes. An equivalent of lithium hydride
must be transferred from the initial adduct to a molecule of
cyclooctatetraene for this reaction to occur. Some phenyl-
cyclooctatriene is also formed.4
Addition reactions initiated by electrophilic attack
proceed with bridging and addition to the cyclobutene type double
bond. Chlorination,1'5 hydration,1 and reaction with mercuric
acetate1'6 are examples.
- i y
OAc
.CI
CI
N2CHCOOEt
OAc
^-4_
COOEt
CH2CHO
Reactions with peracids1 ' 7 or ethyl diazoacetate8 form
three membered ring derivatives with retention of the eight
membered ring.
With strong oxidizing agents, monosubstituted or para-
di -substituted benzene derivatives are formed
Aqueous
permanganate yields benzaldehyde and benzoic acid. Alkaline
hypochlorite yields terephthaldialdehyde, benzaldehyde, and
benzoic acid. Chromic acid yields terephthaldialdehyde and
terephthalic acid.
Chlorocyclooctatetraene, when heated in an inert
atmosphere, rearranges to cis-P-chlorostyrene5' 9 which is
thermodynamically more stable. Bromocyclooctatetraene reacts
with lithium to give cyclooctatetraenyl lithium, which reacts
with carbon dioxide to form cyclooctetraenecarboxylic acid.10
Reactions of Bicyclo (4.2.0) octadiene structures: Nucleophilic
substitution leads to several different types of structures.
With 7,8-dichlorobicyclo (4.2.0) octa-2,4-diene, the Wo
chlorine atoms may be replaced by acetate without change in the
ring system.1'11 Methanolysis, however, leads to ring opening
and formation of a,p-dimethoxyethylbenze ne.i Reaction of the
dichloro compound with sodium methoxide gives 2,4,6-cyclo-
heptatriene-1-carboxaldehyde dimethyl acetal.6
KOAc
2NaOCH3
CH(0CH3)s
OAc
OAc
Nal
Acetone
J\
vN
^ A
CHCH20CH3
0CH3
-80-
Elimination reactions initiated by nucleophilic attack
regenerate cyclooctatetraene structures by a reversal of the
bridging step. The dichloro compound gives chlorocyclooctatetra
ene when it reacts with phenyllithium, and cyclooctatetraene
when it reacts with sodium iodide in acetone.9
Reactions o
to BO- 100'
l,3,b-cyclo
(4.2.0) oct
may be demo
or ozonizat
acid. Dime
ene to give
Pyrolysis o
phthalate .
f Cyclooctatriene Structures: By heating briefly
a mobile equilibrium is established between
octatriene (85$) and its valence tautomer^ bicyclo
a-2,4-diene . 12 The presence of the bicyclic isomer
nstrated by hydrcgenation to bicyclo (4.2.0) octane
ion and peroxidation to cis-1 . 2- cyclobutanecarboxylic
thylacetylenedicarboxylate adds to 1,3,5-cyclooctatri
an adduct possessing the cyclobutane structure.
f the adduct gives cyclobutene and o -dimethyl
V
^ //
'/
C00CH3
i
C
Hi
c
v. C00CH3
V 'COOCH3
n
coocHa
coochs
coochs
1 , 3^5-cyclooctatriene-T-one, formed by the lithium
diethylamide catalyzed rearrangement of cyclooctatetraene
oxide,7'13 is also in equilibrium with a valence tautomer,
bicyclo (4.2.01 octa-2, 4-diene-7-one . About 5$ of the bicyclic
isomer is present.
\N
^/ *
0
.OEt
OEt
A S
V
p-Ts0H
^
y OEt
The reaction of 1, 3>5~-cyclooctatriene-7-one with maleic
anhydride gives an adduct with the cyclobutanone structure.
With ethyl orthoformate . l,3,5-cyclooctatriene-7-one forms a
ketal which splits out ethanol to form ethoxycyclooctatetraene
when heated with jD-toluenesulfonic acid.13
-31-
REFERENCES
1. Reppe, W., Schlicting, 0., Klager, K., and Toepel, T. ,
Ann., 560, 1 (1948).
2. Cope, A. C, Stevens, C. L. , and Hochstein, F. A., J. Am.
Chem. Soc, 72, 2510 (1950).
3. Craig, L. E. , Elfson, R. M., and Ressa, T. J., J. Am. Chem.
Soc, 75, 480 (1953).
4. Cope, A. C. and Kinter, M. R., J. Am. Chem. Soc, 72, 630
(1950).
5- Cope, A. C. and Burg, M. , J. Am. Chem. Soc, 74, 169 (1952)
6. Cope, A. C, Nelson, N. A., and Smith; D. S., J. Am. Chem.
Soc, 76, 1100 (1954).
7. Cope, A. C. and Tiffany, M. D. , J. Am. Chem. Soc, 4158
(1951).
8. Akiyoshi, S., and Matsuda, T. , J. Am. Chem. Soc, 77,
2476 (1955).
9. Benson, R. E. and Cairns, T. L. . J. Am. Chem. Soc, 72,
5355 (1950).
10. Cope, A. C, Burg, M. , aid Fen ton, S. V.r., J. Am. Chem. Soc,
74, 173 (1952).
11. Cope, A. C. and Herrick, E. C, J. Am. Chem. Soc, 72,
983 (1950).
12. Cope, A. C, Haven, A. C, Jr., Ramp, L. F. , and Trumbull,
E. R., J. Am. Chem. Soc, 74, 48?'6 (1952).
13- Cope, A. C., Schaeren, S. F., and Trumbull, E. R. , J. Am.
Chem. Soc, 76, 1096 (1954).
-82-
SOME ASPECTS OP THE MECH/.NISMS OF CATALYTIC
hydrogen; TION
Reported by C. K. Sauers May 18, 1956
Heterogeneous catalysis, of which hydrogenation is only
one example, contains such dissimilar transformations as the
Fischer-Tropsch synthesis, the Oxo process, catalytic dehydro-
genation, petroleum "cracking", the ortho-para hydrogen
conversion, and the Haber process for ammonia.1 Principles
derived from a study of the course of any one of these re-
actions have been generally applied to studies of them all and
correlations between them have been particularly useful in
attempts to understand their mechanisms. It should not be
thought, however, that the mechanisms are identical; in the
field of hydrogenation alone there are almost as many detailed
mechanisms as there are reactions which have been thoroughly
studied.2 For this reason, this abstract is concerned with the
elucidation of some general principles which will then be
applied to a few specific examples of the reduction of un-
saturated molecules.
Perhaps the most intriguing fact about hydrogenation is
the activity and selectivity of certain metals in promoting
the reaction. A large amount of research has been devoted to
the study of metals involved in hydrogenation reactions and the
results have led to a substantial increase in our understanding
of the processes involved.3 The overall process in the
hydrogenation of an olefin involves the breaking of a carbon-
carbon bond and of a hydrogen-hydrogen bond with the resultant
formation of two new carbon-hydrogen bonds. The cleavage
steps usually occur homolytically,3 but the energies required
to unpair the electrons in a carbon-carbon or hydrogen-hydrogen
bond are so large and the resulting radicals are so unstable
that some unique role in supplying this energy and in stabiliz-
ing the radical products must be performed by the catalyst.
It is known that metals of the transition group are capable
of adsorbing large amounts of hydrogen, deuterium and unsaturated
molecules by a process known as chemisorption, 4 and illustrated
below for ethylene and hydrogen: sri 6
H\ /-H
C=.C H_C C'—H
/~
Metal Surface
H — H
I ) f \( \ I
This process can continue to occur in this simple manner until
a monolayer of adsorbed molecules completely covers these metals
Thus the first step in a hydrogenation reaction is the formation
of radicals on the surface of the metal in such a manner that
these radicals are stable relative to free radicals.
-83-
Another characteristic which is demanded of these species is
that they be held weakly enough so that reaction may take place
and the products desorbed. This is necessary because new
molecules must occupy the surface sites in order for the reaction
to continue.
The ability of certain transition metals to function in
these processes of adsorption and desorption can be largely
explained in terms of the electronic structural theory of metals
advanced by Pauling.7 This theory proposes that the bonding
orbitals of the transition metals are hybrids of d, s, and p
atomic orbitals and that metallic and atomic orbitals of mainly
d character remain which gives these metals some of their
characteristic properties. Dowden8 and Dilke, Maxted, and Eley9
suggested that the high activity of catalysts depends upon
chemisorption involving the atomic d orbital. It was shown that
a change in the magnetic susceptibility of palladium occurs
upon adsorption of dimethyl sulfide.9 Beeck then supplied very
convincing evidence for such bonding of hydrogen and ethylene
to various metal surfaces. He showed that as the "percent d
character"7, of the metallic bonds was increased, the heats of
adsorption of both hydrogen and ethylene were decreased and
that the catalytic metals had both low heats of adsorption and
high amounts of "d character".10 This correlation leads to an
expected order of metal activity,
Rh > Pd > Pt > Ni / Pe > W~Cr— Ta,
which is in general agreement with the rates of hydrogenation
of ethylene over these metals.
Another correlation which is based on the geometric
arrangement of atoms in metal crystals can be made. This
relationship is not quite so basic because the geometry of
metals depends in turn on electronic factors. However a
consideration of geometry will enable us to understand why
only certain transition metals are particularly active catalysts
when all of them have the requisite "d character'.11 If an
olefin is chemisorbed on a metal surface, it has a carbon-carbon
bond distance close to 1.5^ 8 and the bond angles will try to
approximate 109° 28' . Since differences exist in the metal to
metal atom distances, various chemisorbed molecules will have
varying degrees of strain. On the 111 plance of nickel, the
atoms are 2.47 % apart and an olefin may be bonded so that
the C-C-Ni angle is 105° 28'. On the 110 plane some nickel
atoms are spaced J>.50 ft apart giving rise to a chemisorbed
ethylene C-C-Ni angle of 122° 57' which represents considerably
more strain. Hydrogenation proceeds faster on the 110 face
because for high activity adsorption must be both rapid and
weak. Figure I shows the results of applying this reasoning
to a series of transition metals.12
-84-
0
-1.0
Log k for
the Hydrog-
enation of
Ethylene -3«0
log (absolute/
cm /sec . )
-5.0
o W
oTa
o Cr
3-0 3-5 4.0
Interatomic distances 8
Figure 1
4.5
5-0
The catalytic hydrogenation of ethylene over nickel has
been extensively studied, yet there is still no general
agreement concerning the details of its mechanism.2 The initial
rate kinetics in the gas phase are usually reported to be
- dP = k [ H2 ] [ C2H4 ] °, though the
dT
ethylene exponent is sometimes slightly negative . s' 14 This
indicates that ethylene is adsorbed preferentially on the
catalyst surface. That addition does not occur in one step
has been demonstrated by much experimental evidence. It was
shown by Twigg that the infrared spectrum of ethanes obtained
by hydrogenation with a non-equilibrated mixture of H2 and D2
is identical to that obtained from an equilibrated mixture
containing H2, D2 and HD.15 If the reaction is interrupted
in the beginning stages, ethanes found have less than the
stoichemetric amount of deuterium.16
Thus the existence of half hydrogenated states has been
postulated. 2,ir These are of the nature CH3CH2--Ni. The
process for their formation is the most widely disputed detail
in the mechanism of ethylene hydrogenation, and many proposals,
all in some way supported by experimental evidence, have been
advanced. 13 Once they are formed, they supply a ready
explanation for the fact that in the deuteration of ethylene,
ethylenes and ethanes have been detected containing from 0 to 4
or 6 deuterium atoms. These half -hydrogenated states are
important in all the hydrogenations studied though their method
of formation may be different in each case.
In spite of these wide differences, some general principles
have evolved concerning olefin hydrogenations. The rates of
these reactions obey the following expression where E is the
energy of the desorption process, A is the Arrhenius frequency
factor, R is the ideal gas constant, and T is the absolute
temperature.3
-E/RT
Specific rate = A e
-35-
Increasing the olefin substitution decreases E but at the same
time decreases the effectiveness of collisions and thus decreases
A. These effects tend to cancel each other and lead to the
interesting result that the rates for addition to simple olefins
vary little with substitution.2
Acetylene hydrogenation presents an interesting case because
the expected half hydrogenated state can "rearrange" to a vinyl
radical. That this occurs is substantiated by the evidence of
polymers formed in many acetylene hydrogenations . 18
The hydrogenation of cyclopropane occurs in a somewhat
different manner from simple olefin hydrogenation.19 In this
case hydrogen atoms are preferentially adsorbed on the catalyst
and thus may react either one or two at a time with the
approaching gaseous cyclopropane. In cases where the reaction
involves addition of one atom of hydrogen the resulting
half-hydrogenated state can readily give rise to products con-
taining 0 to 8 deuterium atoms. Since hydrogen or deuterium
is preferentially adsorbed, the expected course rate law,
-sj£ = k [ C3H6] [ D2 ] ° is observed experimentally over
platinum from -18 to 200°.
In the catalytic hydrogenation of benzene and of aromatics
in general, the picture is again slightly different.20'21 A
consideration of two possible structures for a chemisorbed
benzene molecule,
'/ NS
H -^ AH
/- — \S~" x A and B
leads to the conclusion that B should be far more stable than
A, and the fact that no cyclohexene or cyclohexadiene is
detected at intermediate stages in the reaction, substantiates
this. Some attempts have been made to correlate metal surface
structure with catalytic activity in cyclohexane dehydrogenation
and benzene hydrogenation, but in the latter case these attempts
lead to conflicting reports in the literature.22
The study of more complicated molecules, which in general
seem to have simpler mechanisms, has led to further knowledge
concerning the stereochemistry of the reaction. There are many
examples of stereospecific hydrogenations, but only a few are
chosen for consideration here. Siegel has shown that hydrogena-
tion of methyl substituted cyclohexanones where methyl's
preference for the equatorial position controls the stereo-
chemistry in the starting material leads to addition from the
side where the non-bonded interactions between C3 and C5 of the
ring and the catalyst are at a minimum.23 If other effects
are equal, this principle is general for cyclohexanones.
Cholestanone gives a-cholestanol, while coprostanone leads to
P-coprostanol upon hydrogenation.24
-86-
Further evidence for stereospecificity is given in the
3-a- and B-cholesterol series. The a-derivative undergoes
hydrogenation from the top of the molecule giving the a-
coprostanol while 3-P-cholesterol gives B-cholestanol . 25
This evidence for high stereospecificity does not supply
proof that the mechanisms for these reactions are simple
additions. In at least one complex molecule, hydrogenation re-
actions employing deuterium have shown that the mechanism is
still complicated. To explain the fact that cholesteryl acetate
upon hydrogenation with deuterium in acetic acid-d over platinum
produces cholestanyl acetate with 2.55 D/mole, Pukishima has
postulated a migration of the point of attachment of the
chemisorbed molecule via a half hydrogenated state.26 This is
done by addition of a deuterium and loss of a hydrogen and
leads to the observed incorporation of the more than theoretical
amount of deuterium. Oxidation of various positions to carbonyl
groups and subsequent exchange has substantiated his hypothesis.
Though much work has been done on the mechanisms of
hydrogenation, the picture is still far from clear and even
more work remains to be done before a complete understanding of
these reactions at metal surfaces can be obtained.
BIBLIOGRAPHY
1. P. H. Emmett, (Editor), "Catalysis", Reinhold Publishing
Corporation, Vols. I, II, and III, New York, (1954-1955).
2. G. C. Bond, Quart. Rev., 8, 279 (1954).
3- B. M. W. Trapnell, ibid., 8, 4o4 (1954).
4. J. E. Lennard-Jones, Trans. Faraday Soc, 28, 333 (1932).
5. E. B. Maxted, J. Chem. Soc, 1990 (1949).
6. J. Sheridan, J. Chem. Soc, 373 (1944).
7. L. Pauling, Phys. Review, 54, 899 (1938); Proc Roy. Soc,
A, 1^6, 3^3 (1949).
8. D. A. Dowden, Research, 1, 239 (1948); J. Chem. Soc, 242
(1950).
9. M. H. Dilke, E. B. Maxted and D. D. Eley, Nature, l6l,
804 (1948).
10. 0. Beeck, Discuss. Faraday Soc, 8, 118 (1950).
11. J. H. Twigg and E. K. Rideal, Trans. Faraday Soc, 36, 533
(19^0).
12. 0. Beeck, Rev. Mod. Physics, 17, 6l (1945).
13* "Heterogeneous Catalysis", Discuss. Faraday Soc, 8, 3(1950)
14. N. Thon and H. A. Taylor, J. Am. Chem. Soc, 75, 2747 (1953)
D. D. Eley, Quart. Rev., 3, 209 (1949); T. Keii, J. Chem.
Phys., 22, 144 (1954).
15. J. H. Twigg, Discuss. Faraday Soc, 7, 152 (1950 ).
16. J. Turkevich, D. 0. Schissler and P. Irsa, J. Phys. Chem.,
55, 1078 (1951).
17. I. Horiuti and M. Polyani, Trans. Faraday Soc, 30, 1164
(1934). —
18. P. Sebatier and J. B. Senderens, Compt. rend., 128, 1173
(1899).
19. G. C. Bond and J. Turkevich, Trans. Faraday Soc, 50, 1335
(1954).
20. A. A. Balandin, Z. physikal . Chem., 2 B, 289 (1929); ibid.,
3 B, 167 (1929).
r*
-87-
21. B. M. W. Trapnell, "Advances in Catalysis", Academic Press,
vol. 3, New York, (1951).
22. J. H. Long, J. C. W. Frazer and E. Ott, J. Am. Chem. Soc . ,
56, 1101 (193*0; P. H. Emmett and N. Skau, J. Am. Chem.
Soc, 65, 1029 (1943); 0. Beeck and A. W. Ritchie, Discuss.
Faraday Soc, 8, 159 (1950).
23. S. Siegel, J. Am. Chem. Soc, 75, 1317 (1953).
24. L. Ruzicka, Helv. Chim. Acta., 19E, 90 (1936).
25. J. R. Lewis and C. W. Shoppee, Chem. and Ind. , 897 (1953);
E. B. Hershberg et.al., J. Am. Chem. Soc, 73, 1144 (1951).
26. D. K. Fukushima and T. F. Gallagher, J. Am. Chem. Soc,
77, 139 (1955).
*..*»
-88-
ORGANIC PEROXIDES
Reported by J . C. Little
May 18, 1956
Almost every type of organic compound has been subjected
to peroxidation. The valuable intermediates provided by organic
peroxides are receiving new and widespread attention. It is
worthwhile, therefore, to review these compounds as a class.
1. Peracids1
I. Preparation
A. RC02R' + H2O2
Low Temp. (H )
R'= -H or -COR
B. RCHO + 02 (or 02-03)
C. RC0C1 + H2O2
hV
■>
RCO3H
RCO3H
RCO3H
D. R2C=C=0 + H2O2
R2CHCO3H
E. RCO2BO2H2 + H202
F. (RC0)20 + NaB03
RCO3H
RCO3H
II. Reactions
A. Oxidation of Unsaturated Compounds
l) Epoxide (Oxirane) Formation;
RCO3H
no catalyst
-> ">C C<C
\0-
Perbenzoic, monoperphthalic and peracetic acids effect
epoxide formation under mild conditions in a convenient solvent
yields are high and product isolation is not difficult. The
peracid is usually made in situ; active oxygen is supplied by
hydrogen peroxide or molecular^oxygen (air) and the peracid
is consumed as it is formed.
Example2:
0
0CO3H
o^CH-CH-CH-CH3 CHC13,0°(8 hrs? J
•0
.0
A
,CH-CH— CH-CH3
Other examples: Ref. 3-9
-89-
2) Preparation of a-glycols:
">€=C
RCO3H
H
(+)
HO
Peracetic acid is by far the most popular means of effecting
this transformation. Again the procedure of producing the
peracid ijy situ is usual. Performic acid has been found to be
highly effective for isolated double bonds.10 A comparative
newcomer, peroxytrifluoroacetic acid, has been useful with
negatively substituted olefins.11'19'20
Examples
12.
£H3
OH OH
1) CH3C03H,25°
02
2) KOH
■=5.
CH:
02
Other examples, Ref. 1, 1J>
3) Miscellaneous:
Peracids also attack active aromatic double bonds to give
various oxidation products including quinones and ring-scission
acids.
Example
14
CH3CO3H
25c
,^\
->
y
C02H
NVVCH=CHC02H HCT^/
80$ io#
Peracid oxidation of a,P-unsaturated ketones gives vinyl
esters. The epoxide is probably not an intermediate in this
reaction.5
Example
15.
0
0CH=CH(J
CH«
CH3CO3H
0-CH=CHO-CCH3
-90-
B. Oxidation of Organic Sulfur Compounds
A very efficient and widely used application of organic
peracids is the oxidation of organic sulfides and mercaptans to
sulfoxides and sulfones. 1,ie
0 0
r— S— R' K5°§?L> r— 3— R' 5S2sJL.> R— S— R'
0
C. Oxidation of Amines and Azo Compounds
Amines are oxidized by peracids to nitroso, azo, azoxy
and nitro compounds.1
Example14:
NH2
^
CH3CO3H
NO;
0
t
-> 0 N=N 0 +
8%
n
The oxidation of azo compounds to azoxy compounds proceeds
in high yields. 1 ,17> ia A specific reagent in the conversion of
amines to nitro compounds is peroxytrifluoroacetic acid.19*20'21
This reagent also converts nitrosaraines to nitramines. 22
Example
21
CI
NH2
CI
^X^
CI
no2
Cl Jl CI
CF3C03H
v
CH2CI2, reflux
Cl
98?o
The oxidation of amines to amine oxides proceeds smoothly with
perbenzoic and monoperphthalic acids. 23>24 Certain N-alkyl-
arylamines, however, give o-hydroxy compounds in modest yields.25
D. Oxidation of Aldehydes
Aldehydes are oxidized to the corresponding acids in
good yields by peracids, with the exception that with phenolic
aldehydes , the aldehyde group is replaced by a phenolic
hydroxyl (Dakin Reaction) .26> 2V
Example
28.
CHO
CH3CO3H
60-70°
_.\
\\_0H
E. Oxidation of Ketones
Monoketones are in general not affected by peracids
although the Baeyer-Vil lager rearrangement wherein the ketone
is converted to an ester has been observed.29 Qui nones and
a-diketones are oxidized to the corresponding diacids.1 The
peroxidation of enol acetates has been utilized to prepare
a-hydroxy ketones from ketones in the steroid field.30
F. Oxidation of Organic Iodine Compounds
Peracetic acid oxidizes aryl iodides to iodoso acetates.1
The latter compounds are useful as oxidizing agents for certain
primary aromatic amines.31 If perbenzoic acid is used the
iodoxy compounds are obtained.1
Example32: I
CH3CO3H
CHCI3
->
AcO-I-OAc
y
G. Use of Peracids in Structure Determination
Peracids have been invaluable in the location of double
bonds, etc., in a molecule as well as in effecting desired
degradations under mild conditions.1
2. Peroxide Derivatives of Acids33
I. Preparation
A. RC0C1 + Na202
0
B. ArCHO + (R-C)20
H
C R— C— C0C1
R'-C— C0C1
+ Na202
0 Q
li it
R-C-00-C-R'
peranhydride
0 0
Op !! H
-l5 — ^ ArC-00-C-R
mixed peranhydride
H x>0
-> R— C C
R'-C C^
H ^0
Superoxide
V
-92-
ExampleJ*:
34 .
C0C1
Z \..coci
Na202
*
D. RCOC1 + R'02H
Hydroperoxide
->
/?
RCOOR '
Perester
3. Peroxide Derivatives of Aldehydes and Ketones33 ' 35
I. Preparation
^02H
=>C=0 M2. >
or 02
R2C
\
OH
Hydroxy hydroperoxide
R2C
X02H
Dihydroperoxide
y
0
-0
\,
R2C NCR2
N0H HO^
X
0
■0
R2C "CR2
X02H H0X
Dihydroxydialkylperoxide Hydroxyhydroperoxy-
dialkylperoxide
0 0
R2CT XCR2
x0 0'
R2C CR2
xo2h mi
Bis-hydroperoxy-
dialkylperoxide
Dialkyl-bis_-
peroxide
Nearly all of the above structure types have been reported
from the peroxidation of cyclohexanone under various
conditions.33'35
4. Peroxide Derivatives of Olefins and Other Hydrocarbons
I. Preparation or Formation36' 37>38
A. R-H + 02 W or heat ^ R02H
B.
>c=c — c
H
0;
? 1
>c=c
•c —
I or
02H
I.
H
-9>
Example39:
H^.02H
y\ — ch3
o2
dark, heat
CH3
O2
hzy
->
/^CH3
*02H
V1
It is generally agreed that the autoxidation of olefins
proceeds by initial attack on the allylic hydrogen.41 When
there is no allylic hydrogen, no autoxidation takes place in
the case of aliphatic olefins. Aromatic olefins such as stilbene
yield epoxides and glycol esters only after a peroxidation
catalyst is added.
C.
R
R
:C-R"
1
X
Ha02 or O2
R
>C-R"
R 02H
Example
40 .
(CH3)2C-C=C-C(CH3)2
OH
OH
H202
IP"
-> (CH3)2C-C=C-C(CH3)2
02H 02H
(80jS)
D.
42
>C=C
o3
->
>'%
\
0 0
/
E.
hzy
0
6
Transannular Peroxide
Molecular oxygen adds quite readily to conjugated dienes
to form peroxide bridges. Polynuclear aromatic hydrocarbons
and many steroid series have been investigated and shown to
form stable transannular peroxides.43-45
5. Other Reactions of Organic Peroxides
35
A. Reduction
R-O-O-R'
[H]
^
R-OH + R'-OH
Various reduction methods have been used and often
selective procedures can be found to yield cleavage or
preservation of the -0-0- bond.46'47
-94-
46.
Example*":
OH
X
z-
H2(Pd/c)
alcohol
4>
y\
Ha(Pt)
alcohol
■>
6
A.
B. Dehydration
-H20
->
R
R'
>S
C=0
Example
48
\,
H
02H
KOH
-*
\o^o
C. Rearrangement
RO-OH ^ RO or RO •
©
A Rearrangement
Examples:
1)49-si /f\_/^s
H02 \)2H
CI CI
Ac20,H2S04 nn s/~
or Pb(OAc)4 Vq
2)
52
NO-
CHC13
CI CI
OH
4)54 C9Hi9C02H 80-100° C9HieC02H + C9H19OH
H ~
50% efo
5)55 CH2=CH-CH2-S-CH2-CH=CH2 + t-Bu02H CH3°H \
0 50° ^
CH2=CH-CH2-S'-CH2-CH=CH2 (Quantitative )
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