70-14,050
KAUFFMAN, Karl Clinton, 1941- THE KINETICS OF BASE-CATALYZED ENOLIZATION OF 2-PHENYLCYCLOALKANONES AND CYCLOALKYL PHENYL KETONES.
The Ohio State University, Ph.D., 1969 Ch emis t ry , organi c
University Microfilms, Inc., Ann Arbor, Michigan
THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED THE KINETICS OF BASE-CATALYZED ENOLIZATION
OF 2-PHENYLCYCLOALKANONES AND CYCLOALKYL
PHENYL KETONES
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University
By
Karl Clinton Kauffman, B.S., M.S,
The Ohio State University 1969
Approved by
Adviser Department of Chemistry PLEASE NOTE:
Not original copy. Some pages have indistinct print. Filmed as received.
UNIVERSITY MICROFILMS ACKNOWLEDGMENTS
The author is deeply grateful to Dr. Harold
Shechter for the suggestion of this problem, his interest and guidance during the course of the investi gation, and for his assistance in the preparation of this manuscript.
Tho author wishes to express his appreciation to the Department of Chemistry of The Ohio State Uni versity for assistantship funds. He is deeply grateful to members of the staff for their cooperation, and to fellow graduate students for their help in numerous ways.
XX VITA
March 5, 1941 ...... Born, Dayton, Ohio
1 9 6 3 ...... B.S., University of Dayton Dayton, Ohio
1963-1966 ...... Teaching Assistant, Depart ment of Chemistry, The Ohio State University, Columbus, Ohio
1 9 6 6 ...... M.S., The Ohio State Univer sity, Columbus, Ohio
I 966-I969 ...... Research Assistant, Depart ment of Chemistry, The Ohio State University, Columbus, Ohio
PUBLICATIONS
H. W. Amburn, K. C. Kauffman, and H. Shechter, "Investi gation of Base-catalyzed Enolization of Cyclopropyl Ketones," J. Amer. Chem. S o c . , 91, 530 (I969).
XIX CONTENTS Page
ACKNOWLEDGMENTS ...... ii
VITA ...... iii
LIST OF T A B L E S ...... vi
LIST OF FIGURES ...... ix
I. STATEMENT OF RESEARCH ...... 1
II. HISTORICAL ...... 4
III. RESULTS AND DISCUSSION ...... 35 A. Bromination of 2-phenylcyclo- a l k a r . o n e s ...... 35
B. Deuterium exchange of cyeloallcyl phenyl ketones ...... 7I
C. Deuterium exchange of 2-phenyl- cycloalkanones ...... 98
IV. EXPERIMENTAL ...... IO6
Synthesis of 2-phenylcycloalkanones .... 106
General 1-Phenylcyclopentene 2-Phenylcyclopentanol 2-Phenylcyclopentanone semicarbazone 2-Phenylcyclopentanone 1-Phenylcyclohexene 2-Phenylcyclohexanone semicarbazone 2-Phenylcyclohcxanone Cinnamyl chloride Diethyl cinnamylmalonate Diethyl(3-bromo-3-phenylpropyl)malonate 2-Phenyleyclobutane-l,1-dicarboxylic acid 2-Phenylcyclobutanone semicarbazone 2-Phenylcyclobutanone iv CONTENTS (Continued)
Kinetics of bromination of 2-phenylcycloalkanones ...... 120
General Kinetics of bromination Bromination of 2-phenylcycloalkanones
Kinetics of deuterium exchange ...... 124
General Kinetics of deuterium exchange Deuterium exchange of cycloalkyl phenyl ketones Deuterium exchange of diisopropyl ketone Deuterium exchange of 2-phenylcyclo alkanones TABLES Table No. Page
1. Enol Content of Selected Ketones ...... 2.4.
2. Enol Contents of Cyclic K e t o n e s ...... %g
3. Effect of Solvent on Keto-enol Equilibrium of Ethyl Acetoacetate . . . 19
4 . Rates of Bromination of Alkyl Phenyl Ketones in 75% Acetic Acid— 0.5M Hydrochloric Acid at 2 5 ...... 20
5 . Acid-catalyzed Bromination of Cyclo- alkanones in 90^ Acetic Acid and Equilibria between Methylenecyclo- alkanes and 1-Methylcycloalkenes .... 21
6. Relative Rates of Bromination of Cyclo alkyl Phenyl Ketones in 90% Acetic A c i d ...... 23
7 . Bromination of 2-Phenylcycloalkanones in 90% Acetic Acid— 0.05M Hydrochloric Acid at 30° ...... 24
8. Rates of Enolization and Ionization Equilibrium Constants of Some Ketones. . 27
9 . Kinetic Acidities of Hydrocarbons Toward Cesium Cyclohexylamide at 50° ...... 29
10. The Effect of Cation on the Position of Enolate Equilibria ...... 3I
11. Base-catalyzed Rates of Deuterium Ex change of Cycloalkanones and Cycloalkyl Phenyl Ketones at 30 34
12. Data for Bromination of 2-Phenylcyclo- hexanone in Acetic Acid— Sodium Acetate at 30° ...... 38 vi TABLES (Continued)
Table No. Page
13. Effects of Sodium Acetate on the Kinetic Bromination of 2-Phenylcycloalkanones in Acetic acid at 3 0 ...... 4I
1 4 . Representative Data for Bromination of 2-Phenylcyclohexanone in 50^ Acetic Acid-0.5M Sodium Acetate at 45 .... 43
1 5. at 40° .... 45
1 6. at 30° .... 47
1 7 . Bromination of 2-Phenylcyclopentanone at 4 0 ...... 49
1 8 . at 3 0 ...... 51
19 . Representative Data for Bromination of 2-Phenylcyclopentanone in 50% Acetic Acid-0.5OM Sodium Acetate at 20 53
20. at 40° .55
21. at 30° 57
22. Representative Data for Bromination of 2-Phenylcyclobutanone in 50^ Acetic Acid-0.5OOH Sodium Acetate at 20° . . . 59
2 3 . Bromination of 2-Phenylcycloalkanones in 50% Acetic Acid-0.500K Sodium Acetate at Various Temperatures .... 6l
24 . Bromination of 2-Phenylcycloalkanones in 50% Aq. H0Ac-0.5M 0Ac“ Added .... 63
25. Deuterium Exchange of Cyclopropyl and Isopropyl Ketones in Dimethylformamide- Deuterium Oxide/Sodium Deuteroxide at 60° ...... 78
vii TABLES (Continued)
Table No. Ease
26. Deuterium Exchange of Cyclopropyl and Isopropyl Ketones in Dimethylformaniide- Deuterium oxide/Sodium Deuteroxide at 60° ...... 80
27. Représentât!'/e Data for Deuterium Exchange of Cycloalkyl Phenyl Ketones in 0.005M Sodium Deuteroxide/D„0- Diozane at 3 0 ...... 90
28. The Rate Constants and the Relative Rates of Deuterium Exchange of Cycloalkyl Phenyl Ketones in Dioxane-Deuterium ^ Oxide/O.OOSM Sodium Deuteroxide at 30 • 91
29. Base-Catalyzed Deuterium Exchange in Dioxane-Deuterium Oxide using ^ 0.006m Sodium Deuteroxide at 47•5 . . . 93
3 0 . Ratios of Base-Catalyzed Hydrogen Exchange of Cyclopropyl and Isopropyl Ketones in Methanol with Sodium M e t h o x i d e ...... 95
31. Deuterium Exchange of 2-Phenylcyclo- alkanones in 50% Deuteroacetic Acid- Deuterium Oxide-0.5M Sodium Acetate . . 103
n i x FIGURES Figure No. Page
1. Typical data for bromination of 2-phenyl- cyclohexanone in acetic acid-sodium acetate at 3 0 ...... 39
2. Bromination of 2-phenylcycloalkanones in 5OŸ0 acetic acid-sodium acetate at 30° ...... 42
3. Typical graph of kinetic data for 2-phenylcyclohexanone in 50^ acetic acid-0.5M sodium acetate at 45 .... 44
4 . at 40° .... 46
5. at 30° .... 48
6. Typical graph of kinetic data for 2-phenylcyclopentanone in S0% acetic acid-0.5M sodium acetate at 40 . . . . 50
7. at 30° . . . . 52
8. at 20 . . . . 84
9 . Typical graph of kinetic data for 2-phenylcyclobutanone in 50% acetic acid-0.5M sodium acetate at 40 . . . . 56
10. at 30° . . . . 58
11. at 20° .... 60 12. Bromination of 2-Phenylcycloalkanones in 50^ acetic acid-0.5M sodium a c e t a t e ...... 62
XX FIGURES (Continued)
Figure No. Page
13. The n.m.r..spectrum of diisopropyl k e t o n e ...... 75
14. The n.m.r. spectrum of dicyclopropyl k e t o n e ...... 76
15. The n.m.r. spectrum of isopropyl phenyl k e t o n e ...... 77
16. Plot of kinetic data for deuterium exchange of isopropyl phenyl ketone in dimethylformamide-deuterium oxide at 6 0 ° ...... 79
17. Plot of kinetic data for deuterium exchange of diisopropyl ketone in dimethylformamide-deuterium oxide at 60°
18. The n.m.r. spectrum of cyclopropyl phenyl ketone ...... 82
19. The n.m.r. spectrum of cyclobutyl phenyl ketone ...... 83
20. The n.m.r. spectrum of cyclopentyl phenyl ketone ...... 84
21. The n.m.r. spectrum of cyclohexyl phenyl ketone ...... 85
22. Typical plot of kinetic data for deuterium exchange of cyclobutyl phenyl ketone in dioxane-deuterium oxide-0.005M sodium deuteroxide at 30'' ...... 86
23. Typical plot of kinetic data for deuterium exchange of cyclopentyl phenyl ketone in dioxane-deuterium oxide-0.005M sodium deuteroxide at 3 0 ° ...... 87
X FIGURES (Continued)
Figure No. Page
24. Typical plot of kinetic data for deuterium exchange of cyclohexyl phenyl ketone in dioxane-deuterium oxidc-0.OO5M sodium deuteroxide at 3 0 ° ...... 88
25. Typical plot of kinetic data for deuterium exchange of isopropyl phenyl ketone in dioxane-deuterium oxide-0.005M sodium deuteroxide at 3 0 ° ...... 89
XI I. STATEMENT OF RESEARCH
Aldehydes and ketones having hydrogen atoms in
positions alpha to the carbonyl groups are isomerized to
enols by acids and converted to enolate ions by bases.
Such processes are among the most important known to
organic chemistry; however the theory of such processes
is subject to conjecture and has been developed primarily
in terms of electrical factors involving inductive and
hyperconjugative effects.
Recently studies of enolization of homologous
cyclic ketones have indicated that ring size leads to opposite or discontinuous ordering effects for the acid-
and base-catalyzed processes. Thus the relative rates of
acid-catalyzed bromination of homologous cycloalkanones
in 90% acetic acid— 0.05M hydrochloric acid at 30^ are: cyclobutanone, 1; cyclopentanone, ISO; cyclohexanone,
793; cycloheptanone, 101; and cyclooctanone, 603
Cg> Cg> Cy C^). The relative rates of base-catalyzed deuterium exchange of the cycloalkanones in dimethyl- formamide-triethylamine at 40° are: cyclobutanone, 290; cyclopentanone, 85; cyclohexanone, 12; and
1 2 cycloheptanone, 2.4 (C^> C^>C^>C^). The ordering of reactivities for acid-catalyzed enolization of the cyclo alkanones is interpretable on the basis of steric factors in transition states which are similar in structure to the intermediate enols; the base-catalyzed processes are presumed to be controlled by the s-character of the bond between the alpha carbon and the enolizable hydrogen atom.
It has been subsequently found in this laboratory that the relative rates of acid-catalyzed bromination of
2-phenylcycloalkanones in 90% acetic acid— 0.05M hydro chloric acid at 30° are: 2-phenylcyclobutanone, 1;
2-phenylcyclopentanone, 8.6; 2-phenylcyclohexanone, 5.6; and 2-phenylcycloheptanone, 1. The order of reactivity with respect to ring size in this system is 5> 6 >7 = 4; and this differs considerably from that for the cyclo alkanones. The ordering of reactivities of the 2-phenyl- cycloalkanones appears to involve steric factors differing somewhat from those of the cycloalkanones.
The present study is concerned with determination of the rates of base-catalyzed enolization of 2-phenyl cycloalkanones as followed by bromination in 50% acetic acid— 0.05M sodium acetate. The rates of enolization of 3
cyclopropyl phenyl ketone, dicyclopropyl ketone, iso
propyl phenyl ketone, and diisopropyl ketone were studied
by deuterium exchange in dioxane-deuterium oxide with
0.17M sodium deuteroxide catalyst. The results of the
latter investigation were in such disagreement with
earlier reports than an investigation of cyclopropyl
phenyl ketone and higher homologs was undertaken. The
rates of enolization of cycloalkyl phenyl ketones was
studied by base-catalyzed deuterium exchange in dioxane-
deuterium oxide with 0.005M sodium deuteroxide as catalyst.
The objectives of this study were to determine the
effects of ring size on reactivity, to evaluate further the effect of the s-character of the bond between a-carbon
and enolizable hydrogen and to elucidate the important
features of the transition states of these systems. II. HISTORICAL
Enolization.— Aldehydes and ketones bavin" hydrogen on carbon alpha to the carbonyl group are isomerized to enols (I) by acids and converted to enolate ions (ll) by bases. Such acid- and base-catalyzed processes have been of major interest in the development of structural,
^ O H ^0' =cC^ ^ c = c : I II synthetic, and physical-organic chemistry.
The mechanisms of acid- and base-catalyzed enoli zation of aldehydes and ketones have been extensively studied. The acid-catalyzed process is generally believed to involve rate-determining attack on the conjugate acid of the carbonyl compound by an environmental base as illus trated in Equations 1 and 2. Base-catalyzed enolization
0 "^OH h '*' + RCHgCR ---- RCHgCR (1) + R /fOH R / O H B + RCH^CR '^C = c (2) H// \ II '^R B"H + BTl'^
involves rate-controlling bimolecular attack on alpha
hydrogen of the aldehyde or ketone as in Equation 3.
0 R xO———HA 0 \ " HA / ,+ B: + RCH CR C — C ►•RCH=C + BH (3) /I \ H I R R I B - - H
Major evidence for the mechanisms proposed is derived from
kinetic data and from demonstration that in either the acid-
or base-catalyzed processes, the rates of halogénation,
deuteration, and racemization at asymmetrically substituted
a-carbon atoms are identical for any ketone.^ The mechanism
(l) (a) H. M. Dawson and M. S. Leslie, J. Chem. Soc., 9_5^ i860 (1909); (b) P. D. Bartlett, J. Amer. Chem. Soc., 967 (1934); (c) C. K. Ingold and C. L. Wilson, J. Chem. Soc., 773 (1934); (d) C. K. Ingold, S. K. Hsu, and C. L. Wilson, ibid., 78 (1938); (e) W. D. Walters and K. F. Bonhoeffer, Z. Physik. Chem., Al82, 265 (1938).
sequence involved for acid-catalyzed reaction of phenyl sec —butyl ketone is sho;m in Equations 4 and 5- The
observation that the measured rates of halogénation.
deuterium exchange and racemization are identical stems CH^CHg OH \ 2 H ,c - c C^H c . c / 6 5 slow' ir / \ CH, CII, V s
circii 0 II fast 2 CX-C-CJH_ + HX (4) 6 5 fast CII D,L
CH„CH
CD-C-C (5) 6 "5
CH,
o\ 7 from the fact that the carbonyl compound is converted to the intermediate enol in an initial rate-determining pro cess. In base-catalyzed operations, the reaction rates are also equal, since the carbonyl compound is converted to intermediate enolate ion in the rate-determining process.
More recently there has arisen some question as to 2 the validity of this mechanism in certain systems. Rappe
(2) C. Rappe, Acta Chem. Scand., 2^, 219 (1968). has recently reported that the rates and orientation of deuterium exchange of 2-butanone differ from those for bromination of the same ketone. The ratio of 3-halogena- tion to 1-halogenation (called ) was ft>und to be 2.7 in acid, 7.0-7.5 in buffer solution (pH=5-7), and zero in strongly basic solutions (pH> 12, haloform reaction).
Deuterium exchange in 2-butanone gives a ratio of 3-deutera- tion (called K^) equal to 2.5 in acid solution and 0.6-0.7 in all basic solutions (pH=5-14) . Rappe further reports that the bromination of 2-butanone is 30 times faster than iodination of the same ketone in acetate buffer solution and 4-5 times faster in solutions of sodium hydroxide.
Finally it is reported that upon bromination in deutero acetic acid, the bromine color is completely gone before 8 any deuterium cxoiiange occurs. Rappe proposed that deu terium exchange a- d halogénation go via the same mechanism in acidic solution, but that in bases, deuterium exchange goes through the enolate ion while halogénation proceeds through two different mechanisms, neither of which involves enolate ion. The precise mechanisms other than rate- determining enolization has not been offered however.
The effects of structure on the rates of enoliza tion of various related ketones have been studied. Acid- catalyzed enolization of acetophenones (Equation 6) is
0 CCH. _H ^ ’-=rT-T (G)
X m,p accelerated by electron-donating and retarded by electron- withdrawing meta or para substituents. The electrical effects are the opposite for base-catalyzed enolization of 3 the meta and para substituted acetophenones (Equation 7)•
C=CH (7)
X m,p
(3) (a) D.P. Evans, V. G. Morgan, and H. B. Watson, J. Chem. Soc., II67 (1935)j (B) V. G. Morgan and H. B. Watson, ibid., 1173 (1935). 9
These results indicate that the transition state for acid- catalyzed enolization is more electron-deficient than is the ground state, whereas for the base-catalyzed process the transition state is electron-rich relative to the ground state.
The products of acid- and base-catalyzed halogéna tion of unsymmetrical ketones usually differ. Halogénation of alkyl methyl ketones and cycloalkyl methyl ketones in acidic media generally occurs in alkyl and cycloalkyl rather than in methyl groups (Equation 8) and is the
Saytzeff type in that the more substituted enol is formed the more rapidly. Base-catalyzed halogénation of such
(4) (a) II. M. E. Cardwell and A. E. J. Kilner, J. Chem. Soc., 2430 (1951); (b) H. M. E. Cardwell, ibid., 2442 (1951). ketones takes place preferentially in the methyl group
(Equation 9).^^ The position of attack of alkyl methyl
0 + 0 RgCHCCHj RgCXCCHg (8)
0 _ 0 RgCHCCHg B ^ RgCHCCHgX (9) ^2 10
ketones by bases is analogous to that in Hofmann elimina
tion of quaternary ammonium compounds. The halogenated
products formed in the acid-catalyzed processes are consis
tent with initial formation of a reactive intermediate (ill)'
from a transition state in which positive charge is devel
oping on the a-carbon. Such a transition state would be
stabilized by electron-donating effects of the inductive
and hyperconjugative type. For the base-catalyzed process
halogénation will occur preferentially in methyl groups
on the basis that the electron-rich transition state leading
to IV^ will be formed more rapidly since centers of
(5) R. Breslow, "Organic Reaction Mechanisms," W. A. Benjamin, Inc., New York, N. Y,, 1965.
carbanionic character are usually generated preferentially 6 at the least substituted carbon atom.
IOH 0 ------'C - CHj] [RgCHCCHg ^
III IV
(6) D. J. Cram, "Fundamentals of Carbanion Chemistry," Academic Press, Inc., New York, N. Y., 1965, p. 21. 11 7 Bell and Lidwell have studied the catalytic con-
(7) P. Bell and 0. M. Lidwell, Proc. Roy. Soc. [A], 176, 88 (1940).
stants for iodination of acetone and some halogenated
acetones. As bases, hydroxides and salts of carboxylic
acids (e.g. acetate, trimethylacetate, chloroacetate,
and glycolate) were used. In a Br^nsted plot it was
found that the catalytic constants for the weak bases give
a straight line, while constants for hydroxide were three to four powers of ten too small. They interpret the reac- 2 tions as general base-catalyzed. Rappe suggests, however, that the data are consistent with the operation of two different base-catalyzed mechanisms, but does not elaborate.
Additional information concerning the mechanisms g of enolization has been provided by Swain et al. The
(8)(a) C. G. Swain, E. C. Stivers, J. F. Reuwer, Jr., and L. J. Schaad, J. Amer. Chem. Soc., 5885 (1958); (b) C. G. Swain, A. J. DiMilo, and J. P. Cordner, ibid., 80 , 5983 (1958); (c) C. G. Swain and A. S. Rosenberg, ibid., 83, 2154 (1961); (d) C. G. Swain, ibid., 72, 4578 (1950). first-order rate constant for enolization of acetone in acetic acid buffers in water solution at 25° has the form 12
A kinetic argument based on the relative magnitudes of the
experimental catalytic coefficients ( , k^^ ..... , k^) was
presented^^ to show that catalysis of enolization by acetic 4“ acid was probably due primarily to hydronium ion (II^O )
and acetate ion (OAc ) .
Two possible mechanisms involving hydronium ion
and acetate ion exist; either one-step (concerted.
Equation 10),
+ I I _ 11 , , H O +0=C-C-H+ AcO HO + HO - C = C + HOAc (lO) 3 1 I or two-step (Equations 11 and 12).
H^O"^ + 0 = C- C- H H„0 + lÆ = C - C - H (ll) 3 I ^ 1
— I I ~ I 1 HÔ=C-Ç-H+ OAc sloi^ HO - C = Ç + HOAc (12)
The experimentally determined isotope effect is in accord with the value calculated assuming the operation of a two- step mechanism.
The timing of the proton transfer in enolization has been elucidated from isotope effects.It was initially proposed that when stronger bases effect enoli zation, the proton is not tightly bound to the a-carbon in the transition state and completion of bond formation between the attacking base and the a-hydrogen is slight. 13
The main role of the base was presumed to involve repul sion of the electron pair toward a-carbon (Equation 13)•
0 = C - C ; H + :B -^[O = C - C: H :B] 0 - C = c( (13) ' ' -rBII 8 c In later work the degree of bond breaking during the hydrogen transfer is proposed to be somewhat different. Calculations of expected isotope effects in cases where enolizable hydrogen is not transferred, half transferred and completely transferred to solvent are reported. The observed isotope effects seem to corres pond to a transition state ranging from close to symmetri cal for strong catalysts (H^O^ or OH ) or reactive substrates to one close to products (enol or enolate ion) without catalysis or with less reactive substrates. The identity of the reacting species is as postulated previous ly, (i.e., as in Equations 11 and 12).
Stabilities of enols.— The equilibrium stabilities of enols and enolate ions relative to their parent car bonyl compounds have been determined for various ketones.
The thermodynamic factors involved in such systems are of interest in interpretation of kinetic data for enolization with the structures (and the stabilities) of the rate- controlling transition states are similar to those of the enols or enolates. 14
Table 1 lists the enol content of several ketones
in the absence of solvents. Cyclohexanone is much more
enolic than is acetone. This is true chiefly because
TABLE 1 ENOL CONTENT OF SELECTED KETONES
Compound Enol, % Compound Enol, %
CHjCOCHg 0.0025 CHgCOCHfCHgïCOCHj 33.0
0 . 20 CII^COCOCI-L 0.0056 O- 3 CHgCOCHgCOCH 80.0 C ÿ " 100
PhCOCHgCOCH 99.0 95.0
enolization of acetone involves extensive loss of freedom of rotation when a carbon-carbon single bond becomes rigidly double-bonded (Equation 14); on the other hand, cyclohexanone is relatively rigid and thus the relative loss in rotational freedom is less on enolization (the entropy change is more favorable. Equation 15). 15 0 OH CH C - CII^ — 3, dig = C - CHg (14)
0 OH oil 0-0 (15)
A second thermodynamic factor involved in enoliza tion is illustrated by comparison of biacetyl and 1,2-cyclo- hexanedione. In biacetyl the two carbonyl groups are trans oriented to minimize dipole-dipole repulsion;
0 A II CH I . e .
Y ”3 0"1 however in the cyclic diketone, the carbonyl groups are held so that repulsion is strong. Enolization helps re lieve cis dipole opposition; therefore, 1,2-cyclohexane- dione is more completely enolized.
Extended conjugation may be a principal factor in enolization of ketones. Thus benzoylacetone is more highly enolized than is acetylacetone.
0 OH 0 OH CHgCCH^CCHj (T jyC-CH =CCH
80% enol 99% enol 16
Hydrogen bonding affects the stability of enols.
Thus the enol of acetylacetone may be stabilized by intra molecular hydrogen bonding as illustrated by Equation l6.
s ? CH.CCH.CCH, ---- *. CH^-C C-CH^ (l6) 0^6 a ^ / 3 CH
Intramolecular hydrogen bonding is not required for enolization however, since 1,3-cyclohexanediones are almost completely enolic; in such cases conjugation in the enol and restricted rotation in the ketone allow the extensive enolization.
Atoms forming an effectively conjugated system should lie in or near a common plane. Therefore any structural feature which hinders coplanarity of the enol will repress enolization. Thus a methyl group in the
3-position of acetylacetone diminishes enolization by over S0%.
Ring size also affects keto-enol equilibrium. It might be anticipated that a smaller ring would accept the double bond of an enol less readily since rehybridization 2 of the a-carbon atom of a cyclic ketone to sp introduces extensive bond angle strain in the rest of the ring.
Cyclopropanone should therefore have a very small enol content as is presumably the case. For cyclobutanone 17 2 the strain of introducing a second sp center in the ring would be less than for cyclopropanone, and so the equi librium should lie somewhat more toward enol. If indeed angle strain effects are controlling, cyclopentanone should contain still more enol, and cyclohexanone, in 2 which there is still less angle strain in going to sp hybridization about o(-carbon, should favor enol even more.
The enol contents of cycloalkanones are 9 shown in Table 2. There is alternation in which a
(9) A. Gero, J. Org. Chem. , 3156 (196I) . cyclic ketone having an even number of carbon atoms con tains more enol than the odd-ring ketone either above or below it in the series. Within the even- or odd-ring series, however, there is a tendency toward less enol in the smaller rings, consistent with increased ring strain in the enols. The alternation is presumed by Gero to be caused by "some factor by which both ends of a chain of an even number of carbon atoms are attached to a double bond. This situation is realized only by the keto form in an odd-carbon ring, and by the enol form in an even-carbon ring." 18
TABLE 2
ENOL CONTENTS OF CYCLIC KETONES
Ketone Enol. content, %
Cyclobutanone 0.55
Cyclopentanone 0.09
Cyclohexanone 1.18
Cycloheptanone 0.56
Cyclooctanone 9.3
Cyclononanone 4.0
Cyclodecanone 6.1
The results of Schwarzenbach and Wittmer^^ are
(lO) G. Schwarzenbach and C. V/ittmer, Helv. Chim. Acta, 30, 656, 669 (1947). only in fair agreement with those of Gero. They report that in water, the percentage enol content of cyclo- hexanone (20 x 10 ) is greater than that from cyclo pentanone (4.8 X 10 ^) . Results in disagreement with those previously summarized and certainly with present 11 strain theory were reported by Bell and Smith, who
(11) R. P. Bell and P. W. Smith, J.Chem. Soc., 241 (1966). 19
found the enol content for cyclopentanone to be
1.3 X 10 and O.4I x 10 for cyclohexanone.
Since the keto form of a diketone or ketoestcr
is invariably more polar than their enols, the enol:keto
ratio for a given pair of tautomers at equilibrium in
solution is greater in the least polar solvents. Data 12 for acetoacetic ester are tabulated below.
(12) , E. S. Gould, "Mechanism and Structure in Organic Chemistry," HoDt, Rinehart and Winstein, New York, N. Y . , 1959, p. 380.
TABLE 3
EFFECT OF SOLVENT ON KETO-ENOL EQUILIBRIUM OF ETHYL ACETOACETATE
Solvent HOAc Eton Benzene Hexane (Neat) H 2O
% Enol 0.4 5.7 10.5 16.2 46.4 7.7
There appears to be an approximate parallel be tween the expected equilibrium conversion of a ketone to
its enol and the rate of its acid-catalyzed enolization.
The rates of bromination of various alkyl phenyl ketones in 75% acetic acid— 0.5M hydrochloric acid at 25°
(Table 4) are generally those expected on the basis of 20
TABLE 4
RATES OF BROMINATION OF ALKYL PHENYL KETONES IN ACETIC ACID— 0.5M HYDROCHLORIC ACID AT 25°
Compound k (sec.
0 PhC-CHj 0.241
-CH2C 113 0.104
-CH2CH2CH3 0.0721
-Cn^CH^CH^CHj 0.0851
-CH 0.0213 -CK 3
-CH 0.0325
^ C H 2CH3
structural factors in the parent ketones and their 13 corresponding enols. Sterically larger groups hinder
(13) D. P. Evans, J. Chem. Soc., 1434 (1938). coplanarity in the enol. Therefore, in systems in which the transition state resembles enol, the activation energy for ketones branched in alpha positions will be relatively large and reaction rate correspondingly slower. 21
Acid-catalyzed enolization.— With the exception of cyclopentanone and cyclohexanone, the rates of acid- catalyzed enolization of cycloalkanones roughly parallel the free energy differences for the equilibria between methylenecycloalkanes and 1-methylcycloalkenes (Table 5)^^
(14) (a) H. Shechter, M. J. Collis, R. Dessy, Y. Okuzumi, and A. Chen, J. Amer. Chem. Soc., 8^, 2905 (1961); (b) A. C. Cope, D. Ambros, E. Ciganek, C. F. Howell, and Z. Jacura, ibid., 82, 1750 (I96O); (c) E. Gil-Av and J. Herling, Tet. Let., 27 (1961) (d) R. B. Turner, J. Amer. Chem. Soc., 1424 (1958).
TABLE 5
ACID-CATALYZED BROMINATION OF CYCLOALKANONES IN 90% ACETIC ACID AND EQUILIBRIA BETWEEN METHYLENE CYCLOALKANES AND 1-METHYLCYCLOALKENES
Relative A ir A S'”' Ketone rates (30°) Kcal/mole e.u. A F-
Cyclobutanone 1 - 1.05
Cyclopentanone 150 20.4 -10.1 -4.17
Cyclohexanone 793 20.1 -7.8 - 3.24
Cycloheptanone 101 20.2 -11.7 . -2.55
Cyclooctanone 603 - 3.79
— A F for the process; ^^^2 ^^3 22
There is, however, correlation between the enol contents of cyclopentanone and cyclohexanone in water according to Schwarzenbach and V/ittmer and the rates of their acid- catalyzed enolizations.
The failure in correlation of enolization of five- and six-membered ketones with the equilibria of the methylenecycloalkanes and 1-methylcycloalkcncs is 14a attributed to possible differences in solvation energies for the enolizations and for the isomerizations as follows:
"On the supposition that the interactions of a solvent are greater for the ketones than for the enols whereas those for the mcthylene- cycloalkanes and 1-nethylcycloalkcnes are similar, it is possible that cyclopentanone will be solvent stabilized relative to cyclo hexanone because of its greater dipole moment, rigidity and more favorable stereochemistry. The relatively greater ground state energy of cyclohexanone than of cyclopentanone in such an environment may thus be expressed in the enolization rates."
The relative rates of acid-catalyzed enolization of cycloalkyl phenyl ketones in 90^ acetic acid at 29.9 3-4 cl are listed in Table 6. The result of particular interest is that the rate of acid-catalyzed enolization of cyclobutyl phenyl ketone is much greater than that of cyclohexyl phenyl ketone and only slightly less than that of cyclopentyl phenyl ketone. It is to be expected 23
TABLE 6
RELATIVE RATES OF BROMINATION OF CYCLOALKYL PIIEKYL KETONES IN 90% ACETIC ACID
Ketone Relative rate at 29.9°
Cyclopropyl phenyl ketone 1
Cyclobutyl phenyl ketone 31.2
Cyclopentyl phenyl ketone 60.5
Cyclohexyl phenyl ketone 4.28 that because of angle strain, a four-membered ring which is tetragonally substituted will resist conversion to its trigonally related enol, V. The relatively rapid rate of enolization of cyclobutyl phenyl ketone may re sult from smaller cis steric effects in the transition state related to V and VI, and thus there is relatively large conjugative interaction of the benzal and cyclo- butylidene groups with the developing carbon-carbon double bond. Additional effects which may be expressed
Ph OH Ph OH Ph OH Ph OH A V VI VII VIII 24 in the reactivity of cyclobutyl phenyl ketone are the removal of 1,2-non-bonded interactions on enolization and the relatively minimal steric restriction to solva tion during the reaction. The relative inability of cyclopropyl phenyl ketone to undergo enolization is interpretable in terms of the large strain and re hybridization energies involved in the formation of the transition state of the related enol VIII, in which a double bond is exo to a three-membered ring.
Relative reactivities and thermodynamic data for acid-catalyzed enolization of 2-phenylcycloalkanones in
90% acetic acid— 0.05M hydrochloric acid are summarized in Table 7.^^
(15) H. Shechter and T. Sulzberg, unpublished results.
TABLE 7 BROMINATION OF 2-PHENYLCYCLOALKANONES IN 90% ACETIC ACID— 0. GSM HYDROCHLORIC ACID AT 30°
Ketone RGl- rate ( T u . )
2-Phenyleyclobutanone 1.0 17.3 -16.8
2-Phenylcyclopentanone 8.6l 15.6 -21.1
2-Phenylcyclohexanone 5.63 18.5 -20.2
2-Phenylcycloheptanone 1.04 15.3 -16.9 25
The relative ordering of rates of enolization of the 2-phenylcycloalkanones with varying ring size is
5^ 6> 7 = 4. These results are different than those for cycloalkanones (6> 5 = 7 ^ 4)• It is of interest that the rates of enolization of 2-phenylcyclohexanone and
2-phenylcycloheptanone are only 3.8 and 5.5 times as great as for cyclohexanone and cycloheptanone on a comparable statistical basis; whereas the relative rates of enolization of 2-phenylcyclobutanone and 2-phenylcyclo- pentanone are 534 and 30 times greater, respectively, than for cyclobutanone and cyclopentanone. There is thus a relatively large increase in rate of enolization of
2-phenylcyclobutanone as compared to cyclobutanone but yet the absolute rate of enolization of 2-phenylcyclo butanone is less than those of its five- and six-membered homologs. It is apparent that the relatively accelerated rate of enolization of 2-phenylcyclobutanone stems from the extensive and possibly coplanar hybridization of the phenyl group in a transition state close to that of
2-phenyl-l-cyclobutenol (IX); even with the contribution of the phenyl group, such a transition state is apparently greater in energy than that of its cyclopentanone and cyclohexanone analogs because of the angle strain 26 involved in the di-trigonally substituted four-membered ring enol (IX).
on GIT I n u I PH
< y XII
The fact that 2-phenylcjcLopentanone undergoes acid-catalyzed enolization more rapidly than does
2-phenylcyclohexanone, whereas the opposite order is the case for cyclopentanone and cyclohexanone, indi cates that an additional feature is imposed upon
2-phenylcyclopentanone and 2-phenylcyclohexanone other than steric factors associated with usual exo and endo effects in five- and six-membered rings. It is possible that 2-phenylcyclopentanone enolizes more rapidly than does 2-phenylcyclohexanone because of less cis inter action of the phenyl group with the enol function in the transition state leading to the enol X than for the six- membered homolog (Xl). Because of the wider angles about the external bonds of the unsaturated center in
X than in XI, it . is anticipated that there will be greater near-planar participation of the phenyl group in stabilization of the transition state related to
2-phenyl-l-cyclopentenol (X) than for 27
2-phenyl-l-cyclohexanol (XI). The relative retardation
of 2-phenylcycloheptanone may also be related to cis
eclipsing factors of the phenyl and hydroxyl groups in
the transition state leading to XII.
Stability of enolate ions.— Data are available
(Table 8) in certain systems which allow correlation of
the rates of base-catalyzed enolization with equilibrium
stability of enolate ions as expressed by values.^
In general factors which stabilize the enolate ion
(extended conjugation, coplanarity, or the presence of electron-attracting groups) lower the energy of a transi tion state in which the a-proton is being removed.
TABLE 8 RATES OF ENOLIZATION AND IONIZATION EQUILIBRIUM CONSTANTS OF SOME KETONES
Compound k (sec."l)A %a-
CHjCOCHj 4.7 X 10"^° 10-20
CH COCHgCl 5.5 X 10"G 3 X 10-^7
CHgCOCHClg 7.3 X 10"? 10-^5
R H i— r " + h o '*'; K = -pi - Î Ç - 3 " “2
The ketones in Table 8 enolize more rapidly as chlorine is introduced into alpha positions. The 28
corresponding enolate ions of the haloketones also have
increased stability as measured by the equilibrium con
stants. The greater stabilities of chlorinated ketones
are probably due to the inductive effect of chlorine; this effect carries over into the rate of ionization in which the transition state resembles the enolate ion
(Equation 17)• os’ 0 ll
(17) A— 0H_ + H 3O
The acidity of a C-H bond is also affected by hybridization. Hydrogens in acetylene, in which carbon is sp-hybridized, are much more acidic than those of 2 ethylene, which has sp -hybridized carbons. Ethylene in turn is a stronger acid than ethane, in which the 3 carbon atoms are sp -hybridized. Hybridization coeffici ents have been calculated^^ for these hydrocarbons and
(16) C. A. Coulson and W. E. Moffitt, Phil. Mag., 40, 1 (1949). others, including some cycloalkanes. This coefficient reflects the s-character of the carbon orbital directed toward hydrogen and thus in part expresses the ionic 29
character of the C-H bond; acetylene, 1.36; ethylene,
I.4I; ethane, 1.73; cyclopropane, 1.51; cyclobutane, 1.67;
and cyclopentane, 1.73* The s-character of the hydrogens
in cycloalkanes will thus vary as a function of ring size
in the order 3^ 4^ 5.
Very recently the acidities of homologous cyclo
alkanes were determined kinetically by measurement of
tritium incorporation from N-tritiated cyclohexylamine 17 as catalyzed by cesium cyclohexylamide. These acidi ties are tabulated below (Table 9).
(17) A. Streitwieser, Jr., R. A. Caldwell, and W. R. Young, J. Amer. Chem. Soc., 91, 529 (1969).
TABLE 9 KINETIC ACIDITIES OF HYDROCARBONS TOWARD CESIUM CYCLOHEXYLAMIDE AT 50°
Hydrocarbon Relative rate J(^^C-H)
Cyclopropane (7.0 - 0.9) x 10^ I6I
Cyclobutane 28 - 10 134
Cyclopentane 5.72 ~ 0.27 128
Cyclohexane 1.00 124
Cycloheptane O .76 - 0.09 123 + Cyclooctane O .64 - O.O6 122 30
As suggested above, it is known that in smaller rings, the strain introduced by forcing carbon-carbon bonds to be at smaller than tetrahedral angles may be relieved by rehybridization of the orbitals about carbon such that the carbon-carbon bonds assume more p-character and the exocyclic C-H bonds necessarily have greater s-character. The more s-character in a C-H bond, the greater is the acidity of that bond. Cyclopropane, the most strained monocyclic hydrocarbon, should thus have the most acidic hydrogen. This is in fact observed in
Table 9. Further, the larger the ring becomes, the less acidic is the hydrocarbon; 3 > » 4 » 5> 6? 7— 8. 13 Values of the coupling constants j( C-H) have 18 been shown by Larrabee and Closs to give a quantitative
(18) G. L. Closs and R. B. Larrabee, Tet. Let., 287 (1965). correlation when plotted against the kinetic acidities of bicyclobutane and cyclopropane derivatives. A similar correlation was found by Streitwieser for the cycloalkanes in Table 9. This correlation is taken to indicate that the dominant factor in cycloalkane acidity is the amount of s-character in the exocyclic C-H bond. 31
The solvated cation associated with an enolate ion influences the equilibrium stability of the enolate.
Lithiiun enolates favor the less highly substituted enol ate more than do the corresponding sodium or potassium enolates (Table 10).^^ Since the bond from oxygen to
(19) II. 0. House and V. Kramar, J. Org. Chem., 28, 3362 (1963).
TABLE 10 THE EFFECT OF THE CATION ON THE POSITION OF ENOLATE EQUILIBRIA
Position of equilibrium, % by Ketone Cation D^O quenching experiments
9" 9- Me^CH-C=CHMe Me2C=C-CH2Me
Me.CHCOCHgMe K 90 10
Na 82 18
Li 98 2
9- 9" nBu—CH2~C—CHg nBu-CH=C-CH2 nBu-CHgCOCHg K 58 42
Li 88 12
lithium is more covalent than those to sodium or potassium, the lithium cation with its solvent environment might be expected to have the greatest steric bulk, and so favor 32
formation of the less highly substituted enolates. 20 Malhotra and Johnson have calculated the strain energy
(20) S, K. Malhotra and F . Johnson, J. Amer. Chem. Soc., 87, 5513 (1965).
for interaction between the solvated ion pair an an ad jacent quasi-equatorial substituent in the enolate of
2,6-dimethylcyclohexanone.The solvent shell surround ing the oxygen-metal moiety in enolates XIV-XIII is presumed to interact sterically with the quasi-equatorial methyl group in XIV; thus the steric interaction is ex pected to be relieved by moving the methyl group into the quasi-axial position (XIIl). This transformation however introduces an opposing 1,3-diaxial interaction between the methyl group and the hydrogen on the 4-posi tion. If the magnitude of this 1,3-diaxial interaction
CH^ CH
h: ^ 3 XIV XIII and the equilibrium constant are known, then the energy for interaction of the solvent shell and the alkyl group can be estimated. The enolate of 2,6-dimethylcyclohexa- none, as formed from the ketone and potassium t-butoxide 33
in various solvents was thus quenched with acetic acid
(a process which is stereoelectronically controlled)
and led to equilibrium concentrations of cis- and trans-
2,6-dimethylcyclohexanone. The strain energy for inter
action of the quasi-equatorial methyl group with enolate
oxygen and its solvent shell was thus found to vary
between 0.57 kcal/mole and 1,18 kcal/mole in various
solvents.
Base-catalyzed enolization.— The relative orders of rates of base-catalyzed deuterium exchange of cyclo
alkanones and cycloalkyl phenyl ketones in dimethyl- formamide (DMF)^^^ (Table 11) parallel the ease of formation of the corresponding carbanions as predicted by the hybridization coefficients. The order of reac tivity with respect to ring size is 4> 5> 6> 7 for cyclo alkanones and 3^ 4^ 5^ 6 for cycloalkyl phenyl ketones.
These orders parallel that of the acidity of the C-H bonds as measured by Streitwieser and expressed by hybridization coefficients of Coulson and Moffitt. 34
TABLE 11 BASE-CATALYZED RATES OF DEUTERIUM EXCHANGE OF CYCLOALKANONES AND CYCLOALKYL PHENYL KETONES AT 30°
AEa AS Ketone Rel. rates (kcal/mole) (e.u.)
Cyclobutanone 290 12.3 -31
Cyclopentanone 85 15.9 -26
Cyclohexanone 12 12.2 “42
Cycloheptanone 2.4 14.6 -37
Cyclopropyl phenyl ketone 20 15.7 -38
Cyclobutyl phenyl ketone 17 16.8 -35
Cyclopentyl phenyl ketone 5.7 13.1 -48
Cyclohexyl phenyl ketone 1.0 17.0 -39 III. RESULTS AND DISCUSSION
A. Bromination of 2-phenyl cycloalkanones
The initial study involved determination of the pseudo first-order rate constants and thermodynamic parameters for the base-catalyzed enolization of homo logous 2-phenylcycloalkanones as indicated in Equation 19.
0 0 o"
H -B I1 + Ph •Ph Ph + B
(CH,)» ( C H j
The system chosen for the investigation was bromination in the presence of excess sodium acetate in aqueous acetic acid. Acetic acid has historically been the solvent preferred for base-catalyzed halogénation of ketones; the solvent dissolves large quantities of sodium acetate which functions as the principal source of basic catalysis. Although use of acetic acid intro duces the complication of having several acidic and basic catalysts in the reaction medium it is still much pre ferred as a solvent over other organic cosolvents since
35 36
acetic acid docs not react with bromine at an appreciable rake, and allows use of excess sodium acetate to minimize the contribution of acid-catalyzed terms. Attempts to use other organic cosolvents in the present study were unsuccessful because of their facile bromination.
Bromination was followed by the classical iodo- metric method involving titration with sodium thiosulfate.
Reactions were followed to approximately 25% completion, after which catalysis by hydrogen bromide formed during reaction caused accelerated deviation from a straight- line plot of the data. Several kinetic runs were made for each ketone at each of the various conditions employed, and satisfactory linearity of plots and precision of the rate constants were observed.
The products of bromination of the 2-phenylcyclo- alkanones under kinetic conditions were studied by n.m.r. and v.p.e. methods. Integration of the proton n.m.r. signals showed that when about 40% of the benzyl proton had been removed, no detectable bromination had occurred at the other a-positions of the 2-phenylcycloalkanones.
Vapor-phase chromatography (FFAP on Chromsorb W) showed only one bromination product.
It was first noted that bromination of the 2-phenyl cycloalkanones in glacial acetic acid in the absence of 37 added acetate ion gave relative reactivities dramatical ly different from those of Sulzberg^^ for 2-phenylcyclo alkanones as determined in 90% acetic acid with 0.05M hydrochloric acid added. Whereas in the acid-catalyzed enolizations the order observed was 5^ 6 > 4» the present results revealed a relative reactivity of 4^ 5 > 6
(Table 12) . The present results are taken to indicate that halogénation of ketones in glacial acetic acid, even in the absence of added base, is not predominantly acid- catalyzed.
The bromination of 2-phenylcyclohexanone was then investigated in glacial acetic acid, using various con centrations of added sodium acetate in order to determine the dependence of the rate constant on added acetate, and in order to find rates conveniently followed by manual titration. It is Icnown from previous work in this laboratory that cyclopentyl phenyl ketone with bromine in 90% acetic acid at 14° gives rate constants of enoli- —7 —1 zation of 13.8 x 10 sec. with 0.05M hydrochloric acid as catalyst. That is, the pseudo first-order rate con stant is not directly proportional to acid concentration.
The result observed during the present work was that addition of small amounts of sodium acetate to 100% 38
TABLE 12
EFFECTS OF ACETIC ACID AND SODIUM ACETATE CONCENTRATION ON THE KINETICS OF BROMINATION OF 2-PHENYLCYCLOHEXANONE AT 30°
Solvent [OAc-] {,% acetic acid) (moles/liter) X 10^ (sec.*"^)
100 0.830 565 0.500 1340 0.415 1160 0.250 2095
So • 0.500 154 0.375 195 0.250 209
50 2.00 191 1.00 150 0.50 78.7
acetic acid actually lowered the rate constants of the bromination (Table 12). Upon repeating the experiments with sodium acetate in 1 S% acetic acid, it was found that the response, although in the same direction, was of lesser magnitude. (Table 12 and Figure 1). Bromina tion of 2-phenylcyclohexanone in 50^ aqueous acetic acid, however, was found to increase in rate slightly as the condensation of sodium acetate was increased from 0.50 molar to 2.00 molar, as expected for bromination catalyzed predominantly by acetate ion. 39
2200 -
1800 Glaci al ocetic oci d
1400
I % 1000 o
X
6 0 0 75% acetic acid 50% acetic acid 200
0 1.0 2.0 3.0 [OAc-]
Figure 1. Typical Data for Bromination of 2-Phenylcyclohexanone in Acetic Acid/Sodium Acetate at 30°. 40
2-Phenylcyclohexanone, 2-phenylcyclopentanone, and 2-phenylcyclobutanone were then brominated in 50/5 aqueous acetic acid at various sodium acetate concentra tions at 30°. The rate constants for bromination of all three ketones decreased markedly when a small amount of sodium acetate was added to the aqueous acetic acid.
However, very little response was noted in buffer solu tions having 0.125-0.50M of added sodium acetate in 50% aqueous acetic acid (See Table 13 and Figure 2).
The pseudo first-order rate constants for bromi nation of the 2-phenylcycloalkanones were then determined at three different temperatures in 50^ aqueous acetic acid containing 0.50M sodium acetate. The thermodynamic parameters were calculated as described in the Experi mental Section (Tables 14-24 and Figures 3-12).
Later, brominations of the 2-phenylcycloalkanones were carried out at an acetate concentration of l.OGM. 41 TABLE 13
EFFECTS OF SODIUM ACETATE ON THE KINETIC BROMINATION OF 2-PHENYLCYCLOALKANONES IN ACETIC ACID AT 30°
7 -1 Sodium acetate k^ X 10 sec. Cone, (moles/liter) O O
1.00 150 1601 4000
0. 500 82.6 570 1004
0. 250 104 722 ——
0.125 127 758 781
Zero 548 1778 1920
The data from this table are plotted in F igure 2 42
40
38
36
34
32
30
28
26
24
22 20
18
16
14
12 Ph 10 8
6 Ph 4
2
0 TTO (nioles/liter) Fig.2.— The effect of sodium acetate on the rate constant for bromination of 2-phenylcycloalkanones in 50^ acetic acid at 30° TABLE 34
REPRESENTATIVE DATA FOR BROMINATION OF 2-PHENYLCYCLOHEXANONE IN 50% ACETIC ACID- 0.5M SODIWI ACETATE AT 45°
Time Vol SgO^ meq S^O. meq Br„ meq Br^ meq ketone log [ketone]+2— (min) req.(ml,) (ml. X .01) left used left- (0.06l0-[Br^])
0.0 17.68 0.1768 0.0884 0.0000 0.0610 0.7853 9.65 17.46 0.1746 0.0873 0.0011 0.0599 0.7774 20.25 17.23 0.1723 0.0861 0.0023 0.0587 0.7686 39.07 16.80 O.I68O 0.0840 . 0.0044 0.0566 0.7528 59.25 16.42 O.I642 0.0821 0.0063 0.0547 0.7380 69.40 16.26 0.1626 0.0813 0.0071 0.0539 0.7316 91.20 15.82 0.1582 0.0791 0.0093 0.0517 0.7135 111.88 15.54 0.1554 0.0777 0.0107 0.0503 0.7016 130.16 15.13 0.1513 0.0756 0.0128 0.0482 0.6830 146.55 14.81 0.1481 0.0740 0.0144 0.0466 0 . 6684
— Initial concentration of 2-phenylcyclohexanone was 0.0122M. — Data are plotted in Figure 3.
0 0 .77
.76
.75
,— ü c o ■p ü .73 tC' o iH
.71
.70
0 10 20 30 50 60 70 80 90 100 110 12 0 130 140 t (min) 3.--Typical plot of kinetic data for bromination of 2-phenyl cyc2 ohexanone in 5 0^4 acetic acid-0.5M sodium acetate at 45 4=. TABLE 15 REPRESENTATIVE DATA FOR BROMINATION OF 2-PHENYLCYCLOHEXANONE IN 50% ACETIC ACID-0.5M SODIUM ACETATE AT 40°
Time Vol meq S^O^ meq Br meq Br^ meq ketone log [ketone]+2 — (min) left used left- req. (ml.) (ml. X .01) (SgO=/2) (0.0550-[Br^])
0.0 23.76 0.2376 0.1188 0.0000 0.0550 0.7436
11.00 23.59 0.2359 0.1179 0.0009 0.0541 0.73320
29.45 23.32 0.2332 0.1166 0.0022 0.0528 0.72263
58.77 22.88 0.2288 0.1144 0.0044 0.0506 0.70415
72.70 22.63 0.2263 0.1131 0.0057 0.0493 0.69285
110.5 22.22 0.2222 0.1111 0.0077 0.0473 0.67486
145.0 21.92 0.2192 0.1096 0.0092 0.0458 0.66087
— Initial concentration of 2-phenylcyclohexanone was O.OllOM, — Data are plotted in Figure 4. .74
.73
.72,
.71 o c $ .70 ü .X fcD .69 o «H .68
.67
. 66
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 time (min.) FiS.4.— Typical plot oP kinetic data Por bromination oP 2-phcnylcyclohcxanonc in 50% acetic acid-0,5>î sodium acetate at 40^ •P=. ON TABLE 16 REPRESENTATIVE DATA FOR BROMINATION OF 2-PHENYLCYCLOHEXANONE IN 50% ACETIC ACID-0.5M SODIUM ACETATE AT 30°
Time vol meq S^O^ meq Br„ meq Br^ meq ketone log [ketone]+2 — left used left — (min) req. (ml.) (ml. X .01) (SgOpz (0.0635-[Br^])
0.0 28.46 0.2846 0.1423 0.0000 0.0635 0.80277 8.42 28.41 0.2841 0.1420 0.0003 0.0632 0.80072 62.17 28.18 0.2818 0.1409 0.0014 0.0621 0.79309 134.1 27.66 0.2766 0.1383 0.0040 0.0595 0.77452 196.2 27.40 0.2740 0.1370 0.0053 0.0582 0.76492 255.3 27.21 0.2721 0.1360 0.0063 0.0572 0.75740
— Initial concentration of 2-phenylcyclohexanone was 0.0127M — Data are plotted in Figure 5* <ù c o +> V4) bO O H
.73
100 200 300 time (min.) Fig, 5.--Typic.nl plot: of kinetic data for bromination of 2-phcnyl- cyclolicxanonc in 50,1 acetic acid-0. 5M sodium acetate at 30
CO TABLE 17 BROMINATION OF 2-PHENYLCYCLOPENTANONE AT 40*
Time Vol S O meq S^O^ meq Br meq Br^ meq ketone log [ketone]+2 (min) req. (ml.) (ml. X .01) left used left (Sgoy2) (0.0550-[Br^])
0.0 31.04 0.3104 0.1552 0.0000 0.0550 0.74036 3.83 30.66 0.3066 0.1533 0.0019 0.0531 0.72509 12.67 29.80 0.2980 0.1490 0.0062 0.0488 0.68842 17.23 29.27 0.2927 0.1463 0.0089 0.0461 0.66370 21.43 28.91 0.2891 0.1445 0.0107 0.0443 0.64640 25.53 28.48 0.2847 0.1423 0.0129 0.0421 0.62428
3 b — Initial concentration of 2-phenylcyclopentanone was O.OllOM. — Data are plotted in Figure 6.
vO .74
.73
.72
.71 I—I
.67
. 66
.65
10 20 30 time (min.) o cyclopcntanonc in accllc ac:id~0.5M sodium acebnt.c at 40 o TABLE 18 BROMINATION OF 2-rHENYLCYCLOPENTANONE AT 30*
Time Vol S 0^ meq S^O^ meq Br meq Br^ meq ketone log [ketone]+2 (min) req. (ml.) (ml. X .01) left used left (SgO=/2) (0.06l0-[Brg])
0.0 31.57 0.3157 0.1578 0.0000 0.0610 0.78533 3.67 31.44 0.3144 0,1572 0.0006 0.0604 0.78104 18.97 30.88 0.3088 0.1544 0.0034 0.0576 0.76042 37.02 30.25 0.3025 0.1512 0.0066 0.0544 0.73560 53.40 29.60 0.2960 0.1480 0.0098 0.0512 0.70927 67.87 29.09 0.2909 0.1454 0.0124 0.0486 0.68664
b — Initial concentration of 2-phenylcyclopentanone was 0.0122M. — Data are plotted in Figure 7.
Ln H .79
.78
.77
.76
.75
.74
73
.72
.71
.70
.69 10 20 time (min.) Fi . 7. --Typical pl(?t of kinetic dnta for brominat ion of 2-phcnyl o eye] open tan one in 50^ acetic acid-0. 5'î sodium acetate at 30 Ln to TABLE 19 REPRESENTATIVE DATA FOR BROMINATION OF 2-PHENYLCYCLOPENTANONE IN 50% ACETIC ACID-0.500M SODIUM ACETATE AT 20°
Time vol SjOj' meq S^O^ meq Br„ meq Br meq ketoneüL log [ketone]]+2b (min) left_ ^ used left req. (ml. ) (ml. X .01) (820^ 2) (0.0398-[Br^])
0.0 22.31 0.2231 0.1116 0.0000 0.0398 0.5999 5.18 22.27 0.2227 0.1114 0.0002 0.0396 0.5977 21.63 22.19 0.2219 0.1109 0.0007 0.0391 0.5922 43.97 21.86 0.2186 0.1093 0.0023 0.0375 0.5740 65.50 21.74 0.2174 0.1087 0.0029 0.0369 0.5670 93.80 21.49 0.2149 0.1074 0.0042 0.0356 0.5514 121.36 21.12 0.2112 0.1056 0.0060 0.0338 0.5292
a b Initial concentration of 2-phenylcyclopent anone was O.OO786M. — Data are plotted in Figure 8.
Ln .63
.62
.61
.60 I—I o .59 C o ■p « .58 I___ I
O .56
.55
.54
.53
20 40 . , . V 60 80 100 time (inin.) Fig. 8.— Typical plot oC kinebic data for bromination of 2-phenylcyclo pcntanonc in 50/u acetic acid-0. 5M sodium acetate at 20 TABLE 20 REPRESENTATIVE DATA FOR BROMINATION OF 2-PIIENYLCYCLOBUTANONE IN S0% ACETIC ACID-0.500M SODIUM ACETATE AT 40°
Time Vol meq S^0^= meq Br meq Br^ meq ketone log [ketone]+2 Ë (min.) req. (ml.) (ml. X .01) left used left — (0.0378-[Br^]) (^2°9/2)
0.0 21.24 0.2124 0.1062 0.0000 0.0378 0.5775 20.92 2.80 20.92 0.2092 0.1046 0.0016 0.0362 0.5587
6.00 20.51 0.2051 0.1026 0.0036 0.0342 0.5740
9.30 20.29 0.2029 0.1015 0.0047 0.0331 0.5198
12.68 19.95 0.1995 0.0998 0.0064 0.0314 0.4969
16.33 19.60 0.1960 0.0980 0.0082 0.0296 0.4713
^ Initial concentration of 2-phenylcyclobutanone v;as 0,00757^^« " Data are plotted in Figure 9.
Ln Ln I___ I
.47
20 time (min.) Fig. 9.— Typical plot of ki.netlc data for bromination of 2-phenyleyelo- bubanonc in acot.jc acid-0. 5M sodium acetate at 40 o\ TABLE 21 REPRESENTATIVE DATA FOR BROMINATION OF 2-PIIENYLCYCLOBUTANONE IN 50^ ACETIC ACID-0.500M SODIUM ACETATE AT 30°
Time vol Sj03 meq S^O^ meq Br„ meq Br^ meq ketone log [ketone]+2 left used left (min) req. (ml.) (ml. X .01) (SgOy/2) (0.0372-[Brg]) ‘V " t >
0.0 24.69 0.2469 0.1234 0.0000 0.0372 0.5705 2.97 24.55 0.2455 0.1227 0.0007 0.0365 0.5623 6.50 24.38 0.2438 0.1219 0.0015 0.0357 0.5527 11.50 24.18 0.2418 0.1209 0.0025 0.0347 0.5403 16.50 23.91 0.2391 0.1195 0.0039 0.0333 0.5224 26.58 23.40 0.2340 0.1170 0.0064 0.0380 0.4885 33.97 23.06 0.2306 0.1153 0.0081 0.0291 0.4639
— Initial concentration of 2-phenylcyclobutanone was 0.00743M. — Data are plotted in Figure JO.
Ln G C O -P VG
O fH
49
lu 20 time (min.) Fif^. iO.— Tj’picaü plot of kinetic da(:a for bromination of 2-plienylcyclo- On butanonc in 50^' acetic acid-0. Sîi sodium acetate at 30 GO TABLE 22
REPRESENTAUVE DATA FOR BROMINATION OF 2-PHENYLCYCLOBUTANONE IN 50% ACETIC ACID-0.500M SODIUM ACETATE AT 20°
Time Vol S 2O3 = meq 5^0 meq Br_ meq Br^ meq ketone — log [ketonel+2 — (min) left used left req. (ml.')(ml. X .01) (S20]/2) (0 .0276-[Br2])
0.0 21.75 0.2175 0.1088 0.0000 0.0276 0.4409
10.17 21.64 0.2164 0.1082 0.0006 0.0270 0.4314
37.49 21.35 0.2135 0.1068 0.0020 0.0256 0.4082
58.07 21.11 0.2111 . 0.1056 0.0032 0.0244 0.3880
80.02 20.88 0.2088 0.1044 0.0044 0.0232 0.3655
109.10 20.63 0.2063 0.1032 0.0056 0.0220 0.3424
132.28 20.38 0.2038 0.1019 0.0069 0.0207 0.3160
— Initial concentration of 2-phenylcyclobutanone v;as 0.00552M. — Data are plotted in Figure 11.
Ln vO .43
I—I o c o 4J u
I___ I to o r 4
.34 .33 .32
20 100 time (min.) Fi^. 11.--Typical plot of kinetic data for bromination of 2-phenyl- cyclobutanc in 50^^ acetic acid-0. 5^' sodium acetate at 20
On O 61
TABLE 2 3 BROMINATION OF 2-.PHENYLCYCLOALKANONES IN 50^ ACETIC ACID-0.500M SODIUM ACETATE AT VARIOUS TEMPERATURES
k X 10^ (sec Ketone 20° 30° 40° 45°
80.5 227 301 78.5 197 323 86.1 85.2 average 82.3±3.1 212+15 312I 11
209 556 1720 193 586 1630 192 592 1550 548 1870 average 198+7.3 570±19 1692+102
357 1190 2490 346 972 2420 920 1000 average 35115.5 10201110 2455135 2 . 0
1.8
1.6 o 1**4 o H + 1.2
H Ph 1.0 o .8 H Ph ..6
,4 Ph
:2
0 .00310 .00320 .00350 .00360 .00370
F i f r , 32.— Enthalpies oP actlvailon for bromination oP 2-phonylcyclo- nlkanoncs in 50/» acetic ac i.d-0. 5M sodium acetate to TABLE 24 BROMINATION OF 2-PlIENYLCYCLOALKANONES IN 50% AQ. lIOAc-O.SM OAc“ ADDED
R e l .rate ' A S + 20° 30° 40° 30° Kcal/mole ^ 45°
352+5 1004+74 2460+35 12.2 17.0 -33.7*2.4
198±7 570+36 1692-102 7.0 18.8 - 29.7+ 2.1
82.6±3 212+15 312+11 1.0 16.3 -43.0+1.9
o\ co 64
There was nearly linear increase in the rate constants
of 2-phenylcyclohexanone and 2-phenylcyclopentanone from
those measured at 0.50M sodium acetate. The increase in the rate constant for 2-phenylcyclobutanone appears to have been considerably greater than the increase in added sodium acetate. 21 Dawson and Spivey noted that small amounts of
(21) H. M. Dawson and E. Spivey, J. Chem. Soc., 2180 (1930). sodium acetate in dilute acetic acid depress the rate constant for iodination of acetone. However the plot of the first-order rate constant against sodium acetate concentration rapidly reaches a minimum and thereafter the rate constant increases in direct proportion to the concentration of sodium acetate. For the enolization of acetone in aqueous acetic acid— sodium acetate buffer, the pseudo first-order rate constant may be expressed as
k = 6x10"^ + 5.6xlO"4[H 0+] + 1.3xl0"^[H0Ac] 6 + 7[0H“] + 3.3x10" [OAc"] + 3.5xlo" [HOAc][OAc"] (20)
The initial effect of adding sodium acetate is to decrease hydrogen ion concentration, and the hydrogen-ion term is seen to be a relatively large contributor to the overall 65 rate constant. The point is soon reached, however, where
the hydrogen ion concentration has become so small that
the combined base terms predominate. Elsewhere it was
found that for halogénation of cyclopentyl phenyl ketone
in acetic acid catalyzed by hydrochloric acid the pseudo
first-order rate constant increases much more rapidly 14 n than the concentration of hydrochloric acid added.
Discussion. The relative reactivity in base-
catalyzed enolization of 2-phenylcycloalkanones with
respect to ring size in 50% acetic acid is thus 4> 5 > 6.
This ordering is decidedly different from that found for
enolization of 2-phenylcycloalkanones in 90%> acetic acid 15 catalyzed by 0.05M hydrochloric acid ( 5 > 6> 4=7).
■The relative reactivity in the present system is also markedly different from that for acid-catalyzed enolization
of cycloalkanones in 90%> acetic acid— 0.50M hydrochloric
acid (6> 8 7 » 4) but is the same as that for base-
catalyzed enolization of cycloalkanones in dimethylformamide-
triethylaraine (4^5^6> 7)^^^ or in water.The absolute
(22) A. Schriesheim, R. J. Muller, and C. A. Rowe, Jr., J. Amer. Chem. Soc., ^4, 3164 (1962). magnitudes of the relative reactivities of enolization are similar for cycloalkanones and 2-phenylcycloalkanones 66 when base catalyzed. Thus Dessy et a2. in Shechter 1 ^ et al . report: cyclobutanone, 24; cyclopentanone, 7.1; and cyclohexanone, 1.0. Schriesheim and co-workers have 22 found : cyclobutanone, 15.5; cyclopentanone, 9.9; and cyclohexanone, 1,0. In the present work, in 50^ acetic acid-0.5M sodium acetate within the homologous 2-phenyl- cycloalkanones the relative rates are: 2-phenylcyclobutanone,
12; 2-phenylcyclopentanone, 7.1; and 2-phenylcyclohexanone,
1.0. Also in the present work the relative rates of enoli zation of 2-phenylcycloalkanones in S0% acetic acid— l.OM sodium acetate are: 2-phenylcyclobutanone, 2 6 .6 ; 2-phenyl- cyclopentanone, 10.0; and 2-phenylcyclohexanone 1.00.
The present results are not satisfactorily ex plained by the concept of stability of double bonds in cyclic systems. The introduction of double bonds into 2 2 rings would lead to an order 6 ^ 5 4. The order
(23) H. C. Brown and M, Borowski, J. Amer. Chem. Soc., 74, 1884 (1952).
(6^5^^ 4) is indeed observed for the rates of acid- catalyzed enolization of cycloalkanones, in which the 14a transition states are very near enol in character.
Nor does the relative order resemble that found when one member of a ring undergoes a change in coordination 2 3 number of four to three, which is 5^6^^ 4. 67
The result of particular interest in the present
work is the surprising reactivity of 2-phenylcyclobuta
none toward enolization. Such reactivity when cyclobutane
derivatives are attacked by base seems to be the general
case. Numerous investigators have reported the ready
enolization of cyclobutanones, and nitrocyclobutane was very recently reported to be much more readily neutralized by base than the larger homologs.
(2 4) P. W, K. Flanagan, H, W. Amburn, H. W. Stone, J. G. Traynham, and H. Shechter, ibid., 91, 2797 (1969).
One factor which likely leads to the observed order of enolization is the effect of ring size on the acidity of the attacked hydrogens. It is known that hybridization changes in going to smaller ring size result in greater s-character of the C-H bond. The in creased s-character of the exo bonds with decreasing ring size is evident in the carbonyl stretching frequencies 2 5a for cycloalkanones, which increase from cyclohexanone
(25) (a) R. Bellamy, "Infrared Spectra of Com plex Molecules," John Wiley and Sons, Inc., New York, N. Y . , 1959. (b) M. Tamres and S. Searles, J. Amer. Chem. Soc., 2100 (1959). (c) H. J. Campbell and J. T. Edwards, Can. J. Chem. , 3^, 2109 (i960) . to cyclobutanone. The effect is also reflected in the 68 basicities of these ketones as measured by hydrogen bonding^^ or by ultraviolet spectral shifts,
7>6>5>4- In the time since the start of the present work, Streitwieserhas measured the acidities of cycloalkanes, and found that the smaller rings bear more acidic hydrogens, again consistent with increasing s-character of the exo bond.
A stereochemical factor may influence the s-character of the bond between a-carbon and attached hydrogen in cycloalkanones. As a carbocyclic ring be comes smaller, and particularly if it contains a trigonal site, the C-C-C bond angles decrease, whereas the II-C-H exocyclic bond angles increase. The dihedral angle between the p-orbital of the carbonyl carbon and the exocyclic
a-C-H bond is thus decreased as the ring becomes smaller.
The electronegative carbonyl group then may more effec tively attract the electrons in the a-C-H bond of a cyclobutanone than in larger ring ketones.
A significant factor which can lead to the greater rates of base-catalyzed enolization of cyclo butanones than of their higher homologs might lie in the favored geometry of the carbanionic transition states of the 4-membered ring ketones. In a carbanionic transition state, RgC:, which is not delocalized and not subject to 69
internal repulsion outlets, the unshared electron pair
would prefer to occupy a pure 2s_ orbital and the sub
stituent groups (R) would be bonded to carbanionic
carbon via three mutually perpendicular 2p-orbitals.
Such a carbanionic transition state would have geometry which is preferably pyramidal in which the substituent axes are 90°. An alternate possibility is that in the
absence of steric effects, an alpha carbanionic transi tion state from a ketone might be expected to have maximum stability if it is highly delocalized through the carbonyl 2 oxygen and has sp stereochemistry. The results of the present investigation are certainly not compatible with the proposition that there is high order delocalization in the transition state which involves the carbonyl group. It thus may be that solvated transition states leading to solvated enolates, because of severe internal 2 steric and cis effects, might have less sp character ? and more p or sp (pyramidal) character than formerly supposed. If indeed the preferred geometry of a carban ionic transition state is that demanded by p orbital requirements, it is quite logical that there will be much less reorganization of cyclobutanones than of their higher homologs upon base-catalyzed enolization. An alternate but yet similar and possibly more satisfactory 70
interpretation is that there will be greater advantage
compromise in the p requirements of a non-delocalized 2 pyramidal carbanion and the sp requirements of a de
localized planar enolate in 4-niembered cycloalkanones
than for their higher homologs.
Still another feature of a cyclobutanone which
will assist formation of its carbanionic transition
state is the rigid and relatively flat conformation of
the 4-membered ring system. The a-hydrogen is highly
axial and thus sterically available to attack by a base.
Furthermore, in conversion of a cyclobutanone, a rela tively rigid cycloalkanone, to its carbanionic transition state, there will not be the loss of freedom that will occur with larger-ring ketones. Finally, since cyclo butanones are relatively flat, rigid, and polar, they should be more highly solvated in the ground state than are their higher homologs. The carbanionic transition states formed from cyclobutanones may be solvated with less rearrangement of solvent than is the case for the higher cyclic ketones.
Some attention should now be directed to the greater reactivity of 2-phenylcyclopentanone than that of 2-phenylcyclohexanone toward enolization. The same order of reactivity was observed in base-catalyzed 71 enolization of unsubstituted cyclopentanone and cyclo- hexanonc. The same factors as described above for the reactivity of 2-phenylcyclobutanone apply. The exo H-C-H bond angle of 2-phenylcyclopentanone is greater than that of 2-phenylcyclohexanone leading to a more favorable alignment of the a-hydrogen. Entropy and better solva tion of ground and transition states also favor the more rigid 5-membered ring.
B . Base-catalyzed deuterium exchange of cycloalkyl phenyl ketones 14a It has been reported (see Historical, p. 21) that the first-order rate constants for base-catalyzed deuterium exchange of cycloalkyl phenyl ketones decrease in the order;
3^4^ 5^ 6, approaching the open-chain analog isopropyl phenyl ketone as an approximate limit (Equation 21)
(21)
o n f 110 / \T)
The reactivity observed for cyclopropyl phenyl ketone is consistent with the findings of several investi gations of similar cyclopropyl systems. Walborsky et al.^^
(26) H. M. Walborsky, A. A. Yousseff, and J. M. Motes, J. Amer. Chem. Soc., 8^, 2465 (1962). 72
have reported that deuterium exchange of 2,2-diphenylcyclo-
propyl cyanide catalyzed by sodium methoxide in methanol-d,
at 50° has a first-order rate constant of 5-48 x 10 ^
— 1 sec. , while under the same conditions the open chain
analog 2-methyl-3,3-diphenylpropionitrile exchanges more -6 slowly in that its first-order rate constant is 1.75 x 10
sec. ^. The same authors also observed that the cyclo
propyl cyanide undergoes racemization more than 8000 times
slower than exchange and it was concluded that the cyclopropyl anion though readily generated tends to preserve its pyramidal stereochemistry.
The kinetic acidity of cyclopropanes has also 27 been observed by Breslow and coworkers in that base-
(27) R . Breslow, J. Brown, and J. J. Gajewski, ibid., £9, 4383 (1967). catalyzed deuterium exchange occurs 12 times more rapidly in cyclopropyl phenyl sulfone than in isopropyl phenyl sulfone. Sulfur d-orbitals may be important in delocali zation in a carbanionic transition state.
A further example of base-catalyzed reactivity of cyclopropyl derivatives has been found in that cis-
2,3-diphenyl-trans-l-benzoylcyclopropane in potassium ethoxide in ethanol-o-d-dimethoxyethane at 40 undergoes 73 deuterium exchange with a pseudo first-order rate constant of 1.44 X 10 ^ sec. In the same environment at 70° the unsaturated analog, 1,2-diphenyl-3-benzoylcyclopropene has a rate constant for exchange of 3.19 x 10 ^ sec.
The much greater rate of exchange (a factor of *^6000) of the benzoylcyclopropane than the benzoylcyclopropene was used as evidence for the antiaromaticity of conjugated cyclopropene anions.
Finally, it has been found that cis-2-phenylcyclo- propyl methyl ketone undergoes epimerization at 60° catalyzed by 0.7N Corey anion in dimethylsulfoxide.
(28/ C. Agami and M. Audouin, C. R. Acad. Sci. Paris, Ser. C . , 26^, 1256 (1969).
The reactivity reported for cyclopropyl phenyl 14 â ketone with respect to base-catalyzed enolization is inconsistent, however, with experiments that reveal that nitrocyclopropanes resist neutralization and base- catalyzed deuterium exchange and are much weaker protonic 29 acids than their homologs or acyclic analogs. Further-
(29) (a) H. B. Hass and H.Shechter, J. Amer. Chem. Soc., 75, 1382 (1953). (b) P. W. K. Flanagan, H. W. Amburn, H. W. Stone, J. G. Traynham, and H. Shech ter, ibid., 91, 2797 (1969). more, salts of cyclopropane-carboxylic acid do not undergo 74 isotopic exchange in deuterium oxide at temperatures in
which deuterium incorporation into its higher homologs 30 and into salts of isobutyric acid is extensive.
(30) (a) A. P. Bottini and A. J. Davidson, J. Org. Chem., 30, 3302 (1965); (b) J. G. Atkinson, J. J. Csakvary, G . T. Herbert, and R. S. Stuart, J. Amer. Chem. Soc., 90, 498 (I968).
Finally it was very difficult to develop an adequate
interpretation of the remarkable reactivity of cyclo
propyl ketones and cyclopropyl cyanides with respect to
base-catalyzed enolization.
A study was thus initiated of the base-catalyzed
deuterium exchange of cyclopropyl phenyl ketone and di-
cyclopropyl ketone and also of the open-chain analogs,
isopropyl phenyl ketone and diisopyrpyl ketone. The
System chosen for the investigation was dimethylforma-
mide-deuterium oxide with O.13-0.17M sodium ethoxide
as catalyst at 60°. Pseudo first-order plots (up to 60%
completion) (Pig.l6) were obtained by plotting the data
from integration of the n.m.r. spectra (Figs. 13-15)
of aliquots, of the reaction mixture quenched and worked-
up at various measured intervals (see Experimental, pJ.27
for details). The results showed (Tables 25-26)
that in the present experiments cyclopropyl phenyl ketone >1 iN*r* h^smw^w W W t > v«rV wq^V » ^ * M V K
Fig. 13.--The n.m.r. spectrum of diisopropyl ketone
Ln • h J k
Fig. 14.--The n.m.r, spectrum of dicyclopropyl ketone
o\ Fig. 15.— The n.m.r. spectrum of isopropyl phenyl ketone 78 TADLE 25
DEUTERIUM EXCHANGE OF CYCLOPROPYL AND ISOPROPYL KETONES IN DIMETIIYLFORMAMIDE-DEUTERIUM OXIDE/SODIUM DEUTEROXIDE o AT 60
Ketone [ketone] [DgO] [NaOD] Time ^a-liycl ro^on^ (min.) referenec
Diisopropyl l.OM 8 . 3M 0.13M 0 1.03 390 0.74 630 0.82 1200 0.60
Dicyclo propyl 1.5 10 0.17 0 1.0 1700
Isopropyl phenyl 1.25 10 0.17 0 0.99 240 0.82 640 0.61 1050 0.45
Cyclopropyl. phenyl 1.2' 10 0.17 0 1.0 3500 1.1 79
1
I—1 ü c o ü I_; fcO O r4 .70
) 60 500 1000 1250550 tine (nin.) Fig\ 16.— Plot of kinetic data for deuterium cxciian^e of isopropyl phenyl ketone in dimcthyl- fornanide-deuterium oxide at 60
1
c c c
I___ I
0 r-i .80
.70
500 time (min.) 1000 Fig. 17.— Plot of kinetic data for deuterium exchange of diisopropgl ketone in dimethylformamide deuterium oxide at 60 80'
TABLE 26
DEUTEETUM EXCHANGE OF CYCLOPROPYL AND ISOPROPYL KETONES IN DIMETIIYLFORMAMIDE-DEUTERIUM OXIDE/SODIUM DEUTEROXIDE AT 60°
Ketone [ketone] [B30] [NaOD] k^1 X 10 1 sec. —1
Diisopropyl l.OM 8.3M 0.13M 7.0
Dicyclo propyl 1.5 10 0.17 » zero
Isopropyl phenyl 1.25 10 0.17 12.0
Cyclopropyl phenyl 1.2 10 0.17 zero 81
and dicyclopropyl ketone are essentially resistant to
exchange (Table 26) whereas diisopropyl ketone is 40%
exchanged in 20 hours (k^= 7 x 10 ^sec. and iso
propyl phenyl ketone is 55-58% exchanged in 17.5 hours
(k^ = 1.2 X 10 '^sec. ^) . Qualitative agreement was
found in low-voltage mass spectral analysis.
Such findings suggested that the results of ,14a ■ T J , previous work included some very serious errors, per
haps due to impurities or unsuitable methods of measure ment, and it was decided to reinvestigate the kinetics
of base-catalyzed deuterium exchange of the entire
series of homologous cycloalkyl phenyl ketones.
DimethyIformamide was unsuitable as a reaction solvent as some difficulty was encountered in reproducing
linearity of the plots and precision of the data. As a
result, the cycloalkyl phenyl ketones were exchanged in dioxane-deuterium oxide with 0.005M sodium deuteroxide
as catalyst at 30°. Pseudo first-order plots (Fig. 22-25) of satisfactory linearity and precision were obtained from the data obtained from n.m.r. spectra (Figs. 18-21) of aliquots'. The data are given in Tables 27-28.
The relative order of reactivity found in the present study was; cyclopropyl phenyl ketone, 0; cyclobutyl phenyl ketone, 21.7; cyclopentyl phenyl ketone, 10.0; ! I
i' I NIi i t 1. , i I f . '"Ik
omîTiï Fig. 18.— The n.m.r. spectrum of cyclopropyl phenyl ketone
CO to M l . 'I':,- u - v u
Fig. 19.--The n.m.r. spectrum of cyclobutyl phenyl ketone
00 03 10 10
Fig, 20.— The n.m.r. spectrum of cyclopentyl phenyl ketone
00 4^ Fig. 21.--The n.m.r. spectrum of cyclohexyl phenyl ketone
00 Ln 1 .
o c o +) .90 ü tD O rH
. 80 100 150 oO time (min.) Fig, 22.
00 On l.orJ
.98
.96
.94
.92
.90
.88
.86
.84
.82
.80
100 200 , . / . x'I'J'.J300 4 0 0 time (.niin.) Fis. ^3.— Typicnl plot of Icinctic data for deuterium exchange of cyclo- pentyl phenyl Icctonc in dioxane-deuterium oxide-0.005M sodium deuteroxide at 30° 00 .98
:96
.92
I___ I .90 rH .88
.86
.84
. 82 2000 t.Tine (min.) 4000 6000 Fig. 24.— Typical plot of kinetic data for deuterium exchange of cyclo- hoxyl phenyl Ice tone in dioxane-deul^crium oxidc-O.OOSM sodium deutcroixdc at 30' CO 00 l.OQ
.98
.92 (-1
i_>
.80
78 -
1000 2000 3000 time (min.) Fig. 25.— Typical plot of kinetic data For deuterium excliangc oF isopropyl phenyl ketone in dioxanc-deutord uni oxidc-O.OOSM sodium douteroxido at 30
00 vO 90
TABLE 27 REPRESENTATIVE DATA FOR DEUTERIUM EXCHANGE OF CYCLOALKYL PHENYL KETONES IN O.OOSM SODIUM DEUTEROXIDE/D O-DIOXANE AT 30° ^
Ketone Time /J a-hyclro/^en, r . . ■5 Phenyl ) log[a-hydrogei (min. )
Cyelopropyl phenyl 1.0 1.0 1:^ 1.0 1.0
Cyclobutyl phenyl 0 0.99 1.0 20 0.96 0.98 60 0. 86 0.93 120 0.76 0.88 180 0.67 0.83
Cyclopentyl phenyl 0 1.0 1.0 160 0. 86 0.93 270 0.78 0.89 460 0.68 0.83 570 0.63 0.80 690 0.59 0.77
Cyclohexyl phenyl 0 0.99 1.0 1640 0.94 0.97 4600 0.78 0.89 5935 0.72 0.86
Isopropyl phenyl 0 0.99 1.00 420 0.92 0.96 1380 0.77 0.89 2880 0.65 0.81 4380 0.58 0.76 91 TABLE 28
THE RATE CONSTANTS AND THE RELATIVE RATES OF DEUTERIUM EXCHANGE OF CYCLOALKYL PHENYL KETONES IN DIOXANE- DEUTERIUM OXIDE/O.OOSM SODIUM DEUTEROXIDE AT 30°
7 -1 Ketone X 10 sec. Rel. rates
Cyelopropyl phenyl 0 0
Cyclobutyl phenyl 308 370 339 ± 31 21.7
Cyclopentyl phenyl 164 141 166
Ï57 1 11 10.0
Cyclohexyl phenyl 19.4 11.8 15.6 t 3.8 1.00
Isopropyl phenyl 25.1 18.2 15.2 22.8 ± 5.3 1.41 92
And cyclohexyl phenyl ketone, 1.00. The order of reac
tivity is similar to that found earlier for the cycloalkyl
phenyl ketones, except for the unreactivity of the cyclo-
propyl ketone, and the order in the to cycloalkyl
phenyl ketones is the Same as that for homologous cyclo- *1 y| ^ alkanones and 2-phenylcycloalkanones (present study).
At essentially the same time as the present study 31 was completed and published, several investigators
(31) H. W, Amburn, K. C. Kauffman, and H. Shechter, J. Amer. Chem. Soc., 91, 530 (1969).
also reported that cyelopropyl ketones are quite resis- 32 tant to deuterium exchange. Rappe and Sachs found
(32) C. Rappe and W. H. Sachs, Tetrahedron, 24, 6287 (1968).
that cyelopropyl methyl ketone undergoes deuterium
exchange more than 100 times slower than cyclobutyl
phenyl ketone in dioxane— deuterium oxide at 47*5
(Table 29). 33 Van Wijnen, et al., observed that cyelopropyl
(33) W. Th. van Wijnen, H. Steinberg, and Th. J, de Boer, Reel. Trav. Chim. Pays-Bas, 844 (1968) ketones undergo deuterium exchange using sodium 93 TABLE 29
BASE-CATALYZED DEUTERIUM EXCHANGE IN DIOXANE— DEUTERIUM OXIDE USING O.O0ÔM SODIUM DEUTEROXIDE AT 47-5°
Ketone , k kçjjXlO^sec %D
Acetophenone 365 — —
Cyclopropylmethyl 178 0.08 0.0043x10“' -2 Cyclobutylmethyl 179 . 9.1 5.1x10 -2 Cyclopentylmethyl 26 1.4 5.3x10
Cyclohexylmethyl 44 5.0 11.4x10“^
Isopropylmethyl 91 4.3 4.7x10"^ 94 methox.ide in methanol to be 100-250 times slower than for the corresponding isopropyl ketones (Table
In the systems studied, cyelopropyl ketones are essentially completely resistant to isotopic exchange
(even though their C-IT bonds have greater s-character) .
At least two features may be advanced to explain this resistance. It is possible that the 3-membered ring will not permit introduction of the necessary degree of 2 sp -character at the a-carbon. The charge in the transi tion state thus cannot be easily delocalized. Secondly, it is probable that the conformation of the ground state ketone should be the cis-biAected structure. In this
II COPh _ / COPh 9 [)>=CPh (22)
conformation the -orbital of the carbonyl is aligned so as to conjugate with the p-like C-C bonds of the cyelopropyl group. Therefore the C-H bond to be broken during enolization is not properly aligned parallel to the carbonyl K-^bond for facile breakage to occur without rotation of the cyelopropyl group taking place.
The data of Table 2 8 reveal that cyclobutyl phenyl 95 TABLE 30 RATIOS OF BASE-CATALYZED HYDROGEN EXCHANGE OF CYCLOPROPYL AND ISOPROPYL KETONES IK METHANOL WITH SODIUM METHOXIDE
0
la 2a 3a
0 It c
lb 2b 3b
2b > Zlk = ISO ± 0.15 250 IË. ^ 100 '"la 2a 3c 96
ketone is more rapidly exchanged than any of its higher homologs. Such facile exchange into cyclobutyl phenyl
ketone cannot be explained in terms of creation of a double bond exocyclic to a 4-membered ring or in terms 3 of a change of hybridization of a ring carbon from sp 2 to sp . The factors which influence the reactivity of cyclobutyl phenyl ketone are probably similar to those discussed for base-catalyzed enolization of 2-phenyl- cyclobutanone. The C-H bond of the enolizable position of cyclobutyl phenyl ketone has greater s-character than that of higher cycloalkyl phenyl ketones. Conformation- ally, the enolizable C-H bond should be better aligned with thelT-orbital of the carbonyl group in cyclobutyl phenyl ketone than in cyelopropyl phenyl ketone, since the cyelopropyl phenyl ketone should prefer the cis- bisccted conformation. This should lead to some assistance in breaking the bond of cyclobutyl phenyl ketone. Addi tionally, the H-C-R. bond angle is larger in cyclobutyl phenyl ketone than in its higher homologs, and thus the bond angles are more appropriate for formation of a near- pyramidal carbanionic transition state. Such a carbanionic transition state may achieve an energetically favorable 2 compromise configuration between sp and pyramidal. And finally, the relatively rigid cyclobutyl phenyl ketone 97 should not be required to undergo such unfavorable changes in entropy and solvation during reaction as would its larger, more flexib e ring homologs.
Finally it was found (Table 28 ) that cyclopentyl phenyl ketone undergoes base-catalyzed deuterium exchange faster than cyclohexyl phenyl ketone. The greater reac tivity of the 5-ring ketone may be explained by its ability to undergo coordination change of 4 to 3, its ability to accept exocyclic unsaturation or by factors similar to those given for the rapid exchange of cyclo butyl phenyl ketone. The H-C-R bond angle is greater in cyclopentyl phenyl ketone and therefore the bond angles are more appropriate for stabilization of the incipient carbanion with less motion. And finally, the 5-membered ring derivative is more rigid and smaller than the 6- membered ring analog and so there may be advantageous entropy and solvation during reaction of cyclopentyl phenyl ketone. 98
C . Deuterium exchan/ze of 2-Phenylcycloalkanones
As the present study was nearing completion, there was raised some doubt as to the validity of halogénation of ketones as a method of measuring the rates of enoli- 2 zation of ketones. It was reported by Rappe that the rates and orientation of deuterium exchange of 2-butanone in water with acetate, bicarbonate, carbonate, or hydrox ide bases differ from those for bromination. The ratio of 3-halogenation to 1-halogenation (called was found to be 2.7 in acid, 7-0-7.5 in buffer solutions
(pH = 5-7), and zero in strongly basic solutions (pH^12), haloform reaction). Deuterium exchange in 2-butanone gives a ratio of 3-deuteration to 1-deuteration (called
K^) equal to 2.5 in acid and 0.6-0.7 in basic solutions
(pH = 5-14)• Rappe further reports that the bromination of 2-butanone is 30 times faster than iodination of the same ketone in acetate buffer solution and 4-5 times faster in solutions of sodium hydroxide. Finally it is reported that upon bromination in deuteroacetic acid, the bromine color is completely gone before any deuterium exchange occurs.
The belief that enolization of ketones is rate- determining for halogénation originated with Lapworth, 99 who observed that the sulfuric acid-eatalyzed bromina tion of acetone in dilute aqueous solution was independent of bromine concentration.^^ Lapworth observed that
(34) A. Lapworth, J. Chem. Soc., 85, 30 (1904). chlorine reacted faster than bromine, and the same result 35 was found by Rice and Fryling, who repeated Lapworth's
(35) F. 0. Rice and C. F. Fryling, J. Amer. Chem. Soc., 47, 379 (1925). experiment. However, employing better techniques, it was found that chlorine, bromine, and iodine reacted at the same rate with acetone in dilute aqueous solution
(catalyzed by hydrochloric acid). Dawson and Leslie similarly reported that the reaction of acetone with bromine in dilute aqueous solution as catalyzed by sul furic acid has the same velocity as that with iodine la under the same conditions.
The chlorination of acetone in solutions of per chloric acid was also found to be independent of chlorine, concentration for halogen concentrations of 0.001-0.005K.^
(36) R. P. Bell and K. J. Yates, J. Chem. Soc., 1927 (1962). 1 0 0 Xb was nobed, however, thab for chlorine concentration less than 10 the chlorination also showed first-order dependence on chlorine concentration.
The rate of bromination of 2-^-carboxybenzyl- indan-l-one in acetic acid as catalyzed by hydrogen bromide was reported to be identical to that for racemiza- Ic tion of the same optically-active ketone. Bartlett 37 and Stauffer measured the iodination of d-sec-butyl
(37) P. 0. Bartlett and C. H. Stauffer, J. Amer. Chem. Soc., 57, 2580 (1935). phenyl ketone in glacial acetic acid catalyzed by dilute nitric acid and obtained the same velocity constant as that for the racemization of the same ketone.
The first comparison of halogénation and racemiza- 38 tion in basic medium was made by Hsu and Wilson. They
(38) S. K. Hsu and C. L. Wilson, J. Chem.Soc,, 623 (1936). reported that 2% sodium acetate-catalyzed bromination of d-2-O^-carboxybenzylindan-l-one in 16N acetic acid occurred at a rate only faster than that of the corresponding racemization. This slight difference was 1 0 1 attributed to possible systematic imperfection of the
method. Hsu, Ingold, and Wilson measured the rates of
racemization and deuterium exchange of sec-butyl phenyl
ketone in dioxane-deuterium oxide with 0.13N sodium
deuteroxide as catalyst, and found the two rates to be
nearly equal.The actual difference of was inter
preted as due to the isotope effect of hydrogen in
solvent molecules. 39 Cram and Gosser reported that 1,2-diphenyl-l-
(39) D . J . Cram and L. Gosser, J. Amer. Chem. Soc., 86, 5457 (1964). propanone undergoes deuterium exchange and racemization at identical rates using tripropylamine as base and tert-butyl alcohol-0-cî as solvent in one run and tetra- hydrofuran 1.5M in tert-butyl alcohol-O-d in another.
With the exception of the data by Rappe the above results are consistent with rate-determining formation of enol or enolate followed by very rapid rmction of the enol or enolate with either halogen or deuterium oxide. The results reported for the comparison of halogénation or deuterium exchange with racemization also indicate rate- determining formation of a planar or symmetrical enol or enolate in racemization. 1 0 2 In contrast to the consistency seen above, there
is some conflict in reports of halogénation as catalyzed
by strong bases. Bartlett has found that acetone reacts
with iodine and bromine in aqueous alkali at the same
rate, and that the reaction is first-order with respect
to acetone in both cases.With chlorine however, the
reaction is 100 times slower, and is second-order, being
dependent on chlorine as well as acetone concentration.
It was proposed that in such a kinetic system, hypohalite
ion is the halogenating agent. Similarly bromination
and iodination of acetone were found to proceed at the
same rate in water when catalyzed by sodium hydroxide.
(40) R. P. Bell and H. C. Longuet-Higgins, J. Chem. Soc., 636 (1946).
On the other hand, in investigation of the utility of
reactions of substituted acetophenones with sodium
hypohalite in sodium hydroxide solutions, sodium hypo- broniide gave reactions which were much slower and less complete than those with hypochlorite.^^
(41) A, M, Van Arendonk and M, E, Cupery, J, Amer. Chem. Soc., 53, 3184 (1931). 103
In view of the questions raised by Rappe, it was believed necessary to compare the rates of deuterium exchange of the 2-phenylcycloalkanones with the rates of bromination in similar environments. The exchange was carried out in 50^ deuteroacetic acid-deuterium o oxide with 0.5M sodium acetate as the catalyst at 30 .
Very preliminary rate constants are given in Table 31.
TABLE 31
DEUTERIUM EXCHANGE OF 2-PHENYLCYCLOALKANONES INJ 50^ DEUTEROACETIC ACID-DEUTERIUM 0XIDE-0.5M SODIUM ACETATE
n 7 -1 Ketone X 10 sec. Rel. rates, 30
990 77 — Ph
225 17
12.9 1.0
The relative reactivities were found to be; 2-phenyl- cyclobutanone 77; 2-phenylcyclopentanone, 17; 104 2-phenylcyclohexanone, 1.0. The pseudo first-order rate constants for deuterium exchange are not ehe same as those for base-catalyzed bromination in S0% acetic acid-0.5M sodium acetate. The two rate constants are nearly the same for 2-phenylcyclobutanone. However, they differ by a factor of 2 for 2-phenylcyclopentanone and by a factor of 7 for 2-phenylcyclohexanone. The data would seem to imply more than merely a solvent iso tope effect. It is possible that a competing halogénation reaction, possibly bromination via free radicals,
(Equations 23-25) is operative along with bromination of enolate ion for the larger ring ketones.
Br, 2Br' (23)
^ P h Br‘ C HBr (24) I ^
h + Br, d r Ph + Br* (25) 105 The behavior of the 2-phenylcycloalkanones illustrated in Figure 2 is in accord with such a com plicating mechanism. There 2-phenylcyclohexanone showed relatively little response to added acetate ion. If indeed the six-membered ring is brominating to a great extent by a free radical process, then addition of sodium acetate, which has no effect on radicals present, may not increase the rate of the carbanimic halogénation to the point where it would be reflected (Figure 2) . IV. EXPERIMENTAL
Syntheses of 2-PhenylcycIoalkanones
General.— Solvent diethyl ether and tetrahydrofuran were dried by distillation from lithium aluminum hydride.
Solvent bis(2-methoxyethyl) ether (diglyme) was refluxed over calcium hydride and distilled from lithium aluminum hydride under reduced pressure (20 mm.). Magnesium for synthesis of phenylmagnesium bromide was oven-dried (225°) overnight. Diethyl malonate and cinnamyl alcohol were obtained commercially and distilled prior to use. Reagent grade bromobenzene, cyclopentanone, sodium borohydride, semicarbazide hydrochloride, triethylamine, ethyl chloro- formate, sodium azide, sodium hydride (50% in oil), and pyruvic acid were all used as purchased. Boron trifluoride etherate was redistilled before use (b.p. 121°).
Melting points were determined on a Fischer-Johns melting block and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 137 spectrometer using either potassium bromide disks or sodium chloride plates. Proton n.ra.r. spectra were obtained on a Varian A-60 spectrometer using tetramethylsilane as an internal reference. 106 107 Synthesis of 1-phenylcyclopcntcne.— To dry mag
nesium turnings (27.6 g., 1.15 moles) in dry ether
(200 ml.) in a 2000-ml. three-necked flask equipped
with an addition funnel, motor-driven stirrer, conden
ser, and Drierite tube, bromobenzene (177 g., 1.1 moles)
in dry ether (100 ml.) was added at a rate to maintain
gentle reflux. After stirring the mixture for an addi
tional hour at room temperature, cyclopentanone (84. g. ,
1.0 mole) was added during two hours. Immediately the
salt was hydrolyzed with a solution of ammonium chloride
(100 g.) in water (750 ml.). The organic layer was separated and the aqueous suspension was extracted with ether. The combined ether solutions were filtered through anhydrous magnesium sulfate. Solvent was re moved under reduced pressure, and the residual oil
(159 g.) was treated with a warm fresh 20% solution of sulfuric acid in glacial acetic acid (200 ml.). The mixture was swirled for 30 seconds and then poured into water (100 ml.)— ether (500 ml.). The aqueous layer was separated and the ether solution was washed first with water, then three times with saturated sodium bicarbonate solution, and finally again with water. The solution was filtered through anhydrous magnesium sulfate. The ether was removed under reduced pressure and the residual 108 oil was distilled to yield 1-phenylcyclopentene (125 g. ,
87%), b.p. 76-78° (2.5 mm.) [lit.^^ b.p. 72-74°
(1.5 mm.)].
(42) K. Mislow and A. K. Lazarus, J. Amer. Chem. Soc., 77, 6383 (1955).
Synthesis of 2-phenylcyclopentanol.— Sodium borohydride (4O.O g. , 1.05 moles) was suspended in dry diglyme (400 ml.) in a 1000-ml. flask equipped with a magnetic stirrer, addition funnel, and condenser.
Freshly distilled boron trifluoride etherate (230 g.,
1.6 moles of boron trifluoride) in dry diglyme (100 ml.) was added dropwise. The diborane thus generated was carried by a stream of clean dry nitrogen through Tygon tubing into a solution of 1-phenylcyclopentene (197 £•,
1.22 moles) in dry tetrahydrofuran (750 ml. in a separate
2000-ml. three-necked flask fitted with a mechanical stirrer, condenser, and Drierite tube, and maintained at 0-5° by an ice-water bath. After the addition of boron trifluoride etherate was complete, the diborane generator was brought to reflux temperature and the solu tion was maintained at room temperature. Cold 3N sodium hydroxide solution (32.4 g. of sodium hydroxide in
270 ml. of water) was added cautiously. This was 109 followed inuiiediately by 30% hydrogen peroxide (170 g.,
20% excess) . The mixture was stirred for five hours at room temperature and then poured into water (1000 ml,).
The product was extracted with three 500-ml. portions of ether. The combined ether extracts were dried over anhydrous sodium sulfate overnight. The solution was further dried by filtration through anhydrous magnesium sulfate. The ether was removed under reduced pressure.
The remaining pale-yellow liquid was fractionated using a six-inch column of glass beads and afforded 2-phenyl cyclopentanol (180 g., 91%), b.p. 95-97° (1 mm.) [lit.
(43) C. II. DePuy, G. F. Morris, J. S. Smith, and R. J, Smat, J. Amer.Chem. Soc., 8_7, 2421 (1965). b.p. 80° (0.2 mm.)].
2-rhenylcyclopentanone semicarbazone. — 2-Phenyl- cyclopentanone (l62 g., 1.0 mole) was dissolved in acetone (750 ml.) in a 3000-ml. three-necked flask equipped with an addition funnel, mechanical stirrer, and condenser. Chromic acid solution [from sodium di- chromate dihydrate (220 g., 0.74 mole) and 96% sulfuric acid (150 ml.) in water (lOOO ml.)] was added dropwise.
The solution was kept cool using an ice-water bath.
After the addition was complete, the solution was poured 1 1 0 into 1000 ml of ether. The aqueous layer was removed and
subsequently extracted twice with 500-ml. portions of
ether. The combined ether layers were washed with water,
twice with saturated sodium bicarbonate solution, and
finally again with water. The solution was dried by fil tration through anhydrous magnesium sulfate. The ether was removed under reduced pressure. The residue (103 g. ) was taken up in 95^ ethanol (800 ml.). Water (300 ml.) was added until the solution became slightly turbid. The turbidity was removed with a small amount of 95% ethanol.
Then anhydrous sodium acetate (50 g.) and semicarbazide hydrochloride (50 g.) were added. The mixture was stirred and warmed on a hotplate for 90 minutes, during which a fine white precipitate formed. The mixture was cooled and the crystals isolated by vacuum filtration. The crystals were digested in hot water-ethanol (1:1) for approximately an hour. The mixture was cooled and the crystals isolated by vacuum filtration. The product was dried under vacuum. Yield: 55 g. (25% based on
2-phenylcyclopentanol), m.p. 217- 221^ (d) [lit.
(44) M. Mousseron, R. Jacquier, and H. Christel, Compt. Rend., 236, 92? (1953). m .p. 231- 232° (d)]. Ill
2-Phenylcyclopcntanone. — 2-Phenylcyclopentanonc semicarbazone (18.6 g.) was dissolyed in pyruvic acid^^
(45) A. C. Cope and B. D. Tiffany, J. Amer. Chem. Soc., 73, 4158 (1951).
(47.0 g.). The solution was stored at room temperature under nitrogen for 16 hours with periodic swirling. A finely divided white precipitate formed during the decompo sition, and the reaction mixture became a thick paste eventually. The mixture was diluted with water (200 ml.) neutralized with saturated sodium bicarbonate solution and the aqueous suspension was extracted four times with 50-ml. portions of ether. The combined extracts were washed twice with saturated sodium bicarbonate solution, twice with 10/2 sodium hydroxide solution, and twice with water. The solution was dried over anhydrous magnesium sulfate and decolorized with activated charcoal. The ether was removed under a stream of clean nitrogen at room temperature. The solid remaining was recrystallized twice from Skelly Solve B
(b.p. 60-68°) at -70° in an acetone— Dry Ice bath. The white crystals were isolated by vacuum filtration. During all operations in the purification of the ketone, an atmos- 16 ,46. phere of nitrogen was maintained. The ketone was 1 1 2
(46) It has been reported that 2-phenylcyclo pentanone decomposes on standing in air to d^-benzoylbutanoic acid in 11, 21, and 33 days to the extent of 4.8, 7-4, and 39/2, respectively.
dried overnight in a vacuum desiccator; m.p. 33-34° (lit.^^
m.p. 35-36°). The infrared and n.m.r. spectra of the
product were consistent with the structure of 2-phenyl
cyclopentanone. Vapor phase chromatography using S% FFAP
on Chromsorb W in an Aerograph Hi-Fi instrument attested
to the purity of the sample.
Synthesis of 1-phenylcyclohexene.— Bromobenzene
(314 g., 2.0 moles) in anhydrous ether (500 ml.) was slowly
added to dry magnesium turnings (54 g. , 2.2 moles) in a
3000-ml. flask equipped with a mechanical stirrer, a con
denser and drying tube, and an addition funnel. Cyclohexanone
(196 g., 2.0 moles) in anhydrous ether (300 ml.) was added
at a rate to maintain gentle reflux. Immediately the salt
was hydrolyzed with a solution of ammonium chloride (200 g.)
in water (500 ml.). Extraction with ether, followed by
drying over anhydrous magnesium sulfate and concentration,
afforded 1-phenylcyclohexanol, a yellow oil (192 g.). To this oil was added dilute sulfuric acid (80 ml. of cone,
sulfuric acid in 400 ml. of glacial acetic acid). The solu tion was swirled for 5 min. and then poured into 1500 ml. of water and 750 ml. of ether. The ether layer was washed 113 once with water and four times with saturated sodium bicarbonate solution. The solution was dried by filtration through anhydrous magnesium sulfate and the solvent was re moved under reduced pressure. Distillation yielded 1-phenyl- cyclohexene (166 g . , 52%) b.p. 112° (3 mm.). The infrared spectrum was consistent with the assigned structure.
Synthesis of 2-phenylcyclohexanone semicarbazone.—
Diborane, generated by addition of freshly distilled boron trifluoride etherate (230 g., 1.6 moles) in dry diglyme
(200 ml.) to a suspension of sodium borohydride (40 g . ,
1.05 moles) in dry diglyme (400 ml.) in a 1000-ml. flask equipped with an addition funnel and a magnetic stirrer.
The diborane was carried by a stream of clean dry nitrogen through Tygon tubing into a solution of freshly distilled
1-phenylcyclohexene (166 g., 1.05 moles) in anhydrous ether
(750 ml.). After addition was complete, the diborane generator was kept at reflux overnight. The hydroboration solution was maintained at room temperature. Excess hydride was destroyed by dropwise addition of water (100 ml.).
Chromic acid solution (220 g. of sodium dichromate and
165 ml. of conc. sulfuric acid diluted to 900 ml. with water) was added during 4 hours, maintaining gentle reflux. The mixture was refluxed an additional hour. The aqueous layer was extracted twice with ether. The combined organic 114 layers were washed once with water, 3 times with saturated sodium bicarbonate solution, and dried by filtration through anhydrous magnesium sulfate. Ether was removed under re duced pressure. The residue was taken up in 95% ethanol.
Water was added just to turbidity, and sufficient ethanol was then added dropwise to remove the turbidity. Anhydrous sodium acetate (175 g. ) and semicarbazide hydrochloride
(175 S') were added. The solid formed was filtered and digested in hot 1:1 ethanol-water. The procedure afforded
2-phenylcyclohexanone semicarbazone, m.p. 196-199 •
Synthesis of 2-phsnylcyclohexanone.— 2-Phenylcyclo- hexanone semicarbazone (10.8 g.) was dissolved in pyruvic acid (50 g.). The solution was allowed to stand under nitro gen at room temperature until a thick paste formed. The mixture was diluted with water (100 ml.) and neutralized with saturated sodium bicarbonate solution. The aqueous suspension was extracted three times with ether. The com bined ether layers were washed twice with saturated sodium bicarbonate solution, twice with 10% sodium hydroxide solu tion, and three times with water. The solution was dried over anhydrous magnesium sulfate and concentrated. The
2-phenylcyclohexanone was recrystallized from Skelly Solve B
(b.p. 60-68°) at -70° in an acetone— Dry Ice bath. Traces of solvent were removed under vacuum at 0°; m.p. 58-59 115 (lit,^^ m.p. 54-56°). The infrared and n.m.r. spectra of
(47) M. E. Kuehne, J. Amêr. Chem. See., 8^, 837 (1962). the product were consistent for 2-phenylcyclohexanone.
Vapor phase chromatography using 5% FFAP on Chromsorb W in an Aerograph Hi-Fi instrument attested to the purity of the ketone.
Cinnamvl chloride.— Thionyl chloride (317 g. > 2.67 moles) was added to pyridine (228 g. , 2.85 moles) in chloro form (500 ml.). This solution was added dropwise at 0° to freshly distilled cinnamyl alcohol (303 g. , 2.25 moles) in chloroform (300 ml.). The mixture was refluxed for 3 hours and then cooled. The chloroform solution was washed four times with cold water, and filtered through anhydrous mag nesium sulfate. The solution was concentrated under reduced pressure. Fractionation gave cinnamyl chloride (253 g.,
15%), b.p. 92-94° (3 mm.). The structure was supported by infrared and n.m.r. spectra.
Diethvl cinnamvlmalonate.— Diethyl malonate (265 g. ,
1.65 moles) was added dropwise to a hot solution of sodium
(38.2 g . , 1.65 moles) in ethanol (1200 ml.; dried by refhxing over 15 wt. pet. of sodium followed by distillation).
Cinnamyl chloride (253 g., 1.65 moles) was added to the 116 vigorously stirred solution of sodiomalonic ester at a
rate to maintain gentle reflux. The mixture was rcfluxed
overnight. After the ethanol was removed, the residue was
poured onto water and extracted three times with chloroform
(500 ml.). The chloroform solution was dried by filtration
through anhydrous magnesium sulfate and then concentrated.
Fractionation afforded diethyl cinnamylmalonate (285 g.,
63%), b.p. 170- 178° (1.5 mm.) [Lit.^B b.p. 137-140° (O.l mm.)]
(48) D . Barnard and L. Bateman, J. Chem. Soc., 926 (1950).
Infrared and n.m.r. spectra were consistent with the struc ture of diethyl cinnamylmalonate.
Diethyl( 3-bromo-3-phenylpropyl) malonate.— Dry hydrogen bromide was bubbled through diethyl cinnamylmalonate (285 g.,
1.03 moles) for 5 hours; during this period the temperature rose to 53° and then dropped to that of the laboratory.
After standing overnight the reaction mixture was treated with water and extracted with 1:1 ether-benzene. This solu tion was washed with cold water and with cold aqueous 1% sodium bicarbonate, and then dried by filtration through anhydrous magnesium sulfate. Concentration of the solution afforded a yellow oil (350 g., 95%) which was not further purified. 117 2-Phcnylcyclobutane-l, 1-dicnrboxylic acid.— To a
suspension of sodium hydride (50 g. , 1.03 moles, 50% in
oil) in dry tetrahydrofuran (750 ml., distilled from sodium
hydride) crude diethyl( 3-bromo~3-phenylpropyl)malonate
(350 g.) in dry tetrahydrofuran (200 ml.) was added with
stirring and cooling under nitrogen. Hydrogen evolution
began immediately and continued throughout the addition
Stirring was continued overnight during which most of the
tetrahydrofuran had evaporated. Ice-water was added and
the solution was extracted three times with ether (300 ml.).
The ether was removed under reduced pressure and the residue was treated with alcoholic potassium hydroxide [potassium hydroxide (I64 g . , 2.9 moles) in 1:1 ethanol-water (500 ml.)] at reflux for 3 hours. The ethanol was distilled and the residue treated with water. The aqueous solution was washed three times with ether (200 ml.), and then acidified. The solid acid was isolated via ether— benzene extraction. The solution was concentrated and the acid precipitated.
Washing with cold benzene yielded 2-phenylcyclobutane-l,1- dicarboxylic acid (130 g., 58%), m.p. 176-178° [lit.^^
(49 ) C. Beard and A. Burger, J. Org. Chem., 26, 2335 (1961). m.p. 173-174°]. 118
2-Phcnylcyclobut/r.none semicarbazone.— A solution
2-phcnylcyclobutane-l,1-dicarboxylic acid (22.0 g. ,
0.10 mole) in acetone (40 ml.)-water (50 ml.) in a
1000-ml. three-necked flask fitted with a dropping
funnel, mechanical stirrer, and condenser, and cooled
to between -5° and 0° in a salt-water-ice bath was
treated with triethylamine (24.0 g. , 0.24 mole) in
acetone (200 ml.). This was followed by a solution of
ethyl chloroformate (26.0 g. , 0.24 mole) in acetone (50
ml.), also at -5° to 0°. After the mixture had been
stirred for 30 minutes at -5° to 0°, a solution of sodium
azide (19.6 g. , 0.30 mole) in water (100 ml.) was added.
Stirring was continued for an additional hour at -5° to
0°. The mixture was then poured into 300 ml. of satu
rated aqueous sodium chloride solution. The products of reaction were extracted with two portions of ether (200 ml.). The combined extracts were filtered through anhyd
rous magnesium sulfate. Absolute ethanol (500 ml.) was
added to the dried ether solution. The ether was removed by distillation using a Neiiman take-off condenser, and the ethanol solution was then refluxed for two hours.
The ethanol was distilled, and the residual oil treated with 2% aqueous sulfuric acid (500 ml.). The products were steam distilled. The milky distillate was extracted 119 three times with ether. The combined extracts were fil
tered through anhydrous magnesium sulfate. The ether
was removed under reduced pressure leaving a yellow oil
(10.4 g.). This product was taken up in 95% ethanol
(150 ml.) and water (50 ml.). Anhydrous sodium acetate
(15 g.) and semicarbazide hydrochloride (14 g.) were
added and the solution was warmed and stirred on a hot
plate for two hours. The solution was cooled in a
freezer, and crystallization of the semicarbazone was
induced by scratching the inside of the flask with a
glass rod. The crystals were isolated by vacuum filtra
tion. The crystals were washed with cold ethanol and
then dried under vacuum. The yield of 2-phenyleyclo- butanone semicarbazone was 8.3 g. (25%). The identity
and purity of the sample were confirmed by its infrared
and n.m.r. spectra, and its m.p., 167-168*^ (lit.^S m.p. 164-166°).
2-Phenyleyclobutanone.— 2-Phenyleyelobutanone
semicarbazone (8.3 g,) was dissolved in pyruvic acid^
(23.8 g.) and stored in a nitrogen atmosphere for six
hours with periodic swirling. After a few minutes a
finely-divided white solid began to form; within a few
hours the mixture had become a thick paste. The reac
tion mixture was diluted with water (100 ml.) The 120 aqueous suspension was extracted twice with ether (50 ml.)
The combined ether extracts were decolorized with acti vated charcoal and dried over anhydrous magnesium sulfate.
Ether was removed under a stream of nitrogen at room tem perature. The remaining solid was recrystallized from
Skelly Solve C (b.p. 60-68°) at -70°. Throughout the purification, the ketone was kept under nitrogen whenever possible. Traces of solvent were removed under vacuum in a sublimator at -70° for five hours. The identity and purity of the sample were confirmed by its infrared and n.m.r. spectra and by vapor phase chromatography using 5^ FFAP on Chromsorb W in an Aerograph Hi-Fi instrument.
Kinetics of bromination. General.— 2-Phenylcyclo- hexanone, 2-phenylcyclopentanone, and 2-phenylcyclobuta- none were synthesized or obtained and purified as described above. Their purity was attested by vapor phase chroma tography using 5% FFAP on Chromsorb W. The acetic acid used as solvent was refluxed over excess chromium tri oxide and distilled; the middle fraction was retained.
Demineralized double-distilled water obtained from
The Ohio State University Reagents Laboratory was used as solvent. Analytical reagent anhydrous sodium acetate 1 2 1 (Mallinckrodt) was oven-dried at 225° for 48 hours and
then cooled to room temperature in a desiccator before
being used to catalyze the enolizations. The sodium
thiosulfate solution used in the titrations was pre
pared by The Ohio State University Reagents Laboratory
by accurately diluting standard N/lO sodium thiosulfate.
Kinetics of bromination of 2-phenylcycloalkanones.—
Dnominations were run at a series of temperatures in a
10-gallon water bath thermostatted by a Sargent heater
and circulator and a German-made Jumbo MS D.B.P.
thermostat. Temperatures were measured with a thermom
eter which had been calibrated against a thermometer
obtained from the National Bureau of Standards.
The brominations were run under pseudo first- order conditions in which the initial concentrations of acetate ion were approximately 25 times greater than that of the ketone. The brominations were followed to 2S% completion, after which point the hydrogen bromide formed during bromination began to cause devia tion from the first-order plot.
The bromination of a ketone is first order with respect to ketone but independent of bromine concen tration. The rate constant was evaluated by the use of Equation 25. 1 2 2
k = lor, 10 1^ 2 2 4 ° (26) t (ketone)t
in whlcli (ketone)^ nnd (ketone)^ refer to concentrations
of ketone at t = o and t = tiinc t, respectively. The
rate constant was dctcrnvLncd graphically from the least
squares slope of the line (multiplied by 2.303) ob
tained upon plotting log^^Cketone)^ against time.
The thermodynamic parameters of activation for
the brominations were then calculated from the rate
constants. The rate of a chemical reaction may be
expressed by the equation^^
(27)
(5 0 ) A. A. Frost and R. G. Pearson, "Kinetics and Mechanism," 2nd ed. , 2nd printing, John Wiley and Sons, New York, N. Y., 1962, p. 99- where is the entropy of activation, k is the Boltz- man constant, h is Plank's constant, and is the
enthalpy of activation. On solving for log^^(^)
there is obtained
log (iS) = - f ! — i I ' log (k='"*/^) xogio^T J 2.303R T 2.303 ^ 1 0 h ^ (28)
If As+ is temperature independent, the plot of
log^^(^) versus ^ gives a straight line, and can 123
be evaluated from the slope. If the original equation
is rearranged and appropriate values of the physical
constants are substituted, the equation
AH* i , „ ASt = " Y — + 4.577 ) " "^7.23 (29)
is obtained where kj, is measured in sec.
Bromination of 2-phenylcycloalkanones.— The
important details of the experimental procedure are
given below. A catalyst solution was prepared by weighing
sodium acetate (81.5 g., 0.994 mole) into a 1000-ml. volu
metric flask. Water (500 ml.) and bromine (5.2 ml.) were
added and the solution was then diluted to volume with
acetic acid at 30°. A weighed sample of ketone (approxi
mately 0.002 mole) was placed in a 50-ml. volumetric
flask. Water (25 ml.) was added and the solution was
diluted to volume at 30°. By means of pipets, catalyst
solution (25 ml.) and ketone solution (25 ml.) were
mixed in a glass-stoppered flask at 30°. The reaction medium was therefore approximately 0.500M in acetate ion,
0.050M in bromine, and 0.020M in ketone. At measured time
intervals 5 ml. aliquots were withdrawn and added to
a flask containing 4^ potassium iodide (40 ml.), 0.25 N hydrochloric acid, (5 ml.), and carbon tetrachloride 124
(5 ml.). The iodine liberated was titrated with
0.0100 N sodium thiosulfate solution using starch solution as the indicator.
Kinetics of deuterium exchange. General.—
Solvent dioxane was purified by the method of Wiberg.
Reagent grade 1,4-dioxane (2000 ml) was treated with dilute hydrochloric acid (27 ml. of concentrated hydro- chlorie acid and 200 ml. of water) and refluxed for 15 hours while nitrogen was bubbled through the mixture to entrain liberated acetaldehyde. Pellets of potassium hydroxide were added slowly until a separate yellow layer formed and no more potassium hydroxide dissolved.
The solvent was decanted and the procedure repeated twice more. The dioxane was refluxed with excess sodium for 12 hours, and finally distilled.
Dimethylformamide was dried over Molecular Sieve
4A and distilled.
Cycloalkyl phenyl ketones were obtained from
Aldrich Chemical Company and purified by distillation just before use. Diisopropyl ketone and dicyclopropyl ketone were used as obtained.
Deuterium oxide (> 99-5%) was obtained from
Chemical Samples Company. 125 Kinetics of deuterium exchange.— Deuterium exchange of the various ketones was effected at 30.0 - 0.1 or
60 i 0.1° in kinetic mixtures immersed in a 10-gallon water bath thermostatted by a Sargent heater and circu lator and a German-made Jumbo MS D.B.P. thermostat.
Exchange of active a-hydrogen of the ketones was measured by integration of the n.m.r. spectra of aliquots of the reaction mixtures. The integral of the remaining reactive hydrogen was measured with reference to the integral of the phenyl signal of the ketone on the assumption that the phenyl integral remained constant at 5 hydrogens. In
i ketones in which there was no phenyl group, an alkyl group served as standard.
The exchange reactions were effected under pseudo first-order conditions, since the base was effectively regenerated after each exchange. The rate constant was evaluated by equation 3 0.
^ « 0 ) in which (a-hydrogen)^ and (a-hydrogen)^ refer to the value of the integral of the exchangpable hydrogen compared to that of the phenyl integral at t = o and t = time t, respectively. The rate constant was determined graphically 126 from the slope of the line (multiplied by 2.303) obtained upon plotting log^^ (a-hydrogen)^ against time.
Deuterium exchange of cycloalkyl phenyl ketones.—
The important experimental details are described in the following summary. A catalyst solution was prepared by
— 1 dissolving 0.115 g. (5.00 x 10 mole) of sodium in deuterium oxide at 0°. The sodium deuteroxide solution was diluted to 100 ml. at 30°. A weighed sample of ketone
(0.025 mole) was dissolved in purified dioxane in a 50-ml. volumetric flask. Catalyst solution (5 ml.) was added to the ketone solution, and the reaction mixture was immedi ately diluted to volume with dioxane and vigorously shaken.
Aliquots (10 ml.) were withdrawn at measured intervals
(usually 2-12 hours apart) and quenched with ice-water
(50 ml.) and immediately extracted three times with pentane
(25 ml.). The combined pentane layers were washed rapidly five times with water (25 ml.) and filtered through anhydrous sodium sulfate. Pentane was removed under reduced pressure.
The samples were shown to be pure by vapor phase chroma tography using 5% FFAP on Chromsorb W in an Aerograph Hi-Fi instrument. The n.m.r. spectrum of each sample was recorded and integrated on a Varian A-60 spectrometer. 127
Deuterium exchange of diisopropyl ketone.— Diiso propyl ketone (17.0 g., 0.15 mole) was dissolved in dimethylformamidc in a 100-ml. volumetric flask. Clean sodium (0.46 g., 0.02 mole) was dissolved cautiously in ice-cold DgO (25 ml.). The sodium deuteroxide solution was brought to 60 i 0.1° and then rinsed into the ketone solution, also at 60 1' 0.1°. The reaction solution was diluted to volume at 60°. Since solution was incomplete, the mixture was rapidly transferred to a larger flask and an additional 50 ml. of dimethylformamide was added. At measured intervals 10-ml. aliquots were withdrawn and added to 50 ml. of cold water in a 125-ml. separatory funnel. The mixture was extracted three times with pentane
(25 ml.). The combined pentane layers were washed three times with cold water (25 ml.), and dried by filtration through anhydrous sodium sulfate. Pentane was removed under reduced pressure. Deuterium exchange was analyzed by n.m.r. using a Varian A-60 spectrometer.
The method described above was also used to study the deuterium exchange of isopropylphenyl ketone and the attempted exchange of dicyclopropyl ketone and cyclopropyl phenyl ketone. 128
Deuterium exchange of 2-phcnylcycloalkanoncs.—
The important features of the method are deseribcd below.
A catalyst solution was prepared by dissolving sodium acetate (20.5 g., 0.2 5 mole) in deuterium oxide (125 ml.), and then diluting the solution to 2 50 ml. with deutero- aeetic aeid (from reacting acetic anhydride with deuterium oxide followed by distillation at 30°. A solu tion of 2-phenylcyclohexanone was made by dissolving the ketone (1.74 g. , 0.01 mole) in pure deuteroaeetic acid and diluting the solution to 100 ml. with deuteroaeetic acid at 30°. The reaction was initiated by adding via pipet 25 ml. of ketone solution to 25 ml. of catalyst solution in a 125-ml. conical flask at 30°. Aliquots were withdrawn at measured intervals and added to 75 ml. of cold water. The product was extracted three times with pentane. The combined pentane layers were washed twice with water, once with saturated sodium bicarbonate solution, and finally once again with water. The pentane solution was dried by filtration through an hydrous sodium sulfate. The pentane was removed and a carbon tetrachloride solution of the product was analyzed for deuterium exchange by n.m.r. spectroscopy using a
Varian A-ÔO spectrometer.