1254
National Institute of Arthritis and Metabolic Diseases, which permitted purchase of the Unicam spectrophotometer and provided funds temporarily to pursue the research; they are also grateful for an NSF Under-
graduate Research Participation award to I. D. R. They also thank Professor R. L. Cleland for the generous loan of a constant temperature water circulator, and D. J. Hupe for valuable discussions.
Amine Catalysis of Elimination from a P-Acetoxy Ketone. A Study of Catalysis via Iminium Ion Formation Donald J. Hupe, Martha C. R. Kendall, and Thomas A. Spencer*
Contribution from the Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755. Received June 2, 1971 Abstract: A kinetic study of the elimination of acetic acid from 9-acetoxy-10-methyl-cis-decalone-2 (1) to form 10-methyl-A1~9-octalone-2 (2) in aqueous solution has been made using hydroxide ion, hydronium ion, acetate ion, and a variety of amines as catalysts. General base catalysis is observed, defining distinct Brpnsted lines with fl 0.6 for primary, secondary, and tertiary amines. A mechanism for this elimination reaction involving rate-determining proton abstraction is confirmed by observation of a large primary kinetic isotope effect when the elimination is performed on 1 appropriately labeled with deuterium. With primary amines having pK, < 8, covalent catalysis by amines is also found, involving terms proportional to protonated amine and proportional to protonated amine times free amine. The bell-shaped pH-rate profiles observed as a consequence of the latter term have been completely analyzed into the component general base and covalent catalysis terms. All evidence, including a primary kinetic isotope effect, is consistent with rate-limiting abstraction of an a-proton from an iminium ion by a general base in the bimolecular covalent catalysis. A Brpnsted fl of -0.5 has been determined for this proton abstraction. Temperature-dependence studies indicate that the bimolecular catalysis has a large negative A S (-35 eu), but a relatively small AH* (10 kcal/mol). It is estimated that conversion of a carbonyl compound to a cyanomethyliminium ion increases the rate of a-proton abstraction by a given general base by -IO6. This nucleophilic catalysis is discussed as a model for certain enzymic processes and compared with previous related studies. Evidence is presented which is inconsistent with previously postulated analogous catalysis involving iminium ion formation by imidazole.
*
D
espite several recent studies 1-6 of amine catalysis of carbonyl compound reactions, there still remain many incompletely understood aspects of this biologically important’ type of process, particularly with respect t o the details of covalent catalysis via iminium ion formation by primary and secondary amines. In the preceding paper,8 a study of general base catalysis by amines of the elimination of hydrogen chloride from 9-fluorenylmethyl chloride was made in order to establish a background against which to search for catalysis involving amines as nucleophiles. In this paper, amine-catalyzed elimination of acetic acid from 9-acetoxy- IO-methyl-cis-decalone-2 (1) has been investigated and has, as hoped, provided an opportunity to evaluate and study catalysis involving amine-carbony1 condensation. Proposals of such covalent catalysis by amines, which were first advanced for the decarboxylation of 6-keto (1) L. P. Koshechkina, E. A. Shilov, and A. A. Yasnikov, Ukr. Khim. Zh., 35, 55 (1969), and previous papers in this series. (2) M. L. Bender and A. Williams, J. Amer. Chem. Soc., 88, 2502 (1966). (3) G. E. Lienhard and T-C. Wang, ibid., 90, 3781 (1968). (4) J. Hine, M. S. Cholod, and J. H. Jensen, ibid., 93, 2321 (1971),
and previous papers in this series. (5) L. R. Fedor and W. R. Glave, ibid., 93, 985 (1971), and previous papers in this series. (6) J. A. Feather and V. Gold, J . Chem. Soc., 1752 (1965). (7) See W. P. Jencks, “Catalysis in Chemistry and Enzymology,” McGraw-Hill, New York, N. Y., 1969, especially Chapters 2 and 3 for a review and specific references. (8) T. A. Spencer, M. C. R. Kendall, and I. D. Reingold, J . Amer. Chem. Soc., 94, 1250 (1972).
acidsg and the dealdolization of diacetone alcohol, l o have been extended, with impressive if sometimes ambiguous‘ evidence, to aldehyde and ketone enolization in model systems,*t4and to reactions catalyzed by aldolases” and decarboxylases. l * Of particular relevance to the 6-elimination reaction studied in the present research are Abeles’ investigation of the enzymic conto a-ketogluversion of 2-keto-3-deoxy-~-arabonate tarates emialdehyde, l 3 Fedor’s studies of general base catalyzed @-eliminationsin model systems very similar to ours,j and Hine’s recent finding of intramolecular bifunctional catalysis involving iminium ion formation. The particular P-acetoxy ketone (1) chosen as a substrate for the study described herein, while less readily prepared than other possibilities, has the distinct advantage of undergoing elimination essentially quantitatively to the chromophoric and stable enone 2. It was also chosen because it is the same type of substance we have previously used to study the stereochemistry and mechanism of intramolecular aldol condensation^'^ and keto1 dehydrations. l 5 The catalysts employed were (9) K. J. Pedersen, J . Phys. Chem., 38, 559 (1934). (10) F. H. Westheimer, Ann. N . Y . Acad. Sci., 39, 401 (1940). ( 1 1 ) J. C. Speck, Jr., P. T. Rowley, and B. L. Horecker, J . Amer. Chem. SOC.,85, 1012 (1963). (12) F. H. Westheimer, Proc. Chem. Soc., 253 (1963). (13) D. Portsmouth, A. C. Stoolmiller, and R. H. Abeles, J . B i d . Chem., 242,2751 (1967). (14) T. A. Spencer, K. K. Schmiegel, and K. L. Williamson, J . Amer. Chem. Soc., 85, 3785 (1963); T. A. Spencer, H. S. Neel, D. C. Ward, and K. L. Williamson, J. Org. Chem., 31, 434 (1966).
Journal ojthe American Chemical Society / 94:4 / February 23, 1972
1255
those used in the preceding paper,s augmented by additional amines suggested by the results as the study proceeded.
Results Preparation of the desired P-acetoxy ketone 1 was initially attempted by direct acetylation of the readily available keto1 3,l6 with, for example, isopropenyl acetate. Ir and nmr spectra of the acetylation products indicated that the material was largely 1, but the acetoxy ketone would not crystallize and could not be purified by chromatographic or other methods, all of which caused an increase in the amount of enone 2 in the product. Therefore, the indirect method shown in Scheme I (which was necessary in any case for the preparation of deuterated 1 as discussed below) was adopted.
;
5
1
y; 3
4
7
!P
I
I
Figure I . Plot of pseudo-first-order rate constants, k o b s d , for the reaction of 1 to give 2 L'S. concentration of free 1,4-diazabicyclo[2.2.2]octane (DABCO) at pH 10.37 (O), pH 9.77 (A), and pH 7.89 (a). The intercepts (0) are calculated values of k o ~ [ o H - ]at the respective pH values. (k=[H30+]is negligible at these pH values.)
Scheme I
@:
0
OA: 1
7, R,=OAc; R2-H 8, R,-H; &=OAc 9, R, = OH; R2 = H 10, R, = H; & = OH
2
\
5, R,=OH;RZ=H 6, R,=H; R 2 = O H
OH 3
4
Enone 2 was converted to the crystalline P-oxide 4 by the procedure of Kuehne and Ne1s0n.l~ Hydride reduction of 4 afforded a mixture of the known18 diols 5 and 6 epimeric at C2,and acetylation with isopropenyl acetate converted these to a mixture of the corresponding diacetates 7 and 818 in 33% overall yield from 2. Selective hydrolysis of the secondary acetate groups ,>f 7 and 8 with niethanolic sodium hydroxide at 25" afforded a mixture of hydroxyacetates 9 and 10, which were purified by preparative tlc (54% yield) and oxidized with Jones reagentlg to the desired 1 (88 % yield), which could thus be obtained crystalline and pure, mp 49-50'.
In order t o determine whether the conversion of 1 t o 2 would show a kinetic isotope effect, ketoacetate 1 substituted at Cl with deuterium was also required as a substrate. This was prepared by a completely analogous route starting with pentadeuterio enone 2 ( 2 4 prepared by exhaustive isotopic exchange of 2 in deuteriomethanol-sodium methoxide. Deuterium incorporation was followed to completion by disappearance of the vinyl proton peak in the nmr spectrum of 2. N o loss of deuterium at C1 was detectable after the basic epoxidation of 2-ds. Subsequent reduction with lithium aluminium deuteride, acetylation, and selective (15) T.A. Spencer, H. S. Neel, T. W. Flechtner, and R. A. Zayle, Tetrahedron Lett., 3889 (1965). (16) J. A. Marshall and W. I . Fanta, J . Org. Chem., 29, 2501 (1964). (17) M. E. Kuehne and J. A. Nelson, ibid., 35, 161 (1970). (18) H. B. Henbest and J. McEntee, J . Chem. Soc., 4478 (1961). (19) A. Bowers, T.G. Halsall, E. R. H. Jones, and A . J. Lemin, ibid., 2548 (1953).
hydrolysis all were conducted exactly as with the unlabeled analogs. The final Jones oxidation to 1-Cl-d~ required more vigorous reaction conditions, however, presumably owing to the primary kinetic isotope effect caused by the Cz deuterium atom.20 The nmr spectrum of the product ketoacetate confirmed that it was essentially completely deuterated at C1, for none of the usually readily discernible AB quartet for the C1protons at 6 3.1 ppm could be detected. The reaction of dilute solutions of 1 (and later 1-CId2)in water was monitored by observing the increase in ultraviolet absorption at 247 mp caused by formation of 2. As anticipated, the reaction proceeded essentially quantitatively and afforded excellent pseudo-first-order kinetics under almost 'all catalytic circumstances. The rate of formation of 2 from 1 is described by eq 1
~ A [ R N H ~-k + I ~ ~ A B ~ [ R N H ~ + ] [ B(1) ~]}[~] i
where [H30+]is uH as measured by pH meter, [OH-] is k,/uH, RNH3+ is a protonated primary amine, and B is any general base present. The value of k H was obtained from the slope of a plot of kobsd us. u H , in unbuffered hydrochloric acid solutions at pH < 2. Similarly, koH was determined as the slope of k,,bsd us. K , / u H for unbuffered runs at pH > 9. A pH-independent component ascribable t o water catalysis was not detected. Catalysis proportional to base concentration was observed with acetate buffer and every amine buffer examined. The value of the second-order rate constant for this general base catalysis, kB, was determined from the slope of a plot of kobsd us. the concentration of free amine or acetate ion. The concentration of the general base, [B], was calculated by multiplying the total buffer concentration by Ka/(Ka uH), where K, is the ionization constant of the protonated species. For all tertiary amines, plots of kobsd us. [B] gave straight lines of slope kB and intercept kHIH,O+] koHIOH-1, as illustrated in Figure 1. Since no increase in the slope of the plots was found in any case for runs at pH values well below the pKa, catalysis proportional to protonated
+
+
(20) F. H. Westheimer and N. Nicolaides, J . Amer. Chem. Soc., 71,
25 (1949).
Hupe, Kendall, Spencer
1 Amine Catalysis via Iminium Ion Formation
1256 Table I. Rate Constants for the Reaction of 1 to Form 2 in Water at 25” Catalyst
koH, kH +,Or kg (M-l sec-1)
PKS
1.2 8.0x 3.1 x 1.3 X 1.9x 2.2x 2.5 x 3.2X 2.0x 3.0X 4.6X 5.9x 5.2 x 2.2x 3.5 x 6.7x 1.2x 8.9x 8.9x 3.6x 3.8 x 1.2x 5.7x
15.7 -1.7 11.32= 11.22b 11.loa 10.9Y 10.75d 10.61d 10.19c 9.82e 9.76b 9.49b 9.44f 8.70~ 8.365 7.73h 7.41b 7.06% 6.95j 5 .70k 5.341 4.76m 4.20“
Hydroxide ion Hydronium ion Pyrrolidine Piperidine Hexamethylenimine Quinuclidine Triethylamine N-Butylamine N-Methylpiperidine Piperazine Trimethylamine Allylamine Ethoxyet hylamine
1,4-Diazabicyc10[2~2.2]octane Morpholine Ethyl glycinate N-Methylmorpholine N-Methylimidazole Imidazole 2,2,2-Trifluoroethylamine Cyanomethylamine Acetate ion N,N-Dimethylcyanomethylamine
p H range
9.1-11,5 1.3-1.8 7.6-10.7 7.3-10.9 10.0-10.8 7.4-10.8 10.1-10.8 10.4-11.1 7.3-8.8 9.2-9.3 8,5-9.7 8,8-9.4 8.5-9.6 7.9-8.6 7.8-8.9 5.7-7.7 6.5-7.4 6.6-7.2 6.7-7.2 2.9-7.1 2.9-7.1 4.2-5,O 4,2-5.0
10-5
10-1 10-l 10-1 10-1 10-3 10-3 10-3 10-3
10-2
10-3 10-4 10-4 10-4 10-4 10-5 10-6 10-5 10-6
Total catalyst concn [MI
1.2X 1OV-3 X 1.6X 10-’-5 X 10-2 0.52-0.006 0.50-0.006 0.444.005 0.59-0.01 0.10-0.006 0.40-0.005 0.03-O.002 0.374.005 0,434). 006 0,534.007 0 . 4 0 4 . 005 0,044.01 0.25-0.003 0.504.007 0.38-0.005 0.14-0.009 0.6M.008
0,38-0.02 0.43-0.005 0.38-0.02 0.384.02
No. of runs
52 4 32 36 20 28
16 20 8 12 28 20 20 36 36 28 16 12 16 24 40 12 12
H. K. Hall, Jr., J . Phys. Chem., 60, 63 (1956). * H. K. Hall, Jr., J . Amer. Chem. SOC.,79, 5411 (1957). e C. A. Grob, A. Kaiser, and E. Renk, Chem. Znd. (Londort), 598 (1957). N. A. Lange, “Handbook of Chemistry,” VcGraw-Hill Book Co., Inc., New York, N. Y . , 1961,pp 1203-1204. e J. Bjerrum, “Stability Constants,” Chemical Society, London, 1958,Part I, p 21. f R. C. Cavestri and L. R. Fedor, J . Amer. Chem. Soc., 92, 4610 (1970). 0 The Merck Index, 8th ed, Merck & Co., Inc., Rahway, N. J., 1968,p 1072. 0. H. Emerson and P. L. Kirk, J . Biol. Cliem., 87,597 (1930). Determined in this study by the half-neutralization method. I T.C. Bruice and G. L. Schmit, J . Amer. Chem. SOC.,80, 148 (1958). E. R. Bissel and M. Finger, J. Org. Chem., 24, 1256 (1959). G. W. Stevznson and D. Williamson, J . Amer. Chem. SOC.,80, 5943 (1958). Reference 3. S . Soloway and A. Lipschitz, J . Org. Chem., 23, 613 (1958). Q
tertiary amine is unimportant. For primary and secondary amines with pK, > 9, kB could be obtained as for tertiary amines. For primary amines of low pK,, however, it was necessary t o obtain kB from runs done at
rate constants, k g , are summarized in Table I. A Bronsted plot of log kB L‘S. pK, is shown in Figure 2 . The rationale for drawing three lines of slope /3 = 0.59 is discussed below.
5 4
5
6
7
8
9
IO II P K ~
12
13
14
15
16 6
Figure 2. Brqnsted plot of the logarithms of the second-order rate constants from Table I for the reaction of primary (0),secondary (V), and tertiary (A) amines, and hydroxide ion and acetate ion (n),with 1 to give 2 GS. pK2s of their conjugate acids. The slope of the lines is 9 = 0.59. (The points for the diamines piperazine and DABCO have been corrected according to the relationship given by Jencks, ref 7, p 173.)
Protonated Amine
[MI
Figure 3. Plot of pseudo-first-order rate constants, kobsd, for the conversion of 1 to 2 us. concentration of protonated cyanomethylamine. Experimental points are given for runs at pH 3.81 (A), pH 4.40(V), and pH 5.35 (0). The curves at each pH were calculated from the expression kobsd = kg[RNH2] ~ A [ R N H ~ + ]kAB. [RNH2][RNH3+]using the appropriate rate constants from Table
+
+
11.
pH values well above the pKa in order to minimize other
kinetic terms discussed below.21 All the second-order (21) Morpholine, the only secondary amine studied with pK,
