KINETICS OF BASIC HYDROLYSIS OF A HOMOLOGOUS SERIES OF SUBSTITUTED LACTONES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University % THOMAS JOHN DOUGHERTY, B. 8. The Ohio State University 1959 Approved by Adviser Department of Chemistry ACENOMLEDGMËNT I would like to express my sincerest appreciation to Dr. Harold Shechter for suggestion of this problem, for his gudidance during the course of this investigation, and in particular for many interesting and inspiring discussions throughout the course of writing this dissertation. I should also like to thank my colleagues for the loan of their time and equipment. I am grateful to the Standard Oil Company of Ohio and to the National Science Foundation for fellowship funds. 11 Dedicated to the memory of my Mother whose intellectual curiosity I hope someday to attain. iii TABLE OF CONTENTS Page I. INTRODUCTION 1 II. THEORY AND HISTORY Mechanism of saponification of Lactones. Factors Affecting Saponification Rates of Lactones and Esters..................... 5 Bimolecular Water Hydrolysis of beta-Lactones. lU Reactions of beta -Isovalerolactone in Water . 15 Effect of Solvent on Rates of Saponification of Lactones............................ 16 Previous Investigations............. 17 H I . DISCUSSION AND INTERPRETATION OF RESULTS 23 Scope of Present Investigation ............... 23 Saponification of Homologous Unsubstituted Lactones ................................ 27 Effect of Methyl Substitution on Reactivities of Lactones.............................. 36 Substituted L-membered lactones ..... 37 Substituted 5-membered lactones ....... h2 Substituted 6 -membered lactones ..... kB Substituted 7-membered lactones ........ 51 Relative Effects of Substitution on the Saponifi­ cation of Lactones of Various Ring Size . 52 Entropy Effects on Saponification of Lactones . 59 Summary of Results ........................ 62 IV. EXPERIMENTAL 6It Preparation and Purification of Materials. 6U 1,2-Diraethoxyethane................. 6k 3-Ifydropropanoic Acid Lactone ....... 6k 3-Hydroxy-2-methylpropanoic Acid Lactone 65 3-%droxybutanoic Acid Lactone. .... 66 3-Hydr03qr-2,2-dimethylpropanoic Acid Lactone ........................ 68 3-Hydroxy-3-methylbutanoic Acid Lactone 67 4-Hydroxybutanoic Acid Lactone. .... 69 li-Ifydroxy-2-methylbutanoic Acid Lactone 69 li-Hydroxypentanoic Acid Lactone .... 70 li-Hydroxy-2,2-dimethylbutanoic Acid Lactone 71 IV TABLE OF CONTENTS (CONTD.) Page IV. EXPERIMENTAL (Gontd.) Preparation and Purification of Materials (Gontd.) l|.-Hydroxy-3i3-dimethylbutanoic Acid Lactone. 71 i;-Hydroxy-li-raethylpentanoic Acid Lactone.... 70 . 5-Hydroxypentanoic Acid Lactone............. 73 5“Hydroxy-2-niethylpentanoic Acid Lactone ..... 7k 3“Hydroxyhexanoic Acid Lactone ................. 76 5-Hydro3{y-2,2-diinethylpentanoic Acid Lactone . 77 $-%rdro%y-3,3-dimethylpentano ic Acid Lactone . 76 5-Hydroxy-5“-inethylhexanoic Acid Lactone..... 78 6-Hydroxyhexanoic Acid Lactone............. 79 6-Hydroxyheptanoic Acid Lactone............. 79 Determination of Kinetic Constants............... 80 Equipment................................... 80 Constant Temperature Baths ..................... 80 Conductometric Equipment ....................... 80 Conductivity C e l l s ........................ 81 Hypodermic Syringes. ........................ 81 Kinetic Techniques............................ 81 Solvents and Standard Solutions............. 81 Preparation and Execution of a Kinetic Run .... 82 Calculations.................................. 61; APPENDIX............................................. 93 IIST OF FIGURES Figure Page 1-7 Representative Plots of t (Rcq-R) versus R for Basic Hydrolysis of Lactones.................. 7-26 Activation Energy ( a H^) Plots for Basic hydrolysis of Lactones....................................... 101 VI LIST OF TABLES Table Page I. Saponification Bates and Dipole Moments of Homologous Lactones...................... 8 II. Kinetics of Alkaline Hydrolysis of Homologous Lactones in 1,2-Diraethozyethane-water (63.i|:36.6^ by wt.) by Sodium Hydroxide.............................. 9 III. Effect of Ring Substituents on the Ifydrolysis of Homologous Lactones.............................. 18 IV. Kinetic Data for Saponification of Lactones by Ifydroxide Ion in l:2-Dimethoxyethane-water (ItLby vol. at 2^®) 2h V. Effect of Solvent Composition on Rates of Saponification of Homologous TJnsubstituted Lactones............. 28 VI. Equilibrium Data for Reaction of Ketones with Hydrogen Cyanide. ................................ 2t8 vn. Absolute and Relative Rates of Saponification of Homo­ logous Substituted Lactones...................... 53 VUI. Rates of Hydrolysis of beta-Isovalerolactone as a Function of Concentration ; '.......... 91 IX-XCIX Kinetic Data for Saponification of Lactones by Sodium Hydroxide......................................... 120 Vll I. INTR0DUCTK3Ï The objectives of the present study are: (1) to determine effects of ring size and substituents on the basic hydrolysis of lactones; (2 ) to determine and interpret the kinetic parameters of basic hydrolysis of lactones; (3) to obtain information concerning electrical and steric effects on hydrolysis of various lactones; (ii) to obtain information vith respect to the conformations of lactones and their reaction intermediates; (5) to obtain more information concerning the lack of reactivity of the beta-propio- lactone system; (6 ) to obtain general information concerning kinetic effects in heterocyclic molecules in congparison to their correspond­ ing carbon coiqpounds and; (7) to extend in general the knowledge and theories of cyclic molecules. For these purposes, a homologous series of mono-methyl and gem- dimstiyl substituted lactones containing U, 5, 6 and 7 ring atoms were synthesized and their saponification rates determined at three temperatures in 1 ,2-dimethoxyethane-water (1:1 by volume, 25°). Enthalpies and entropies of activation were calculated from the rate constants at three tenperatures. The parent, unsubstituted lactones of this series were studied for comparison with the sub­ stituted lactones and for comparison with previous data obtained in a solvent of different composition. II. THEORY iWD HISTORY Mechanism of Saponification of Lactones Base-catalyzed hydrolysis of lactones has been a subject of considerable study. The previous investigations ■which are pertinent to -fche present study will be summarized briefly. In common with open-chained esters, the usual mechanism of saponification of lactones involves acyl-oxygen fission with formation of the -hydroxyalkanoate ion (1). The o-verall reaction and -fche apparent mechanism of hydrolysis are indicated as follows: 0 (CÎ2)yj - G — OH fast fast u -0-J slow fast , ^ O 0 - (CHg)^ - GOgH — _Y HO - (CHg)^ - COg . (1) (1) See C. K. Ingold, Structure and Mechanism in Organic Chem- istry, Cornell l&iiversity Press, I-thaca, N.Ÿ., i?^3, chapter lit, p. 7^2 -781, for a discussion of ester l^drolysis. The hydrolysis exhibits second order kinetics, first order with respect to lactone and first order with respect to hydroxide ion. Saponification experiments conducted in water enriched wi-th 0^^ support acyl-oxygen fission in lactones. Bothy^ -butyrolactone (2 ) 2 3 and fi -butyrolactone (3) yield the corresponding hydroxybutanoate ions in which 0^® is introduced only in the carboxylate groupj Equations 2 and 3* (GHg)] - C = 0 + O H ^ — > HO - (GHg)^ - GOg^ ^ ; (2) ÏÏ2 C=o g)l8 , - I + OH --- » HQ - GH (GH3) - GHg - GOg (3) GH3 - CH (2) F. long and L. Friedman, J. Am. Ghem. Soc., 72, 3692 (1950). (3) A. Olson and J. Hyde, J. Am. Ghem. Soc., 2^59 (19W-)* Stereochemical evidence further supports acyl-oxygen fission. Thus, hydrolysis of optically active -butyrolactone by hydroxide ion yields fi -hydroxybutanoic acid with 95-98% retention, (it) In neutral (it) A. Olson and R. Miller, J. Am. Ghem. Soc., 60 , 268? (1938). or slightly acidic solution conplete inversion (98-99%) is noted, indicating alkyl-oxygen fission, whereas in solutions of pH -2 to +2 mixtures of isomers are obtained. Acyl-ozygen fission of simple T A esters by hydroxide is also siçported by 0 (5) and stereochemical (6 ) evidence. (5) M. Poljsmyi and A. Szabo, Trans. Faraday Soc., 508 (193k), (6 ) B. Hoimberg, Her., 2997 (1912). The existence of a reaction intermediate rather than a single transition state in attack of certain esters by hydroxide ion has been adequately demonstrated by Bender (?)• (7) (a) M. Bender, J. A. Chem. Soc., 73, 1626 (1951); (b) ibid., 80 lOkb (1958). ““ In hydrolysis of alkyl (ethyl, ^-propyl and t-butyl) benzoates con­ taining 0^® in the carbonyl group it was found that the 0^® content was decreased in the esters recovered after partial saponification. This demonstrates that an intermediate, symmetrical species must exist sufficiently long to participate in a reversible step, i.e.. 18 <s> 18 pl8 HoO, - OH QH T R - CO-rrR^ + O H ^ R - OR1 :-----► R - Ç - OR^ DH ^---- 6h 18 fi 1 18 A Ç.H R - C - OR + OH R - J - OR <£> RCOg - H + OR It will be assumed in subsequent discussion that saponification of lactones involves a similar intermediate, and further that this 5 intermediate approximates the structure and the energy of the transi­ tion state for the rate-determining step (8). (8) In theory it is possible that (deconçosition of inter­ mediate) is rate-determining. This however does not seriously alter the inteipretation since the transition state for decoagposition of intermediate