SYNTHESES AND PROPERTIES OF HIGHLY STERICALLY HINDERED ALIPHATIC COMPOUNDS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By TADAMIGHI FUKUNAGA, M. S, *************** The Ohio State University 1959 Approved by Adviser Department of Chemistry ACKNOWLEDGMENTS The author expresses his sincere appreciation to Professor Melvin S. Newman for proposing this problem and for the many suggestions he has offered throughout the course of this work. The author also wishes to acknowledge the receipt of the Fellowship sponsored by Wright Air- Development Center for the periods October 1955 to March 1956 and April 1957 to June 1959, and by Research Corporation for the period April 1956 to March 1957. - 1 1 - TABLE OF CONTENTS ACKNOWLEDGMENT ..................................................................................... i l INTRODUCTION ................................................................................................... 1 I. SYNTHESIS OF HIGHLY STERICALLY HINDERED ALIPHATIC NITRIDES ................................................................... 3 A. Historical ........................................... 3 B. Results and Discussion ....................................... 12 II. REACTIONS OF HIGHLY STERICALLY HINDERED ALIPHATIC NITRIDES ............................................................. 21 A. Hydrolysis ...................................................................... 21 B. Lithium Aluminum Hydride Reduction .... 25 I I I. SYNTHESIS OF HIGHLY STERICALLY HINDERED ALIPHATIC ACIDS .......................................................................... 28 A. Historical ............................................ 28 B. Results and Discussion ........................................ 33 IV. REACTIONS OF HIGHLY STERICALLY HINDERED ALIPHATIC ACIDS AND THEIR DERIVATIVES .................. 41 A. Ionization Constants of Acids ...................... 41 B. Reaction of Acids with Ethoxy- acetylene ........................................................................ 52 C. Reaction of Acids with T rifluoro- acetic Anhydride ...................................................... 56 D. Reaction of Acids with Thionyl Chloride ........................................................................... 60 E. Estérification of Acid Chlorides ............... 63 F. Reaction of Acid Chlorides with Ammonia and Sodium Amide (Ketene Formation and Reactions) ........................................................... 63 G. Reaction of Esters and Amides with Lithium Aluminum Hydride .................................. 75 - i i i - TABLE OF CONTENTS (continued) Zâ£e V. SUGGESTION FOR FUTUlffi WORK AND GENERAL PROPERTIES OF HIGHLY STERICALLY HINDERED COMPOUNDS ......................................................... 92 VI. EXPERIMENTAL ......................................................................... 98 Conventions Used in the Discussion of Experimental Work ..................................................... 98 A. Synthesis of Highly Sterically Hindered Aliphatic N itrile ........................ 99 B 1. D iisopropylacetonitrile ...................... 99 2. t-B utylacetonitrile ................................ 101 3 . Alkylation of diisopropylaceto- n itr ile ................................................................ 102 4. Alkylation of t-hutylacetonitrile 104 B. Reactions of Highly Sterically Hindered Aliphatic Nitrile ......................... 106 1. Hydrolysis ........................................................ 106 2. Lithium aluminum hydride reduction 107 C. Synthesis of Highly Sterically Hindered Aliphatic Acids .............................. 110 1. Triisopropylacetic acid ...................... 110 2. Di-t-butylacetic acid ............................ 114 3 . Isopropyl-t-butylacetic acid .......... 122 4. Attempted alkylation of triethyl- methyl dl-t-butylacetate .................... 124 5. Attempted alkylation of triethyl- methyl isopropyl-t-butylacetate .. 126 D. Reactions of Highly Sterically Hindered Aliphatic Acids .............................. 127 1. Ionization constants of acids .... 127 2. Reaction of acids with ethoxy- acetylene ........................................................... 137 3. Reaction of acids with triflu o ro - acetic anhydride ............................... 139 4. Reaction of acids with thionyl chloride .............................. 139 5. Estérification of acid chlorides . I 40 - i v - TABLE OF CONTENTS (continued) Zs-gs 6. Reaction of acid chlorides with ammonia and sodium amide ........................ I 4 I 7. Reaction of di-t-hutylketene ............... 143 8. Attempted preparation of diiso- propylketene ...................................................... 145 9. Reaction of esters and amides with lithium aluminum hydride ........... I 46 AUTOBIOGRAPHY ....................................................................... 155 -V- LIST OF TABLES Table Page I. Alkylation of Nitrile-1 ........................................... 14 II. Alkylation of Hitrile-II ......................................... 15 III. Alkylation of Ilitrile-III ................. 16 IV. Conversion of Witriles to Acids ................... 23 V. Physical Constants of Acids .................................. 42 VI. Ionization Constants of Acids-I, .............. 45 VII. Ionization Constants of Acids-II. ............... 47 VIII. Ionization Constants and Structure of Acids ....................... 51 IX, Lithium Aluminum Hydride Reduction ..... 79 X, Determination of Ionization Constants of Acids ............................................................................. 135 —vi “* LIST OF FIGURES ■Page 1. Direct alkylation of nitriles .............................. 4. 2. C- vs. N-ilkylation of hindered n itr ile s ................................................................................... 10 3 . Synthesis of di-t-butylacetic acid ....... 35 4.. Lithium aluminum hydride reduction of unsubstituted amides ............................................ 85 - v i i - INTRODUCTION The synthesis of highly sterically hindered ali­ phatic compounds has received little previous attention by synthetic organic chemists and, even though a number of tria lk y la c e tic acids and th eir derivatives have been prepared, they bear n-alkyl groups except in a few cases. In this laboratory a systematic approach to the preparation of hindered aliphatic nitriles^ has been (1) M. S. Newman and T. Miwa, unpublished resu lts, i n i t i a t e d . The hindering steric effect on the rate of esteri- 2 fication of hindered aliphatic acids and on the (2 ) (a) K. L. Loening, k, B. G arrett and M. S. Newman, J . Am. Ghem. 8 0 c . 74-. 3929 (1952) j (b) See M, S. Newman, "Steric Effects in Organic Chemistry," John Wiley and Sons, In c., New York, N. Y., 1956, p. 205 f£. hydrolysis of nitriles^ has been studied and it has (3 ) L. Tsai, T. Miwa and M. S. Newman, J. Am. Ghem. S o c ., 23., 2530 (1957). - 1 - —2 — 2b,4 been found that the higher the six number, the more (4 ) M. S. Newman, J. Am. Ghem. Soc., 72, 4783 (1950). slowly the acid is esterified and the nitrile is hydro­ lyzed. Ionization constants of hindered aliphatic 5 acids have also been shown to be subject to steric (5 ) G. S. Hammond and D. H. Hogle, J. Am. Ghem. Sqæ., XL, 3384 (1955). e ffe c ts . The purpose of th is work was to estab lish general methods for preparing highly sterically hindered aliphatic acids and their derivatives and to study the chemical and physico-chemical properties of these compounds. The highly hindered compounds of interest in this work have the following general structure: R^CCOOH, R^CCOGl, R^CCOOR', R^GGONHg and R^CGN where R stands for ethyl, isopropyl and t-b u ty l. In order to emphasize the alkyl groups on the a- carbon atom of these compounds, they w ill be named, throughout this dissertation, as trialkylsubstituted acetic acids and their derivatives and not as dialkyl- substituted acids of RGH2GOOI, although the latter system is more commonly used. I. SYNTHESIS OF HIGHLY STERICALLY HINDERED ALIPHATIC NITRILES I-A. Historical The most widely used method for preparing tri- alkylacetonitriles is direct alkylation^ of substituted (1) See A. 0. Cope, H. L. Holmes and H. 0. House, "Organic Reactions," Vol. IX, John Wiley and Sons, Inc., New York, N. Y ., 1957, p. 107 ff. acetonitriles, as shown in Figure 1. This method was 2 first used for preparing triethylacetonitrile from (2) M. Bockmühl and J. Ehrhard, German Patent, 473,329 (Chem. Zentr.. 1929 II, 218). butyronitrile. The general procedure, which consists of conversion of nitrile to its conjugate base by means of amide ion followed by heating with alkylating reagents, was developed by Ziegler.^ It has been satisfactorily (3) K. Ziegler and H. Ohlinger, Ann.. 495. 84 (1 9 3 2 )} K. Ziegler, French Patent, 728,241 (Cham. Zentr.. 1933 I, 1 1 9 7 ). applied to the synthesis of a number of trialkylaceto-«. nitriles in 50-80% yield.^ Liquid ammonia^*^ has also -3- - 4" E l ? 1 \ base , . GH-GW + ----------- ^ E g - G - G N (l) / 3) * I ^2 R3 0*^ggQ R^-CHg-CN + 2R^X »---------- ^ R 3 -C-GN (2 ) *3 ?3 OHj-OK + 3K3X K3-O-CK (3) ^3 Fig, 1. - Direct alkylation of nitriles. - 5 - (4.) L. &. Walter and S, M. McElvain, J. Am. Ghei Soc. y 5 6 , 1 614 (1 9 3 4 ); G. Newbery and W. Webster, i*. Chem. S oc.. 738 (1947); C. Schuerch, J r. and E. H. Huntress, J. Am. Chem. Soc., 70, 2824 (1948); N. Sperber, D. Papa and E. Schwenk, ib id .. 70., 3091 (1948). (5 ) F. W. Bergstrom and