THE SYNTHESIS OF A WATER-SOLUBLE MOLECULE CONTAINING A HYDROPHOBIC CAVITY by W. HARRY MANDEVILLE B. S. Colorado School of Mines (1971) SUBMITTED IN PARTIAL FULFILLMENT OF'THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY May 16, 1975 Signature of Author / Department of Chemistry May , 1975 Certified by K Thesis Supervisor Accepted by --~~~~~~~~~ ( Chairman, Departmental ARCHIVES Committee JUN 11 1975 -2- This Doctoral. Thesis has been examined by a committee of the Department of Chemistry as follows: Professor Dietmar Seyferth I/ Chairman Professor George MI.Whitesides \K. u- '|Thesis Supervisor Professor K. Barry Sharpless -3- to SUSIE... 143 for CHRISTMAS and SNOW and to MY PARENTS -4- "You know how when you stand in the rain with your mouth open how rarely the raindrops hit your tongue... Chemistry is a lot like that. I like standing in the rain." April 30, 1975 -5- THE SYNTHESIS of a WATER-SOLUBLE MOLECULE CONTAINING a HYDROPHOBIC CAVITY by W. Harry Mandeville Submitted to the Department of Chemistry at the Massachusetts Institute of Technology, May 16, 1975, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ABSTRACT Part I: The Synthesis of a Water-Soluble Molecule Containing a Hydrophobic Cavity The syntheses and characterization of three macrocyclic compounds, cyclohexatriaconta[l,2,13,14,25,26-b,b',b"]tris- quinoxaline (1) cyclohexatriaconta[l,2,13,14,25,26-b,b',b"] tris(diethyl 1H,3H,2-oxoimadazo[4,5-g]quinoxalino-l,3-di- a-acetate) (2) and cyclopentatetraconta[1,2,16,17,31,32-b, b',b"]trisqu'lnoxaline (3 are described. These compounds have been prepared from the benzene derivatives tris(deca- methylene)benzene (7a) and tris(tridecamethylene)benzene (7c) via a ring-opening ozonolysis. Compounds 7a and 7c were prepared from the corresponding cyclic acetylenes, cyclo- dodecyne (4) and cyclopentadecyne ED via a titanium trichloride catalyzed cyclotrimerization. A new, convenient synthesis for the cyclic alkynes 4 and 6, utilizing the corresponding cyclic ketones as starting materials, is also described. One other compound, tris(hendecamethylene)benzene (7b) was also prepared but its ozonolysis did not yield the expected macrocyclic derivative. a 0· _. 0 041 -6- 7a, n 10 4, n=10' 7b, n= 11 (CHFc)n III 5, n=11 2 7o, n13 K, 6. n=13 a i I Part II: The Elucidation of the Mecnanism of Oxidation with Adams' Catalyst. Several mechanisms for the oxidation of alcohols by Adams' catalyst and molecular oxygen are postulated. Each of these mechanisms is discussed with respect to evidence already in the literature and with respect to new evidence found in the present work. The deuterium isotope effect for the oxidation of 2-propanol-dl has been determined to be 1.8. The competitive oxidation of cis- and trans-4-t- butylcyclohexanol has shown the oxidation follows the same stereochemical path as the von Auwers-Skita rule dictates for the reduction of cyclohexanones with hydrogen. The oxidation of cyclobutanol and cyclopentanol show the reaction does not proceed via a homolytic cleavage of a hydrogen-oxygen bond to form a metal-oxygen bond. Part III: Selectivity in Organic Group Transfer in Reactions of Mixed Lithium Diorganocuprates. This work has been published: W. Harry Mandeville and George M. Whitesides, J. Org. Chem., 39, 400 (1974). Thesis Supervisor: George M. Whitesides Title: Professor of Chemistry -7- ACKNOWLEDGEMENTS I would like to gratefully acknowledge the M.I.T. Department of Chemistry for support in the form of a teaching assistantship for the academic year 1971-2 and Professor George M. Whitesides and the National Science Foundation for support in the form of Research Assistantships for the remainder of my stay at M.I.T. I would like to thank Jim Simms for running a "taut ship" in the spec lab and for keeping most of the instruments running most of the time and Dan Traficante for help in taking my carbon-13 nmr spectra. Finally, I would like to thank all of the other Dreyfus inmates who have made my life either miserable or livable during the last four years: Demers and the Beaver, the two other inhabitants of my bay; at times the stench was terrific but we all survived; Hill, the Scarlet Speedster; Lilburn, who says sulfur chemistry has to smell bad, anyway; Cox, for late night beers, poker, softball and for falling for the old raw Easter egg trick; the Turk and Wilson for more nocturnal beer drinking; Michaelson, Q. Kyle, Mad-Dog Dolhun and the other poker players who let me take their money; Bock, Mac, Nate and X, who lived with me in the ghetto at 181 Harvard St.; why was I never mugged; Kaufman, Trzupek, and Bird-Brain, my predecessors in chemical trivia; the Gutman, for financial -8- advice; Costa, for general rowdiness; Kazdin, for 7,000 bad ideas-and one good one; John Ning, for leaving; van Volkom, where did he go; Feitler, Rogers, Foley and the rest of the morons here who kept me from ever getting bored. A last note of thanks is due to Susie; she brought me back to earth on the weekends, and to George; his interest in chemistry was contagious. Thanks also to Katie Hallinan for doing a superb job of typing this thesis. -9- TABLE of CONTENTS Page Part I: The Synthesis of a Water-Soluble Molecule 18 Containing a Hydrophobic Cavity. Cyclododecyne, Cyclotridecyne and Cyclo- 21 pentadecyne. Cyclotrimerization of the Cyclic Acetylenes. 27 Ozonolysis of the Cyclic Trimers of Cyclo- 29 dodecyne, Cyclotridecyne and Cyclopentadecyne Derivatization of the Cyclic a-Diketones. 30 Optimization of the Ozonolysis Conditions. 38 Ozonolysis in Aprotic Solvents. 41 Ozonolysis in heptane. 42 Ozonolysis in methylene chloride. 43 Ozonolysis in a Protic Solvent. 43 Ozonolysis in methanol/methylene chloride. 46 Reduction of Ozonolysis Mixtures. 46 Attempted Oxidation of 7a with Ruthenium 50 Tetroxide. Preparation of a Water-Soluble Derivative. 50 Conclusions. 59 Experimental Section. 60 General. 60 1,l-Dichlorocyclododecane 61 Cyclododecyne (4). 62 Cyclopentadecyne (6). 63 13 ,13-Dibromobicyclo[10.1.0]tridecane. 63 -10- Cyclotrideca-1,2-diene. 64 Cyclotridecyne (5). 64 Tris(decamethylene)benzene (7a). 65 (Cyclododecyne Cyclotrimer.) 4 Tris(hendecamethylene)benzene (7b). 66 (Cyclotridecyne Cyclotrimer.) Tris(tridecamethylene)benzene (7c). 66 (Cyclopentadecyne Cyclotrimer.)- 2-Oximinocyclododecanone. 67 Cyclododecane-1,2-dione. 67 2,3-Decamethylenequinoxaline (la). 67 2,3-Decamethylenequinoxaline dihydro- 67 chloride. Solubility in Water. Attempted Preparation of 1,4-Dimethyl-2,3- 67 decamethylenequinoxaline. Methyl Iodide. Attempted Preparation of 1,4-Dimethyl-2,3- 68 decamethylenequinoxaline. Dimethyl Sulfate. 1,4-Diethyl-2,3-decamethylenequinoxaline. 68 Attempted Preparation of 2,3-Decamethylene- 69 quinoxalinedi-N,N'-oxide. 6-Methyl-2,3-decamethylenequinoxaline. 69 6,7-Dimethyl-2,3-decamethylenequinoxaline. 69 2,3-Decamethylenepyrazine-5,6-dicarboxylic 69 Acid. Potassium Permanganate Oxidation of 2,3-Decamethylenequinoxaline. 2,3-Decamethylene-5,6-dicyanopyrazine. 70 2,3-Decamethylenepyrazine-5,6-dicarboxylic 70 Acid. Hydrolysis of 2,3-Decamethylene-5,6- Dicyanopyrazine. -11- 2,3-Decamethylenepyrazine-5,6-dicarboxylate 71 Dipotassium Salt. Attempted Oxidation of Hexatriaconta[1,2,13 71 14,25,26-b,b',b"]trisquinoxaline (1) with Potassium Permanganate. Attempted Oxidation of 1 with Potassium 71 Permanganate. Phase Transfer. 3,4-Decamethylene-1,2,5-thiadiazole- 72 1,1-dioxide. 3,4-Decamethylene-2,5-diphenylcyclo- 72 pentadienone. Cyclod.odecane-1,2-dioneMonosemicarba- 73 zone. Benzimidazolone (23). 73 5,6-Dinitrobenzimidazolone (24). 73 Diethyl 5,6-dinitrobenzimidazolone-1,3-di- 74 a-acetate (25). Dimethyl 5,6-dinitrobenzimidazolone- 74 1,3-di-a-acetate. 5,6-Dinitrobenzimidazolone-1,3-di-a- 74 acetic Acid. Diethyl 5,6-diaminobenzimidazolone-1,3-di- 75 a-acet:ate (26). Diethyl 1H,3H,2-oxoimidazo[l4,5-g]cyclo- 75 dodeca [b]uinoxaline-1,3-di-a-acetate (27). 1H,3H,2-Oxoimidazo[4,5-g]cyclododeca[b] 76 quinoxaline-1,3-di-a-acetic Acid (28b). Preparative Scale Ozonolysis of 7a. 76 Preferred Method. ' 2,3-DE!camethylenequinoxaline (lb) and Cyclo- 77 hexatriaconta[l,2,13,14,25,26-b,b',b"]tris- quinoxaline Ul. Condensation of the Ozonolysis Product with 14. -12- Ozonolysis of 7a. (General Techniques.) 79 Diethyl lH,3H, 2-oxoimidazo[4,5-2]cyclo 79 dodeca [b] quinoxaline-1,3-di--a-acetate (27). and Cyclohexatriaconta[1,2,13,14,25,2T- b,b',b"]tris(diethyl H,3H,2-oxoimidazo T475-g] quinoxaline-1 ,3di-c-acetate (2). Condensation of the Ozonolysis Product with 25. 2,3-Tridecamethylenequinoxaline and Cyclo- 81 pentatetraconta[1,2,16,17,31,32-b,b' ,b"] trisquinoxaline (3). Ozonolysis of 7c and Condensationwithm4. Ozonolysis of 7b. 82 Part II. The Elucidation of the Mechanism of Oxidation 84 with Adams' Catalyst. Conclusions. 112 Experimental Section. 113 General. 113 Preparation of the Catalyst. (Typical 113 Procedure A.) Preparation of the Catalyst. (Typical 113 Procedure B.) Competitive Oxidation of Cyclobutanol 114 and Cyclopentanol. (Typical Procedure.) 2-Propanol-2-dl. 114 Competitive Oxidation of Propanol-2 and 115 2-Propanol-2-dl with Adams' Catalyst. trans-4-t-Butylcyclohexanol. 115 Separation of cis- from trans-4-t-Butyl- 115 cyclohexanol. Competitive Oxidation of cis- and trans-4- 116 t-Butylcyclohexanol in Acid Medium with Adams' Catalyst. (Typical Procedure.) -13- Part III. Selectivity in Organic Group Transfer in 117 Reactions of Mixed Lithium Diorganocuprates. Appendix. The Attempted Synthesis of Biotin. 118 Conclusions. 123 Experimental Section. 125 General. 125 4,5-Dimethylimidazolone (31). 125 1,3-Diacetyl-4,5-imidazolone (32) . 125 1,3-D.iacetyl-4,5-bis (exomethylene) 125 imidazolone (33). Dimethlyl 4H,7H-dihydro-1, 3-diacetyl- 126 benzimidazolone-5,6-dicarboxylate. Dimethyl 1,3-diacetylbenzimidazolone- 126 5,6-d:icarboxylate. 1,3-Diacetyl 4H,6H-thiopheno[d]imi- 127 dazolone-5,5-dioxide (30).