Western Michigan University ScholarWorks at WMU Master's Theses Graduate College 8-1966 Dimethyl Sulfoxide Oxidation of Primary Alcohols Carmen Vargas Zenarosa Follow this and additional works at: https://scholarworks.wmich.edu/masters_theses Part of the Chemistry Commons Recommended Citation Zenarosa, Carmen Vargas, "Dimethyl Sulfoxide Oxidation of Primary Alcohols" (1966). Master's Theses. 4374. https://scholarworks.wmich.edu/masters_theses/4374 This Masters Thesis-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Master's Theses by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. DIMETHYL SULFOXIDE OXIDATION OF PRIMARY ALCOHOLS by Carmen Vargas Zenarosa A thesis presented to the Faculty of the School of Graduate Studies in partial fulfillment of the Degree of Master of Arts Western Michigan University Kalamazoo, Michigan August, 1966 ACKNOWLEDGMENTS The author wishes to express her appreciation to the members of her committee, Dr, Don C. Iffland and Dr. Donald C, Berndt, for their helpful suggestions and most especially to Dr, Robert E, Harmon for his patience, understanding, and generous amount of time given to insure the completion of this work. Appreciation is also expressed for the assistance given by her. colleagues. The author acknowledges the assistance given by the National Institutes 0f Health for this research project. Carmen Vargas Zenarosa ii TABLE OF CONTENTS Page ACKNOWLEDGMENT ii HISTORICAL 1 INTRODUCTION 5 EXPERIMENTAL 6 General 6 Preparation of Starting Materials 7 1 2 ,3' -0-isopropylideneadenosine 7 1,2:3,4-di-0-isopropylidene-a-D-galactose 8 N-(�-tolyl)-diphenylacetamide 8 Diphenylketene-N-�-tolylimine 8 Oxidation of Primary Alcohols to Aldehydes 9 General procedure for oxidation 9 Oxidation of ethyl alcohol 10 Oxidation of �-phenylethyl alcohol 11 1 Oxidation of 2 ,3' -0-isopropylideneadenosine 12 Oxidation of 1,2:3,4-di-O-isopropylidene- a-D-galactose -------------------------------------- 13 Reaction of dimethyl sulfoxide with the acidic solution of benzonitrile and �-heptyl alcohol ------ 14 Determination of the optimum amount of diphenylketene-N-�-tolylimine ---------------------- 14 DISCUSSION 16 iii Page SUMMARY ----------------------------------- ·---------- 23 BIBLIOGRAPHY 24 VITA 26 iv HISTORICAL A metho.d of selective oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones has been developed recently, namely the use of dimethyl sulfoxide (DMSO) as the oxidizing agent, . l.4 l. either alone or with dicyclohexylcarbodiimide (DCC), acid anhydrides, l.O or alkyl chloroformates The negatively polarized oxygen atom of the sulfoxide group in DMSO is ideally situated for a transfer to many electron-d.eficient substrates. The oxygen of the alcohol coordinates with the sulfur atom of DMSO through its oxygen atom; this is followed byfo-eleminationr: of dimethyl sulfide, thereby resulting in oxidation of the alcohol to an aldehyde. Among the earliest applications of this process have been the l.O 9 l.l. oxidation ofoC-haloketones, ol-haloesters, alkylhalides, alkyl 11.b,20 5 tosylates, and epoxides • Upon heating the compounds with DMSO in the presence of an acid acceptor such as sodium bicarbonate, a ketone or an aldehyde is formed. With primary iodides and tosylates, oxidation is often quite efficient; but with less reactive compounds, the formatiqn of olefins and other by-products frequently occurs. The mechanism usually accepted for this reaction involves nucleo­ philic displacement of a halide or tosylate by the oxygen atom in DMSO to give the intermediate sulfoxonium compound (Ia), which then decomposes into a carbonyl compound by concerted elimination of a proton and e,2 dimethyl sulfide . 1 2 + H + H + I I + CHs- S -.o R-C-XI CHs- S-0-C-R X I R I I CHs CH3 R Ia NaHCOs R-C=OI + R X = halides or tosylates 4 Barton and coworkers have reported that alkyl chloroformates (chloro­ formic acid esters of alcohols) and DMSO react exothermally at room temperature with the formation of a reactive intermediate. The reaction of this intermediate with a base such as triethylamine gave the corres- < ponding aldehydes or ketones, together with dimethyl sulfide. The mechanism proposed was similar to the previous one. H 0 + I II + CHs-S --o .----. ...R-C C + I I 'o/' 'o-S-CHs + Cl CHs R I CH3 (C2Hs)sN + =o + + + + R- CI CH3-SI CO2 (C2Hs)sNH Cl R CHs Carbohydrates have been found to be oxidized readily by the system 13 • DMSO-P205 Phosphorous pentoxide has been found to accelerate the 3 oxidation of hydroxyl groups in carbohydrates to aldehydes and ketones." This method of oxidation is a convenient way to prepare 3-ketoglucose which is a component of some microbial disaccharides. 1 Pfitzner and Moffatt 5 have done extensive work on this aspect of oxidation using, specifically, dicyclohexylcarbodiimide (DCC), and 100% orthopbosphoric acid in dimethylsulfoxide, They have reported that 3- 0-acetylthymidine is converted to the 3-0-acetylthymidine-5-aldehyde which was isolated as its 2,4-dinitrophenylhydrazone in 61% yield. No data on the oxidatio_n of purine nucleosides was given. The mechanism of oxidation resulting from treatment of an alcohol with DMSO and DCC in the presence of a proton source has been elucidated 6 through an isotope experiment and has been postulated to proceed via a nucleophilic attack of DMSO upon the protonated carbodiimide to give the sulfoxonium isourea intermediate (I) which is then attacked by the alcohol to form the alkoxysulfonium compound (II) and the highly insoluble dicyclohexylurea (III). The final step requires the abstrac­ tion of a proton from the alpha carbon atom of the alkoxy group and the concerted collapse of the resulting intermediate to the carbonyl com­ pound and dimethyl sulfide. (1) ON=C=N-0 4 H H H (2) + o-N=i�}-0--=H_ o-�-rr-t-O 0 + RCH20: -+ S-CHs III II � I CHs + (2) R-CH-0-S-CHs I I H CH2 H l RCHO + CHs-S-CHs 12 Recent work,of Lillien has demonstrated that ketenimine undergos acid catalyzed addition of DMSO. It has also been found that ketenimines undergo similar reactions 1 8 as the carbodiimides, for example addition of carboxylic acids and peptide bond formation. 5 INTRODUCTION The purpose of this work is to investigate the possibility of using diphenylketene-N-�-tolylimine or benzonitrile along with dimethyl sulfoxide as an oxidizing agent. Ketenimine has been chosen because it i undergoes reactions similar to carbodiimide, e and benzonitril�, because it can act as a Lewis acid to form the sulfoxonium intermediate. The main purpose of this research is to oxidize the primary alcohol groups of purine nucleosides and carbohydrates. In· order to facilitate the study of this reaction, simple primary alcohols were used. 6 EXPERIMENTAL All melting points reported were corrected and are expressed in degrees centigrade. Thin-layer chromatography was performed on silica gel-G and cellulose powder (Darmstadt). Spots were detected by ultraviolet light, iodine vapor, and 2,4-dinitrophenylhydrazine spray. All ultr�iolet measurements were made on a Cary Model-14 spectro­ photometer, using 95% ethanol as solvent; and infrared spectra were obtained from samples in Nujol mulls using a Beckmann IR-8 Model instrument. The nuclear magnetic resonance spectr� were determined with a Varian A-60 instrument; resonances were measured in cps downfield from tetramethylsilane standard. Elemental analyses were performed by Galbraith Laboratories, Inc. Dry DMS0 was prepared by distillation from calcium hydride under reduced pressure and was stored over anhydrous barium oxide. 1 The stock solution used for the preparation .of 2',3 -0-isopropyl­ idenenucleosides was prepared by adding 100 g of pure-fused zinc chloride to a liter of pur'ified acetone. The acetone was purified by distillation from potassium permanganate, dried over anhydrous sodium sulfate and redistilled. The structure of the productsobtained in the following experiments can be found on page 22. 7 Preparation of Starting Material 1 1 Preparation of 2 ,3 -0-isopropylideneadenosine The desired isopropylidene derivative was prepared according to 3 the method of Baddiley • The purine nucleoside, 0.003 mole, which had been previously dried over phosphorous pentoxide under reduced pressure for at least 5 hr was dissolved in 250 ml of ZnC12-acetone stock solution. The slightly cloudy mixture was kept at room temp�rature for at least 20 hr, and evaporated under reduced pressure to about one third of its original volume. The concentrated solution was poured into 11 of warm barium hydroxide solution which had been prepared by adding 150 g of barium hydroxide octahydrate to 11 of water. The resulting solution was cooled to room temperature and CO2 gas passed through until it was no longer alkaline to litmus. The resulting mixture was filtered, and the precipitate was washed first with boiling water, then with methanol ° (about 350 ml). The filtrate was evaporated at a temperature below 40 to about one third of the original volume. During the evaporation, the 2' ,3' -0-isopropylidene derivative crystallized. The mixture was allowed to stand overnight, and the crystals were collected by filtration and ° dried at100 . A small amount of the product was isolated from the mother ° liQuor after evaporation to dryness at 40 or below. The amount of material recovered from the mother liQuor was relatively small compared to the first crop of crystals isolated, so this step was later omitted from the process. The combined solids were recrystallized from boiling 8 95% methanol. Pure white needle-like crystals were obtained in 59% < ° 3 ° yield, m.p. 219-221 , lit. 220 . Preparation of l,2:3,4-di-0-isopropylidene-o£.....D-galactose 21 The method of Van Grunenberg and coworkers was used for the prep­ aration of the isopropylidene derivative of oC-D-galactose. The finely­ powdered galactose, 0.55 mole, gave 90 g of a syrupy product.