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Dimethyl sulfoxide as a in the Williamson ether synthesis'

RUSSELG. SMITH,ALAN VANTERPOOL, AND H. JEANKULAK' Research Department, Canadian C/iemical Conipany, P.O. Box 99, Edmonton, Alberta Received September 9, 1968

Using the conventional Williamson ether synthesis, n-butyl ether was prepared from , n-butyl , and ri-butyl chloride using excess of the alcohol as solvent in 61 % yield after 14 h reaction time. However, when the excess alcohol was replaced by dimethyl sulfoxide, the yield of ether rose to 95% with 9.5 h reaction time. Other primary alkyl chlorides exhibited similar behavior to n-butyl chloride, but secondary alkyl chlorides and primary alkyl bromides gave little etherification, elimination being the major reaction. Unreactive halides, such as vinyl chloride, phenyl bromide, and 2,4-dinitrobromobenzene, were not etherified in dimethyl sulfoxide. The reaction products obtained from aliphatic dichlorides depended upon the relative positions of the atoms. Secondary reacted to give ethers, but tertiary alcohols were very unreactive. generally gave high yields of ethers, the major product being that in which all but one of the hydroxyl groups became etherified. Under forcing conditions, however, completely etherified polyols could be obtained. Canadian Journal of Chemistry, 47, 2015 (1969)

Introduction greater solvation of anions in protic It has been shown by Cram and co-workers (1) along with the much greater solvation of polar- that dimethyl sulfoxide (DMSO) is a useful ized charged transition states in dipolar aprotic solvent for the Williamson reaction (2). Working solvents. Consequently, for nucleophilic reactions with phenyl bromide and t-butoxide the activation energy is less in dipolar aprotic these authors obtained a greatly enhanced rate solvents than in protic solvents. Rate enhance- and a better overall yield of t-butyl phenyl ether ments by factors as large as 1 x 10" have been in DMSO as compared to the conventional observed for some nucleophilic reactions on synthesis in t-butyl alcohol. transfer from protic solvents to dipolar aprotic Later, workers studied the mechanism of the solvents. rate enhancement in greater detail and extended The use of sodium hydroxide to form alkoxides the application of the reaction in DMSO. and subsequent reaction with alkyl chlorides as Thus, ethers have been prepared from alkoxides reported by Zimmerman and Dathe (11) is of and alkyl sulfonate (3, 4), from carbo- interest since it is considerably less expensive hydrates and dimethyl sulfate or methyl iodide than the conventional use of sodium metal and (5, 6), from phenoxides and butyl halides (7), alkyl bromides. The purpose of the work from methoxide and benzyl chlorides (8), from reported here was to determine the limitations di~henoxides and dihaloaromatic com~ounds and advantages of this method of ether synthesis. (9j, and from methoxide and with Experimental poly [3,3-bis(chloromethyl)oxacyclobutane] (10). In a typical preparation the hydroxyl containing Zimmerman and Dathe (1 1) have shown compound, a stoichiometric excess of sodium hydroxide ethers can be obtained by reaction of the sodium and DMSO (ca. 300 ml per of hydroxylic compound) alkoxide formed from the polyol and sodium was mixed and heated, with stirring. The temperature hydroxide with alkyl chlorides. chosen was 5-10 "C below that at which discoloration The rate enhancement which occurs on trans- occurred (usually 90-110 "C). When the precipitate had changed in physical appearance from a slimy to a granular fer of a nucleophilic reaction from a protic form, the halide (in stoichiometric equivalence with solvent such as t- to a dipolar aprotic caustic) was slowly added at such a rate that the tenipera- solvent such as DMSO has been discussed in a ture could be maintained at ca. 100°C. Stirring and review article by Parker (12). The rate enhance- heating were maintained for 2-3 h after the addition was complete. The mixture was then cooled, and sufficient ment is explained on the basis of the much added to dissolve the precipitated solids. The layers were extracted with ethyl ether, the extracts 'Presented in part to the 49th Annual Conference, combined, dried (), and the ether removed Chemical Institute of Canada, Saskatoon, June 1966. by distillation. The residue was vacuuin flashed, and the 'Present address: 656 Thurber Drive, Columbus, distillate analyzed by hydroxyl value and chroma- Ohio 43215, U.S.A. tography. Peak assignment, where possible, was made CANADIAN JOURNAL OF CHEMISTRY. VOL. 47, 1969

TABLE I Effect of solvent on the yield of n-butyl ether prepared from n-butyl alcohol and 11-butyl chloride

Products obtained Reaction time (h) % Alcohol % Halide For alkoxide For ether converted converted Solvent formation formation to ether to olefin n-Butyl alcohol 4.0 10.0 61* 0 DMSO 2.5 3.5 62t 19 DMSO 7.0 2.5 95 1 'Percent n-C4H9CI converted to ether. +Thirty-seven percent of the alcohol was recovered unchanged. tNot determined. using known compounds. When these were not available, excess of sodium hydroxide and n-butyl chloride the assignment was chosen so as to aqree with the was used over the n-butyl alcohol. determined hydroxyl value. Volatile by-products were trapped in a dry ice - acetone The synthesis gives good results when other bath and analyzed by . primary alcohols and other primary chlorides are used. Thus, n-dodecyl ether was prepared (Table 11) in 54% yield from n-dodecyl alcohol Results and Discussion and n-dodecyl ahloride. In general, it proved difficult to prepare A series of halides was reacted with n-butyl alkoxides at practical synthetic levels in DMSO alcohol to determine the limitations to the type since both sodium hydroxide and the alkoxides of halide which could be used in the synthesis. studied had very limited solubility in DMSO. With isopropyl chloride (Table 11), t-butyl Consequently, long reaction times and high chloride, and n-butyl bromide, the elimination temperatures were necessary for the alkoxide reaction was sufficiently pronounced that little, production stage of the synthesis. Once the if any, etherification occurred. On the other alkoxide had been formed, reaction with alkyl hand, vinyl chloride, 2,4-dinitrobromobenzene, chlorides was rapid and ethers could be obtained and phenyl bromide failed to react at all in good yields. When n-butyl ether was prepared (unreported experiments). This result is in (Table I), it was obtained in 95% yield after a contrast to the work of Cram et al. (1) where total of 9.5 h reaction time of which 7.0 h were however, rigorously anhydrous conditions were required for alkoxide formation. This result employed. compares favorably with a 61 % yield obtained Secondary alcohols, e.g., , after 14 h reaction time, when n-butyl alcohol cyclohexyl alcohol, were found to. be less was used as the solvent instead of DMSO. reactive than n-butyl alcohol, while t-butyl When a reaction time of only 2.5 h for alkoxide alcohol was very unreactive (cf. Cram et al. (1)) formation in DMSO was allowed, the yield of the (Table 11). This lack of reactivity probably ether was only 62 %. relates more to a difficulty in forming the In the synthesis of n-butyl ether in DMSO, a alkoxide than to a difficulty in reacting the portion of the excess n-butyl chloride employed alkoxide with the halide. With phenol the was converted to I-butene. This was particularly satisfactory since reaction did not occur in n-butyl alcohol solvent sodium phenoxide formed easily and was or when aqueous DMSO was employed. If soluble in DMSO. stoichiometrically equivalent quantities of n- The reaction products obtained from aliphatic butyl alcohol, sodium hydroxide, and n-butyl dichlorides depended on their structure. Thus, chloride were used in the synthesis, a low yield the vicinal dihalides studied (Table 111) gave no of n-butyl ether was obtained due to this com- ethers. Instead, appreciable ainounts of acety- #ting elimination. However, good yields of lenes were formed, together with minor amounts n-butyl ether could be obtained if a 1.5 fold of vinyl chlorides. With 1,3-dichloropropane TABLE I1 Ethers from monohydric compounds

Reaction time (h) Products obtained Moles halide Hydroxylic per mole For alkoxide For ether % alcohol % unreacted % halide % unreacted comoound* Halide alcohol formation formation converted to ether alcohol recovered converted to oleh halide detected

d +One to five moles NaOH employed per mole of alcohol. ?Not determined. 2 F E X TABLE 111 2 x Products obtained from the reaction of aliphatic dihalides with n-butyl alcohol 3 Reaction time (h) Other products 3 For butoxide For ether % unreacted % unreacted identified (% based 21X Dihalide formation formation alcohol detected dihalide detected on dihalide) 6 0 Acetylene 30 Vinyl chloride 2 24 Methylacetylene 36 2-Chloropropene 4 3 5 Ally1 chloride 7 Allvl ether 4 ~ucylally1 ether 35 y-Hydroxypropyl Butyl ether 7 8 1,3-Butadiene 42 6-Chlorobutvl Butyl ethe; 6 1,4-Dibutoxybutane 16 +Used 1.0 mole NaOH and 0.5 mole of halide per mole of alcohol. ?Used 1.1 moles NaOH and 1.1 moles of halide per mole of alcohol. TABLE IV n-Butyl ethers of selected polyhydric alcohols made from tz-butyl chloride

Reaction time (h) Reaction temperature Conversion of polyol to for formation For alkoxide For ether Polyol ("a formation formation Monoether (%I Diether (%) Trie her (%) Tetraether (%) 1,2-Dihydroxyethane* 100 3.0 4.5 22 66 - - 1,2-Dihydroxypropanet 110 1 .O 2.0 57 27 - - F 1,2,3-Trihydroxypropane* 140 4.5 4.5 41$ 24 - z *. b 2,2-bis(Hydroxymethy1)- 0 propanet 100 1 .O 2.0 41 36 - - i: 2,2-bis(Hydroxymethy1)- z butanolll* 95 3.0 5.0 0 74 16 - 2,2-bis(Hydroxymethy1)- c8 propanediol-1,3* 95 3.0 8.0 0 4 7 1 20 W 'Used 1.1 moles NaOH and 1.1 moles n-butyl chloride per mole of hydroxyl group. 2 ?Used 1.5 moles NaOH and 1.5 moles n-butyl chloride per mole of hydroxyl group. r $Combines total of the two possible . %

. . t; TABLE V 2 j Selectivity in the preparation of ethers of * n< .ij Reaction time (h) Moles NaOH Moles alkyl chloride % Pentaerythritol converted to -2 used per mole used per mole For alkoxide For ether -w Ether desired pentaerythritol pentaerythritol formation formation Monoether Diether Triether Tetraether %

*Of the various rea-tion conditions examined, those shown gave the highest selectivity to the desired ether. tSolvent was 66% aq. DMSO. $The mixed pentaerythritol alkoxides were isolated and dried before proceeding to ether formation. SMITH ET AL.: DIM [ETHYL SULFOXIDE 2019 there was a substantial amount of elimination to resulted when a large excess of alkyl chloride was give , much of which reacted to form employed with or without concomitant removal a mixture of ethers. However, there was also of water from the system. Previously it had not an appreciable degree of of the halides been found possible to make pentaerythritol resulting, after subsequent reaction, in allyl tetraether in one step (14). The reaction using ether and y-hydroxypropyl butyl ether. 1,4- n-butyl chloride in DMSO resulted in production Dichldrobutane on the other hand, gave 1,3- of 1-butene, n-butyl alcohol, and n-butyl ether butadiene as the major product with minor by-products, but these were absent when the amounts of 1,4-dibutoxybutane and F-chloro- solvent was aqueous DMSO. butyl butyl ether. All these aliphatic dichlorides, Polyallyl ethers of several other polyols were however, were considerably less reactive than prepared. The mixed products were analyzed by n-butyl chloride, as shown by the amount of determining hydroxyl number and iodine num- unreacted 12-butylalcohol detected in the reaction ber. For materials, such as, , , product. and , which contain both primary and The reaction of several polyols with n-butyl secondary hydroxyl groups, there was a low chloride demonstrated (Table IV) that they were conversion (i.e., 10 to 30%) to highly etherified more reactive than the monohydric alcohols products. In each case, there was on an average, examined. This was to be expected on the basis less than one free hydroxyl group remaining. of their higher acidity (13). However, mixtures was resinified by the highly alkaline of products were invariably obtained. Thus, reaction medium. gave 22 % monoether and 66 % diether. With 1,2-, 27 % of the Acknowledgments fully etherified material was obtained along with All analyses were performed by the Analytical 55 % of the monoether. There were two mono- Section of the Research Department of this ethers formed, however; one, presumably Company. 1-butoxy-2-hydroxypropane, to a much greater The authors are indebted to the National extent than the other (49% vs. 6%). With Research Council of Canada for support of this , no monoether was formed, only a work under an Industrial Research Assistant mixture of diethers (34 % of one and 7 % Grant. of the other) and the triether (24 %). Trimethylol- 1. D. J. CRAM,B. RICKBORN,and G. R. KNOX. J. Am. propane and pentaerythritol also formed ethers Chem. Soc. 82, 6412 (1960). 2. A. W. WILLIAMSON.J. Chem. Soc. 4, 229 (1852). in high conversion. The major product was that 3. C. H. SNYDER.Chem. Ind. London, 121 (1963). in which all but one ,of the hydroxyl groups had 4. C. H. SNYDERand A. R. SOTO. J. Org. Chem. 29, been etherified. 12-Octyl chloride reacted with 742 (1964). 5. R. KUHNand H. TRISCHMANN.Ber. 96, 284 (1963). pentaerythritol in a similar manner to 11-butyl 6. K. WALLENFELS.G. BECHTLER.R. KUHN, H. chloride, while benzyl and methallyl chlorides TRISCHMANN,and H. EGGE. ~niew.Chem. Intern. Ed. 2, 515 (1963). gave results more similar to allyl chloride. 7. A. BERGEand J. UGELSTAD.Acta Chem. Scand. 19, An appreciation of the selectivity of the 742 (1965). reaction system, using pentaerythritol as an 8. E. TOMMILAand M. SAVOLAINEN.Acta Chem. Scand. 20, 946 (1966). example can be gained from Table V. With 9. R. N. JOHNSON.A. G. FARNHAM.R. A. CLENDINNING. either butyl or allyl chloride, no conditions were W. FT HALE,'and C. N. MERRIAM. J. Polymer found which gave any appreciable amount of Sci. Pt. A-1, 5, 2375 (1967). Y. MINOURA,K. SHIINA,and K. YOSHIKAWA.J. monoether. Diethers were obtained in modest Poly. Sci. Pt. A-1, 5, 2843 (1967). conversions by using short reaction times for R. ZIMMERMANand W. DATHE. German Patent No. 1,178,840 (to Chemische Werke Albert). June 3,1965. alkoxide formation and by reducing the moles of A. J. PARKER.Quart. Rev. 16, 163 (1962). base and halide per mole of pentaerythritol. J. HINEand M. HINE. J. Am. Chem. Soc. 74, 5266 High conversion to tri-ether resulted when (1 952). 14. W. KI~Yand K. RAICHLE.U.S. Patent No. additional water was added to the solvent or 2.97-4.621 (to Farbcnfabriken Bayer A.-G.). Fcb. 9, by colitrol of the stoicliiometry. Tetra-ethers 1960.