630 J. Org. Chem., Vol. 46, No. 3, 1981 Notes Table I. Desiccant Efficiency in the Dryinga,b of a PyridineC Series residual water content,d ppm desiccant CaH, CaC, BaO 4A sieves 3A sieves
Desiccant Efficiency in Solvent and Reagent Drying. 7. Alcohols’” David R. Burfield and Roger H. Smithers* Department of Chemistry, University of Malaya, Kuala Lumpur 22-11, West Malaysia Received October 22, 1982 For many of their applications in sy
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Desiccant efficiency in solvent drying. 3. Dipolar aprotic solvents David R. Burfield, and Roger H. Smithers J. Org. Chem., 1978, 43 (20), 3966-3968• DOI: 10.1021/jo00414a038 • Publication Date (Web): 01 May 2002 Downloaded from http://pubs.acs.org on May 1, 2009
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3966 J.Org. Chem., Vol. 43, No. 20,1978
Other acetals which are commonly used as protecting groups for alcohols are the tetrahydropyranyl ether (ref 4, p 104), ethoxyethyl ether (S. Chladek and J. Smtt, Chem. Ind. (London), 1719 (1964)), 2-methoxyisopropylether (ref 4, p 107), and 4-methoxytetrahydropyranylether (ref 4, p 108).Removal of all of these groups can be accornpllshed with dilute, aqueous acid. They are prepared from the corresponding vinyl ether with acidcataiysis. The methoxymethyl ether,' as well as our tert-butoxymethyl ether, is prepared from the chloro ether with base catalysis. See, for example, (a) the synthesis of chloromethyl methyl ether: C. S. Marvel and P. K. Potter, "Organic Synthesis", Collect. Vol. I, 2nd ed, A. H. Blatt, Ed., Wiley, New York, N.Y., 1941, p 377; (b) the preparation of methoxyethyl chloromethyl ether: E. J. Corey, J.-L. Gras, and P. Ulrich, Tetrahedron Lett., 809 (1976); and (c) a review on a-halo ethers: L. Summers, Chem. Rev., 55, 301 (1955). Ethers are halogenated on the (Y carbon: M. L. Poutsma in "Methods in Free Radical Chemistry", Vol. 1, E. S.Huyser, Ed., Marcel Dekker, New York, N.Y., 1969, p 137. Methods for the free-radical halogenation of organic compounds have been reviewed: E. S.Huyser, Synthesis, 7 (1970). Sulfuryl chloride has been used to chlorinate tetrahydrofuran (THF): C. G. Kruse, N. L. J. M. Broekhof, and A. van der Gen, Tetrahedron Lett., 1725 (1976). All attempts to isolate the chloro ether by concentration have led to decomposition. J. F. Norris and G. W. Rigby, J. Am. Chern. SOC.,54, 2088 (1932). There is no reaction at 0 O C after 4 h but a satisfactory reaction rate is obtained at room temperature. The water bath is used for cooling purposes only. The 'H NMR spectra of the tert-butoxymethyl ethers show singlets at 6 4.1-4.7 (2 H) and 1.2-1.25 (9 H). The corresponding l3C NMR spectra are also consistent with the proposed structures. For example, the acetal and quaternary carbons are found at 6 89.248 and 74.251, respectively, for the benzyl alcohol acetal and 6 90.038 and 74.068, respectively, for the 1-hexanol acetal.
Desiccant Efficiency in Solvent Drying. 3. Dipolar Aprotic SolventslJ David R. Burfield* and Roger H. Smithers Department of Chemistry, University of Malaya, Kuala Lumpur 22-11, Malaysia Received May 2, 1978
It is generally acknowledged that dipolar aprotic solvents are the media of choice in some reactions and are unique in facilitating others.3 The special solvent effects of molecules such as DMF and Me2SO are attributable to their large dielectric constants coupled with the absence of solvation by hydrogen bonding and typically manifest themselves in properties such as poor anion solvation, voracious cation solvation, and a marked hydrophilicity. For the chemist, this latter feature is unfortunate since small amounts of water in these systems can diminish314their nucleophilicity and may even be hazardous to some operations.5 The drying of these solvents is thus of paramount importance, but in these cases, as previously,' the chemical literature contains little reliable quantitative data. We have recently developed a method of solvent water assay
which utilizes a tritiated water tracer for the determination of water content.6 The method circumvents many of the problems encountered in other assay methods and has provided some new correlations on the efficiency of desiccants.lS* For example, it has been shown that, rather surprisingly, the efficiency of a given desiccant is strongly dependent upon the solvent type,' and there is thus much uncertainty in extrapolating generalizations from one solvent type to another. The method has now been applied to the desiccation of the dipolar aprotics acetone, DMF, MeZSO, and HMPT. Since the dielectric constants of these solvents range between 20.7 (acetone) and 46.7 (MeZSO), their rigorous desiccation is expected to be difficult.
Results and Discussion Drying of Hexamethylphosphoric Triamide (HMPT). Caution! HMPT is a suspected carcinogen. Although in recent years the favored desiccant for H M P T appeared to be calcium h ~ d r i d e drying ,~ has also been previously accomplished with alkali metal^,^^^ alkali metal earth oxides,s and 4A9* and 13Xgbmolecular sieves. The results with the siccatives summarized in Table I are largely self-evident, but the following points are worth noting. The extreme resistance to desiccation is demonstrated by the impossibility of obtaining super-dry lo H M P T under any of the conditions used here. Even sequential drying,ll which was previously found to be effective with acetonitrile,2 falls short in this case. The use of sodium-potassium alloy as a drying agent seems questionable in view of the thermal instability of solutions of alkali metals in solvents of this type.lZ Since phosphorus pentoxide causes loss of material through side reactions, the best procedure for drying H M P T appears to be distillation from calcium hydride followed by storage over molecular sieves. Drying of Dimethylformamide One sources observes that it is doubtful whether distillation alone can remove water from this solvent and recommends a chemical method for the elimination of protonic impurities. 4A molecular sieves, alumina, potassium hydroxide, and calcium hydride have all been endorsed as siccativess for DMF. The results in Table I1 indicate the powerful hydrophilicity of this solvent, although sequential drying with 3A sieves almost achieves super-dryness. Interestingly, and contrary to an earlier suggestion,'3 while some of the basic dessiccants investigated are totally inept, e.g., alumina and potassium carbonate, others such as calcium hydride and potassium hydroxide achieve quite reasonable drying levels. Also, although seldom advocated for use in this circumstance, phosphorus pentoxide is a commendable desiccant. For DMF, however, barring impurities other than water, by far the
Table I. Efficiency of Desiccants in the Drying" of HMPTb desiccant p205
residual solvent water content, ppm 72 h 144 h
595 610 840
307 344 404
Bz03 3A molecular sieves 4A molecular sieves KOH (powdered) Na-K BaO CaO Cas04 A1203
1380 1167 1380 2190 2360 2080 2134
other conditions 22d 80d 190e 295 321f 162Od.g
a Static drying modes unless otherwise specified. Desiccant loading 5% w/v; initial water content 2620 ppm (0.262% w/w). Strongly colored solution. Distilled sample. e Stirring for 24 h followed by distillation. f Sequentially dried sample, 72 h. Significant quantities of dimethylamine are released on distillation.
0022-3263/78/1943-3966$01.00/0 0 1978 American Chemical Society
J . Org. Chem., Vol. 43, No. 20,1978
Table 11. Efficiency of Desiccants in the Drying" of DMFb
residual solvent water content, ppm desiccant
3A molecular sieves
500 879 641 454 1360
167 105 227 134 1110
98 102 108
2060 2090 1970 2310 2500
CaH2 4A molecular sieves KOH (powdered) B203 BaO CaO A1203
other conditions 1.5c 2d
94d 303 890e
a Static drying modes unless otherwise specified. Desiccant loading 5% w/v; initial water content 2860 ppm (0.286% w/w). Sequentially dried sample, 72 h. Distilled Sample. e Stirring for 24 h followed by distillation.
simplest and most effective method is sequential drying with 3A molecular sieves. Drying of Dimethyl Sulfoxide (MezSO). Although calcium hydride14aand molecular sieves14bappear to be approved desiccants, the drying of Me2SO has also been accomplished with a large variety of other siccatives.8Calcium sulfate, alkali earth metal oxides, alkali metal hydroxides, alumina, and, surprisingly perhaps, fractional distillation alone15 have all been utilized. Perhaps the most unexpected result (Table 111) is that fractional distillation, discarding the first 20?hof the distillate, affords desiccation of similar magnitude to that obtained with molecular sieves! This result is most surprising in view of the high dielectric constant and hygroscopicity of MezSO. The interpretation of other results for MezSO is not so straightforward. For many of the basic desiccants, e.g., calcium hydride and calcium and barium oxides, initial dehydration is followed by an increase in apparent water content, and this indicates a base-catalyzed exchange between the acidic a protons of Me2SO and labeled water. This suggestion is supported by a desiccation experiment with powdered potassium hydroxide which gave very little apparent drying. In this case, standing for 2 or 3 h over the desiccant produced yellow solutions, most likely indicating the presence of the dimsyl ion, which would of course lead to labeled solvent through exchange processes.
Although the results with the basic desiccants are therefore not very conclusive, a necessary corollary in the case of calcium hydride is, however, that drying is relatively slow, and perhaps not very efficient. A similar result for this desiccant was noted earlier with acetonitrile.' In summary, although phosphorus pentoxide gave the best drying, it also induced significant decomposition, and the method of choice for Me2SO would appear to be initial fractional distillation followed by sequential drying with molecular sieves. Drying of Acetone. Acetone has been dried with a wide spectrum of desiccants.8 Thus, alumina, calcium chloride, phosphorus pentoxide, and 4A molecular sieves,16as well as calcium and (anhydrous) cupric sulfate, have all been used. Since acetone has the lowest dielectric constant of the solvents investigated here, it might be predicted that its drying should be relatively easy. In fact, in many respects the drying of acetone proved to be the most difficult case. As with MezSO, the root of the difficulty is the acidic a protons, which in this case compounds the drying problem not only by inflating apparent water content by exchange process but also by providing a pathway to self-condensation through enol intermediates. This facet of acetone chemistry makes the choice of a successful desiccant a delicate process. As Table IV shows, mild siccatives such as calcium sulfate are inept; more potent desiccants such as molecular sieves exhibit a short initial drying action but thereafter actually cause disastrous increases in water content by displacement of the condensation equilibrium. This interpretation was confirmed for molecular sieves and other basic desiccants such as barium oxide by gas chromatographic analysis which demonstrated the presence of mesityl oxide in the dried solvent (see Table IV). In summary, while both cupric sulfate and 3A molecular sieves are clearly a t least useful preliminary desiccants, the agent par excellence for acetone is powdered boric anhydride. Using stirring and sequential drying conditions, this siccati gave a solvent containing only 18ppm of water and caused detectable condensation. In fact, the true water content likely to be lower as even with the premise that drying OCCL considerably faster than other processes, some labeling via t enol surely occurs on preparation of the standard wet sol tion. In view of the remarkable efficiency of this desiccant f acetone and acetonitrile,l it is puzzling that boric anhydri is not particularly outstanding for other members of this ser (Tables 1-111). This finding emphasizes once more the danger in assuming the existence of any kind of absolute scale in the efficiency of desiccants for solvent drying.
Table 111. Efficiency of Desiccants in the Dryinga of MezSOb desiccant
4A niolecular sieves 3A molecular sieves none
residual solvent water content, ppm 72 h 144 h 332 269
B203 CaH2 BaO CaO A12013
KzCQ3 KOH (powdered) Cas04
1560 1450 2060 1840 2280 2130h 2140
1820 1770 1740 1920
1740 2251 1800
other conditions 1oc
261 1.4e3f 897g 1802e
Static drying modes unless otherwise specified. Desiccant loading 5% w/v; initial water content 2560 ppm (0.256% w/w). Sequentially dried sample, 72 h. d Fractionally distilled sample. e Distilled sample. f Contaminated by decomposition products. g Stirring for 24 h followed by distillation. Yellow colored solutions.
3968 J. Org. Chem., Vol. 43, No. 20, 1978 Table IV. Efficiency of Desiccants in the DryingD of Acetone residual solvent water content, ppm desiccant
a Static drying modes unless specified otherwise. Desiccant loading 5% w/v; initial water content 2710 ppm (0.271% w/w), unless specified otherwise. c Initial water content 2890 ppm (0.289% w/w). d Stirred, distilled, and sequentially dried, 24 h. e Stirred for 24 h and distilled. f Dried for 24 hand then distilled. g Contamination (2%) by mesityl oxide. Fractionated sample. i Contamination (12%) by mesityl oxide. j Brown-black solutions.
Experimental Section Desiccants. Details of the source, activation, and handling of most of the desiccants have already been described.' Reagent grade cupric sulfate was activated by heating at 320 "C for 15h before use. Barium and calcium oxides were of reagent grade, and a fresh batch was used directly without activation. Solvents, DMF, MeZSO, and HMPT were commercial synthetic grades of 99%purity (Merck).Acetone was of analytical grade (M&B). All solvents were rigorously purified by standard methods.* HMPT and Me2SO were treated by standing over barium oxide overnight, followed by filtration, distillation from calcium hydride, and subsequent storage over 20% w/v 4A molecular sieves. MezSO had bp 74.5-75.0 O C at 12 mmHg, and HMPT had bp 89.0-89.5 "C at -3 mmHg. Commercial DMF was allowed to stand over 4A molecular sieves overnight and was filtered, distilled from phosphorus pentoxide (bp 55.8-56.0 "C at 20 mmHg), allowed to stand over anhydrous potassium carbonate, and subsequently stored over 4A molecular sieves. Analytical grade acetone was allowed to stand over anhydrous potassium carbonate for one day and then over 4A molecular sieves overnight. Fractionation gave material, bp 56.2 OC, which was not stored but used immediately. Gas chromatographic analysis of this material showed it to be free of impurities. Techniques. The procedure used for HMPT serves as an example. A stock solution of HMPT containing 2620 ppm of labeled water was prepared by the addition of 0.50 g of tritiated water, specific activity 0.5 mCi/mL, to the appropriate mass of purified rigorously dried HMPT. Aliquots of the stock solution (15.0 i 0.1 mL) were syringed directly onto the appropriate desiccant contained in a 25 mL clear-fit round-bottom flask, which was immediately stoppered. Experiments were conducted at ambient temperatures (26-30 "C). Where specified, samples were stirred magnetically. Aliquots (1.00 f 0.02 mL) were taken at time intervals as specified in Table I and assayed directly by liquid scintillation counting, as previously Where necessary, viz., in the case of colored solutions or suspected contamination by soluble desiccant residues, samples were distilled before assay. Sequential drying2 was accomplished by decanting monosiccated solvent onto a fresh charge of 5% w/v desiccant. Sampling was then effected at the time intervals given in the table footnotes.
1969,1972,1974and 1975. (4)For an interesting recent study involving Me2SO-H20 mixtures, see L. F. Blackwell and J. L. Woodhead, J. Chem. Soc.. Perkin Trans. 2, 1218 (1975). (5) The reaction of sodium hydride with Me2S0 has been reported to sometimes give rise to violent explosions: inter alia, see L. Brandsma, "Preparative Acetylenic Chemistry", Elsevier, Amsterdam, 1971,p 24.However, in our hands, the same reaction has been carried out a number of times using stringently dried solvent with no untoward effects. While the cause of these accidents remains undetermined, it is noteworthy that the equilibrium water content of Me2S0 is lo%, and it thus seems not unlikely that the origin of these mishaps may lie in the use of insufficiently dried solvents. (6) D. R. Burfield, Anal. Chem., 48,2285 (1976). (7)See,for example, B. M. Trost and Y. Tamaru, J. Am. Chem. Soc.,99,3101
(1977). (8)See references contained in J. A. Riddick and W.B. Bunger, "Organic Solvents", 3rd ed., Wiley-lnterscience, New York, N.Y., 1970. (9)(a) F. Trondlin and C. Ruchardt, Chem. Ber., 110, 2949 (1977);(b) T. J. Wallace and A. Schriesheim, Tetrahedron, 21, 2271 (1965). (10)Here, as the term super-dry denotes solvents containing less than 1 ppm of water. (11) See Experimental Section. (12)C. A. Young and R. R. Dewald, J. Chem. Soc., Chem. Commun., 186 (1977). (13)See S. S.Pizey, "Synthetic Reagents", Vol. 1. Ellis Horwood Ltd., ChiChester, 1974.This author reports that the use of calcium hydride and other basic desiccants in the drying of DMF could produce significant amounts of dimethylamine. However, the presence of this amine would give rise to inflated apparent water contents, and the values observed here, both for statically dried and distilled samples, suggest that this side reaction is of minor importance for these desiccants. (14) (a) D.Martin and H. G. Hauthal, "Dimethyl Sulphoxide", translated by E. S. Halberstadt, Wiley-Halsted, New York, N.Y., 1975.(b) H. E. Baumgarten. Ed.. "Organic Syntheses", Collect. Vol. 5,Wiley, New York. N.Y., 1973, pp 243,756. (15) W. H. Smyrl and C. W. Tobias, J. Electrochem. Soc., 115, 33 (1968). (16)R. L. Meeker, F. Critchfield, and E. T. Bishop, Anal. Chem., 34, 1510
3,4-Dimethyl-cis- bicyclo[ 3.3.0]-3-octene-2,8-dione: A Potentially Useful Pentalenolactone Synthon Martha L. Quesada, Richard H. Schlessinger,* and William H. Parsons Department of Chemistry, University of Rochester, Rochester, New York 14627 Received March 13.1978 Pentalenolactone (1) is an acidic lipophylic antibiotic isolated from the fermentation broth of Streptomyces UC 5319
-1 which exhibits inhibitory activity against nucleic acid synthesis in bacterial cells.1t2Both the novel structural nature of pentalenolactone together with its biological activity prompted us t o consider possible routes to the synthesis of this molecule. Inspection of the literature revealed a number of potential pentalene ~ y n t h o n sthe , ~ most interesting of which was the pentalenedione 2 reported first by Stetter4 and more recently
References and Notes (1)Part I: D.R. Burfield, K. H. Lee, and R. H. Smithers, J. Org. Chem., 42,3060 ( 1977). (2)For Part 2,see D. R. Burfield. G. H. Gan, and R. H. Smithers, J. Appl. Chem. Biotechnol., 28, 23 (1978). (3)See, for example, Heinz Becker et ai., "Organicum, Practical Handbook of Organic Chemistry", translated by B. J. Hazard, Pergamon Press, Braunschweig. 1973,pp 185. 190.See also L. F. Fieser and M. Fieser. "Reagents for Organic Synthesis", Vol. 1-5,Wiley, New York. N.Y., 1967,
by E a t ~ nThe . ~ salient feature of both the Stetter and Eaton routes was the base-induced internal Claisen condensation of the ester 3, which in Eaton's hands gave an excellent yield of the dione 2. These data inspired us t o consider the possi-
0022-3263/78/1943-3968$01.00/0 0 1978 American Chemical Society