Carboxylic acids UIIldergo a rapid and complete acid-catalyzed
methyl esterification in the methanol-trimethoxyborane azeotrope.
The reaction is first order in cariboxylic acid and first order in
strong acid catalyst. Rate constants are very similar to those in
methanol alone. These observations suggest that the mechanism
is the same as that in solvent, methanol-AAc 2. The reaction can be
made the basis of a convenient preparation of methyl esters. It has
been used to prepare methyl benzoate, methyl lactate, and the
methyl ester of phenylalanine. Acid-catalyzed acetal and ketal
formation in the azeotrope is fast but incomplete. Methyl etherification
of tertiary alcohols seems too limited, structurally, to be
generally useful. No acid-catalyzed addition of methanol to acetonitrile
or acrylonitrile could be observed

M. M. Kreevoy

S. S. Kantner

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CROATICA CHEMICA ACTA CCACAA 49 (1) 41-46 (1977) CCA-972 YU ISSN 0011-1643 547.04 Original Sci entific Paper The Methanol-Trimethoxyborane Azeotrope as a Solvent for Acid-Catalyzed Reactions. Methyl Esterification1a M. M. Kreevoy and S. S. Kantner1b Chemical Dynamics Laboratory, Department of Chemi st ry, University of Minnesota, Minneapolis, Minn., 55455, U .S.A. R eceived June 21, 1976 Carboxylic acids UIIldergo a rapid and complete acid-catalyzed methyl esterification in the methanol-trimethoxyborane azeotrope. The reaction is first order in cariboxylic acid and first order in strong acid catalyst. Rate constants are very similar to those in methanol alone. These observations suggest that the mechanism is the same as that in solvent, methanol-AAc 2. The reaction can be made the basis of a convenient preparation of methyl esters. It has been used to prepare methyl benzoate, methyl lactate, and the methyl ester of phenylalanine. Acid-catalyzed acetal and ketal formation in the azeotrope is fast but incomplete. Methyl etherifi-cation of tertiary alcohols seems too limited, structurally, to be generally useful. No acid-catalyzed addition of methanol to aceto-nitrile or acrylonitrile could be observed. In an accompanying paper 2 we have shown that the mobile, low boiling, 1 : 1 azeotrope formed by methanol and trimethoxyborane has no visible or uv spectrum above 220 nm, has a very simple NMR spectrum, and has a substantial window in its ir spectrum which includes the crucial carbonyl stretching region. Theory and experiment suggest that the azeotrope should be a good hydrogen bond donor and a poor hydrogen bond acceptor2• Since the transition states of most H+ catalyzed reactions require fewer strong hydrogen bond acceptor sites than H+ itself (as shown by their inverse solvent hydrogen isotope effects3) a solvent which is a poor hydrogen bond acceptor may accelerate such reactions. The azeotrope should also be moderately dehydrating, because of the hydrolysis of trimethoxyborane to boric acid. The present paper describes a survey of possibly useful acid-catalyzed reactions, including examples of the reactions shown in eqs. 1-5, all conducted in the presence of a strong acid catalyst. NH II RC=N + HOCH3 ~ R--C-OCHa (1) CH2 = CHX + HOCH3 -+ CHsCHX(OCHs) (2) 1 1 RiCOR2 + HOCHs + - B(OCH3)a:t;R1C(OCHal2R2 +- B(OH)a (3) 3 3 1 1 ROH + - B(OCH3)s-+ ROCHa + - B(OH)s (4) 3 3 42 M. M. KREEVOY AND S. KANTNER 1 1 RCOOH + - B(OCH3)a-+ RCOOCHa + - B(OH)s 3 3 (5) Of these, the first two did not proceed at useful rates ; the third is very fast, but does not go to completion; and the fourth proceeds at a useful rate only when R+ is, relatively, a very stable carbocation, such as the triphenylmethyl cation. The fifth reaction was the most successful. It appears to be general, goes rapidly to completion, and the product is readily separated from the solvent, catalyst, and byproduct in most cases. A kinetic study and several small-scale preparations are described. EXPERIMENTAL Materials The preparation oj the azeotrope and the purification of trifluoromethane-sulfonic acid have been described previously2• Lactic acid was used as an 85~/o active aqueous solution, obtained from J. T. Baker Chemical Co. The other organic sub-stances were all obtained from Aldrich Chemical Co., and were used as supplied. Screening Experiments Small-scale screening experiments were carried out in NMR spectrometer tubes. The NMR spectrum of an 0.5 M solution of the proposed substrate was first obtained in the azeotrope as solvent. Sufficient CF3S020H wa$ then added to give the desired acid concentration, from 10-3 to 10-1 M. The NMR spectrum was monitored from time to time over a period up to several days. Faster reactions were allowed to proceed in the spectrometer, at 39 °c. Slower reactions were removed from the spectrometer between observations, and the reactions were allowed to proceed at room temperature, 23-26 °c. The extent of reaction was judged from the intensity of singlets due to OCH3 groups other than that of the azeotrope. Rates of Esterification To measure rates, esterificatiorr was carried out with dilute solutions of the carboxylic acid (usually 0.1 M) in the azeotrope, in an ir spectrophotometer cell equipped with Irtran<"l windows. The progress of the reaction was determined from the growth of the ester carbonyl band, at frequencies between 1733 cm-1 and 1751 cm-1• Qualitatively, the progress of the reactions could also be seen in the decay and ultimate disappearance of the acid carbonyl peaks around 1717 cm-1. In each spectrum the absorptivity around 1950 cm-1 was used as the base line. Rate constants were obtained graphically from eq. 6. 4 Figure 1 shows a typical plot. The symbols have their usual meaning. When spectral observations were not being kl=~ log ( Aoo-A., ) t-t0 A00 -A1 (6) made, the reacting solution was maintained at 25.0 ± 0.1 °c in a conventional thermostat. Preparative Experiments In a typical preparative experiment 50 ml of azeotrope was made up with enough methainolic HCl so that the final solution was 0.09 M in HCl. To this was added 1.5 g of benzoic acid and the mixture was stirred for 10 min at room tem-perature (- 25 °C). During this period the benzoic acid entirely dissolved. The azeotrope was then rapidly distilled off under vacuum at room temperature. The HCl came off with the azeotrope. This left 1.6 g of mixed solid and liquid, 830/o of theoretical yield based on C6H 5COOCH3 plus 1/3 B(OH)a as the expected products. Simple distillation gave 1.0 g of methyl benzoate, identified by its ir spectrum, which was identical with that of authentic methyl benzoate. METHYL ESTERIFICA TION IN METHANOL-TRIMETOXYBORANE .20 -" Ci .10 ~ O'I ..!! -... OS ~ I 8 <{ .02 0 2. 3 5 10·1 t , sec. 43 Figure 1. A typical plot for the evaluation of k1 from eq 6. The initial (CHaCOOH) was 0.1 M. The (CF,S020H) was 0.00843 M. The slope of the plot, which was drawn subjectively, is kt (t - to) /2.3; k1 is 4.47 X io-• sec-1. RESULTS AND DISCUSSION Screening Experiments The NMR spectrum of the azeotrope consists of a strong singlet (relative mtensity 12) at 4.0 ppm and a weak singlet at 5.5 ppm, both measured from tetramethylsilane. Both bands are broad, but are sharpened by the addition of acid. Presumably methoxyl interchange between H and B is fast (but not infinitely fast) on the NMR time scale, in the pure azeotrope, and is catalyzed by acid. Neither acetonitrile nor acrylonitrile, when added to the azeotrope, causes the development of a new signal in the methoxyl region after several days. Both show unchanging spectra essentially the same as those they show in other solvents. It was, therefore, concluded that neither substance reacts with the azeotrope. Acetone, phenylacetaldehyde, acetophenone, and isobutyralde-hyde all caused the immediate development of a methyl signal _downfield from that of the azeotrope in the presence of 10-3 M CF3S020H. Both solutions also developed new singlets in the aliphatic region. However, neither reaction went to completion, as indicated by the persistence of the signals of the unchanged starting materials. Acetone appeared to be about 50'0/o converted to its dimethyl ketal. No hemiacetal or hemiketal was observed. At 0.1 M CF3S020H the methyl peaks of acetone and those of its ketal were beginning to broaden and merge, and the methoxyl peak was beginning to merge with that of the azeotrope. This suggests a half-life for conversion of about 0.1 sec. These 44 M. M. KREEVOY AND S. KANTNER reactions appear to be unsuitable for synthetic purposes because of their failure to go to completion. However, they confirm that the azeotrope is mildly dehydrating; roughly comparable with 2,2-dimethoxypropane. The strong singlet of 0.5 M t-butanol was unchanged after 4 hr in 0.1 M CF3S020H in the azeotrope, and no separate methoxyl signal developed. Under the same conditions triphenylcarbinol gave a separate methoxyl singnal after . 15 min, which became somewhat stronger after 2 days standing. The reaction may well have gone essentially to completion. It was not possible to make a quantitative estimate of its intensity because it was only slightly to the high--field side of the methoxyl signal of the azeotrope. The reaction was judged to be of insufficient generality to justify more work. Acetic acid, dissolved in the azeotrope in the presence of 0.1 M CF,.SOpH, gave a separate methoxyl signal of almost the intensity of the methyl signal, to the high-field side of the azeotrope's methoxyl signal, 15 min after mixing. The methyl signal was· unshifted, presumably b ecause the ester gives a signal at the same position. The relative intensity of the two signals was unchanged even after 24 hr standing. The reaction was judged to have gone essentially to completion. Pivalic, benzoic, steric, lactic, and salicylic acids, as well as leucine and phenylalanine, all behaved similarly. Kinetic Experiments The reactions of acetic, benzoic, and pivalic acids with the azeotrope all went to completion in a few minutes in the presence of 0.1 M CF3S020H, as judged by changes in their ir spectra. In solutions containing 0.1 M acetic acid, k1 for its conversion to ester was directly proportional to (CF,. SO,OH) for values for the latter between 1.6 X 10-a and 2 X 10 ~. as shown in Figure 2. 8 , " I s u " \I) ~ JI .x. ~ 3 0 2. 0 2 .- " a 10 12 14 1' 103 (CF3 S010H} 1 M Figure 2. The rate of CFaS020H catalyzed esterification of 0.1 M acetic acid as a f unction of the strong acid concentration. The slope of this plot is k2 , 5.3 X 10-2 M-• sec·•. METHYL ESTERI.FICATION IN METHANOL-TRIMETOXYBORANE 45 The proportionality constant, k 2 , was 5.3 X 10-2 M-1 sec-1• The average deviatio11 of points from the linear relation is 50/o which is about the expected uncertainty in k1 . In solutions, all containing 1.7 X 10-3 M CF3S020H, the values of k, were 1.30 X 10-4, 0.99 X 10-4, and 0.72 X 10-4 sec-1 for (CH3COOH) 0.05, 0.10, and 0.40, respectively. These changes appear to be outside the uncertainties of the measurements, but they are too small to suggest serious mechanistic complications. They may well be due to increased dimerization of the acetic acid at the higher concentrations. The addition of 2!0/o excess trimethoxyborane to the reaction mixture increases k1 by - 200/o while the addition of Fl/o excess methanol reduces it by - 80/o. These effects, particularly the former, seem to be outside the scatter. Values of k 2 were also obtained for benzoic and pivalic acid. All are shown in Table I, along with the analogous quantities obtained in methanol as a solvent". The close similarity between k2 values in the azeotrope and those in methanol, shown in Table I , suggests that the AAc2 mechanism operates in the former medium, as it does in the latter6 . In the azeotrope CF3S020H appears to be entirely ionized but incompletely dissociated in the concentration range used to esterify acetic acid (- 300/o dissociated at the lower end of the range, ~ 10'0/o at the upper end)2 • It has been shown, however, that ion pair formation constants in the azeotrope are relatively insensitive to structure. If this insen-sitivity extends to the esterification transition state, ion pairs, CF3S020 -H+, TABLE I Rates of Acid-Catalyzed Methyl Esterification Substarnce CH3COOH C6H5COOH (CH3}3CCOOH 5.3 x 10-2 2.5 x 10-4 1.1 x 10-3 5.9 x 10-2 1.9 x 10-4 1.9 x 10-3 a At 25 oc in the methanol-trimethoxyborane azeotrope. 0 At 25 oc in solvent, methanol'. and dissociated ions, H >, would have about the same catalytic coefficients. This would help account for the similarity between k 2 values in methanol (in which the strong acid is almost completely dissociated) and in the azeotrope. It would also account for the observation of constant k 2 values in a range of strong acid concentrations over which the degree of dissociation is changing signi-ficantly. Preparative Experiments The methyl esters of benzoic acid, lactic acid and phenylalanine were prepared by the method described in the experimental section. In the case of lactic acid an 8510/o aqueous solution was used without removing the water. In all cases spectrophotometric methods indicated that the reactions went to com-pletion, and yields of ester plus boric acid after distilling away the solvent and the HCl were near quantitative. The yield of distilled methyl benzoate was 46 M. M. KREEVOY AND S . KANTNER 590/o, and that of methyl lactate was 24°!c>. Methyl lactate was distilled under vacuum, but polymerization in the pot nevertheless seems to have reduced the isolated yield. The product from phen ylalanine was discolored and was lost in attempted further purification without being weighed. Each preparation was carried out only once and it is clear that the isolated yields are not optimal. We believe that the present m ethod of methyl esterification can be made to compare favorably in cost, convenience, yield, and generality, with other available methods;,s. It appears to be particularly useful for hydroxy acids, like lactic. REFERENCES AND NOTES 1. (a) This research was supported by the Ventron Corporation through a research grant to the University of Minnesota, and by the U.S. National Science Foundation through grant 31360X to the University of Minnesota. (b) National Science Foun-dation Undergraduate Research Participant, Summer 1974. 2. M. M. Kr e e v o y, and S. S. Kant n er, Croat ica Cliem. Acta 49 (1977) 31. 3. A. V. W i 11 i, »SdurekataLytische Reaktionen der Organischen Chemie,« Friedr. Vieweg & Sohn, Braunschweig, 1965, pp 85-90. 4. A. A. Frost and R. G. Pe arson, »Kinetics and Mechanism« 2nd. ed., John Wiley & Sons, New York, N. Y., 1961, p. 30. 5. H. A. Smith and J. Burn, J. Amer. Chem. Soc, 6G (1944) 1494. 6. C. K. Ing o 1 d, »Structure and Mechanism in Organic Chemistry s< 2nd ed., Cornell University Press, Ithaca, N. Y., 1969, pp. 1153-1157. 7. E. Bowden, Org. Syn., Con. Vol. II (1943) 414. 8. J. K enyon, Org. Syn., Con. Vol. I (1941) 264. SAZETAK Azeotropna smjesa metanol-trimetoksiboran kao otapalo za kiselo katalizirane reakcije. Priprava metil estera. M. M. Kreevoy i S. S. Kantner Brza i potpuna kiselo katalizirana priprava metilnih estera karboksilnih kiselina moze se provesti u azeotropnoj smjesi metanol-trimetoksiboran. Reakcija je prvog reda s obzirom na karboksilnu kiselinu, i prvog reda obzirom na jaku kiselinu koja sluzi kao katalizator. Konstante brzine reakcije vrlo su slicne konstantama u cistom metanolu. Ta opafanja pokazuju da je mehanizam isti kao u metanolu -AAc2. Opisana reakcija moie sluziti kao osnova za prikladnu pripremu metilnih estera. Upotrijebljena je za pripravu metil-benzoata, metil-laktata i metil-estera fenilala-nina. Kiselo katalizirano nastajanje acetala i ketala u ovoj azeotropnoj smjesi je brzo, no ne tece do kraja. Priprava metilnih etera tercijarnih alkohola previse je ogranicena strukturom spoja da bi bila od opcenite koristi. Kiselo katalizirana adicija metanola na acetonitril ili akrilonitril nije opafona. CHEMICAL DYNAMICS LABORATORY DEPARTMENT OF CHEMISTRY UNIVERSITY OF MINNESOTA MINNEAPOLIS, MINN. 55455., U.S.A. Prispjelo 21. lipnja 1976. 

The Methanol-Trimethoxyborane Azeotrope as a Solvent for Acid-Catalyzed Reactions. Methyl Esterification

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CROATICA CHEMICA ACTA CCACAA 49 (1) 41-46 (1977) CCA-972 YU ISSN 0011-1643 547.04 Original Sci entific Paper The Methanol-Trimethoxyborane Azeotrope as a Solvent for Acid-Catalyzed Reactions. Methyl Esterification1a M. M. Kreevoy and S. S. Kantner1b Chemical Dynamics Laboratory, Department of Chemi st ry, University of Minnesota, Minneapolis, Minn., 55455, U .S.A. R eceived June 21, 1976 Carboxylic acids UIIldergo a rapid and complete acid-catalyzed methyl esterification in the methanol-trimethoxyborane azeotrope. The reaction is first order in cariboxylic acid and first order in strong acid catalyst. Rate constants are very similar to those in methanol alone. These observations suggest that the mechanism is the same as that in solvent, methanol-AAc 2. The reaction can be made the basis of a convenient preparation of methyl esters. It has been used to prepare methyl benzoate, methyl lactate, and the methyl ester of phenylalanine. Acid-catalyzed acetal and ketal formation in the azeotrope is fast but incomplete. Methyl etherifi-cation of tertiary alcohols seems too limited, structurally, to be generally useful. No acid-catalyzed addition of methanol to aceto-nitrile or acrylonitrile could be observed. In an accompanying paper 2 we have shown that the mobile, low boiling, 1 : 1 azeotrope formed by methanol and trimethoxyborane has no visible or uv spectrum above 220 nm, has a very simple NMR spectrum, and has a substantial window in its ir spectrum which includes the crucial carbonyl stretching region. Theory and experiment suggest that the azeotrope should be a good hydrogen bond donor and a poor hydrogen bond acceptor2• Since the transition states of most H+ catalyzed reactions require fewer strong hydrogen bond acceptor sites than H+ itself (as shown by their inverse solvent hydrogen isotope effects3) a solvent which is a poor hydrogen bond acceptor may accelerate such reactions. The azeotrope should also be moderately dehydrating, because of the hydrolysis of trimethoxyborane to boric acid. The present paper describes a survey of possibly useful acid-catalyzed reactions, including examples of the reactions shown in eqs. 1-5, all conducted in the presence of a strong acid catalyst. NH II RC=N + HOCH3 ~ R--C-OCHa (1) CH2 = CHX + HOCH3 -+ CHsCHX(OCHs) (2) 1 1 RiCOR2 + HOCHs + - B(OCH3)a:t;R1C(OCHal2R2 +- B(OH)a (3) 3 3 1 1 ROH + - B(OCH3)s-+ ROCHa + - B(OH)s (4) 3 3 42 M. M. KREEVOY AND S. KANTNER 1 1 RCOOH + - B(OCH3)a-+ RCOOCHa + - B(OH)s 3 3 (5) Of these, the first two did not proceed at useful rates ; the third is very fast, but does not go to completion; and the fourth proceeds at a useful rate only when R+ is, relatively, a very stable carbocation, such as the triphenylmethyl cation. The fifth reaction was the most successful. It appears to be general, goes rapidly to completion, and the product is readily separated from the solvent, catalyst, and byproduct in most cases. A kinetic study and several small-scale preparations are described. EXPERIMENTAL Materials The preparation oj the azeotrope and the purification of trifluoromethane-sulfonic acid have been described previously2• Lactic acid was used as an 85~/o active aqueous solution, obtained from J. T. Baker Chemical Co. The other organic sub-stances were all obtained from Aldrich Chemical Co., and were used as supplied. Screening Experiments Small-scale screening experiments were carried out in NMR spectrometer tubes. The NMR spectrum of an 0.5 M solution of the proposed substrate was first obtained in the azeotrope as solvent. Sufficient CF3S020H wa$ then added to give the desired acid concentration, from 10-3 to 10-1 M. The NMR spectrum was monitored from time to time over a period up to several days. Faster reactions were allowed to proceed in the spectrometer, at 39 °c. Slower reactions were removed from the spectrometer between observations, and the reactions were allowed to proceed at room temperature, 23-26 °c. The extent of reaction was judged from the intensity of singlets due to OCH3 groups other than that of the azeotrope. Rates of Esterification To measure rates, esterificatiorr was carried out with dilute solutions of the carboxylic acid (usually 0.1 M) in the azeotrope, in an ir spectrophotometer cell equipped with Irtran<"l windows. The progress of the reaction was determined from the growth of the ester carbonyl band, at frequencies between 1733 cm-1 and 1751 cm-1• Qualitatively, the progress of the reactions could also be seen in the decay and ultimate disappearance of the acid carbonyl peaks around 1717 cm-1. In each spectrum the absorptivity around 1950 cm-1 was used as the base line. Rate constants were obtained graphically from eq. 6. 4 Figure 1 shows a typical plot. The symbols have their usual meaning. When spectral observations were not being kl=~ log ( Aoo-A., ) t-t0 A00-A1 (6) made, the reacting solution was maintained at 25.0 ± 0.1 °c in a conventional thermostat. Preparative Experiments In a typical preparative experiment 50 ml of azeotrope was made up with enough methainolic HCl so that the final solution was 0.09 M in HCl. To this was added 1.5 g of benzoic acid and the mixture was stirred for 10 min at room tem-perature (- 25 °C). During this period the benzoic acid entirely dissolved. The azeotrope was then rapidly distilled off under vacuum at room temperature. The HCl came off with the azeotrope. This left 1.6 g of mixed solid and liquid, 830/o of theoretical yield based on C6H 5COOCH3 plus 1/3 B(OH)a as the expected products. Simple distillation gave 1.0 g of methyl benzoate, identified by its ir spectrum, which was identical with that of authentic methyl benzoate. METHYL ESTERIFICA TION IN METHANOL-TRIMETOXYBORANE .20 -" Ci .10 ~ O'I ..!! -... OS ~ I 8 <{ .02 0 2. 3 5 10·1 t , sec. 43 Figure 1. A typical plot for the evaluation of k1 from eq 6. The initial (CHaCOOH) was 0.1 M. The (CF,S020H) was 0.00843 M. The slope of the plot, which was drawn subjectively, is kt (t - to) /2.3; k1 is 4.47 X io-• sec-1. RESULTS AND DISCUSSION Screening Experiments The NMR spectrum of the azeotrope consists of a strong singlet (relative mtensity 12) at 4.0 ppm and a weak singlet at 5.5 ppm, both measured from tetramethylsilane. Both bands are broad, but are sharpened by the addition of acid. Presumably methoxyl interchange between H and B is fast (but not infinitely fast) on the NMR time scale, in the pure azeotrope, and is catalyzed by acid. Neither acetonitrile nor acrylonitrile, when added to the azeotrope, causes the development of a new signal in the methoxyl region after several days. Both show unchanging spectra essentially the same as those they show in other solvents. It was, therefore, concluded that neither substance reacts with the azeotrope. Acetone, phenylacetaldehyde, acetophenone, and isobutyralde-hyde all caused the immediate development of a methyl signal _downfield from that of the azeotrope in the presence of 10-3 M CF3S020H. Both solutions also developed new singlets in the aliphatic region. However, neither reaction went to completion, as indicated by the persistence of the signals of the unchanged starting materials. Acetone appeared to be about 50'0/o converted to its dimethyl ketal. No hemiacetal or hemiketal was observed. At 0.1 M CF3S020H the methyl peaks of acetone and those of its ketal were beginning to broaden and merge, and the methoxyl peak was beginning to merge with that of the azeotrope. This suggests a half-life for conversion of about 0.1 sec. These 44 M. M. KREEVOY AND S. KANTNER reactions appear to be unsuitable for synthetic purposes because of their failure to go to completion. However, they confirm that the azeotrope is mildly dehydrating; roughly comparable with 2,2-dimethoxypropane. The strong singlet of 0.5 M t-butanol was unchanged after 4 hr in 0.1 M CF3S020H in the azeotrope, and no separate methoxyl signal developed. Under the same conditions triphenylcarbinol gave a separate methoxyl singnal after . 15 min, which became somewhat stronger after 2 days standing. The reaction may well have gone essentially to completion. It was not possible to make a quantitative estimate of its intensity because it was only slightly to the high--field side of the methoxyl signal of the azeotrope. The reaction was judged to be of insufficient generality to justify more work. Acetic acid, dissolved in the azeotrope in the presence of 0.1 M CF,.SOpH, gave a separate methoxyl signal of almost the intensity of the methyl signal, to the high-field side of the azeotrope's methoxyl signal, 15 min after mixing. The methyl signal was· unshifted, presumably b ecause the ester gives a signal at the same position. The relative intensity of the two signals was unchanged even after 24 hr standing. The reaction was judged to have gone essentially to completion. Pivalic, benzoic, steric, lactic, and salicylic acids, as well as leucine and phenylalanine, all behaved similarly. Kinetic Experiments The reactions of acetic, benzoic, and pivalic acids with the azeotrope all went to completion in a few minutes in the presence of 0.1 M CF3S020H, as judged by changes in their ir spectra. In solutions containing 0.1 M acetic acid, k1 for its conversion to ester was directly proportional to (CF,. SO,OH) for values for the latter between 1.6 X 10-a and 2 X 10 ~. as shown in Figure 2. 8 , " I s u " \I) ~ JI .x. ~ 3 0 2. 0 2 .- " a 10 12 14 1' 103 (CF3 S010H} 1 M Figure 2. The rate of CFaS020H catalyzed esterification of 0.1 M acetic acid as a f unction of the strong acid concentration. The slope of this plot is k2 , 5.3 X 10-2 M-• sec·•. METHYL ESTERI.FICATION IN METHANOL-TRIMETOXYBORANE 45 The proportionality constant, k 2 , was 5.3 X 10-2 M-1 sec-1• The average deviatio11 of points from the linear relation is 50/o which is about the expected uncertainty in k1 . In solutions, all containing 1.7 X 10-3 M CF3S020H, the values of k, were 1.30 X 10-4, 0.99 X 10-4, and 0.72 X 10-4 sec-1 for (CH3COOH) 0.05, 0.10, and 0.40, respectively. These changes appear to be outside the uncertainties of the measurements, but they are too small to suggest serious mechanistic complications. They may well be due to increased dimerization of the acetic acid at the higher concentrations. The addition of 2!0/o excess trimethoxyborane to the reaction mixture increases k1 by - 200/o while the addition of Fl/o excess methanol reduces it by - 80/o. These effects, particularly the former, seem to be outside the scatter. Values of k 2 were also obtained for benzoic and pivalic acid. All are shown in Table I, along with the analogous quantities obtained in methanol as a solvent". The close similarity between k2 values in the azeotrope and those in methanol, shown in Table I , suggests that the AAc2 mechanism operates in the former medium, as it does in the latter6 . In the azeotrope CF3S020H appears to be entirely ionized but incompletely dissociated in the concentration range used to esterify acetic acid (- 300/o dissociated at the lower end of the range, ~ 10'0/o at the upper end)2 • It has been shown, however, that ion pair formation constants in the azeotrope are relatively insensitive to structure. If this insen-sitivity extends to the esterification transition state, ion pairs, CF3S020 -H+, TABLE I Rates of Acid-Catalyzed Methyl Esterification Substarnce CH3COOH C6H5COOH (CH3}3CCOOH 5.3 x 10-2 2.5 x 10-4 1.1 x 10-3 5.9 x 10-2 1.9 x 10-4 1.9 x 10-3 a At 25 oc in the methanol-trimethoxyborane azeotrope. 0 At 25 oc in solvent, methanol'. and dissociated ions, H >, would have about the same catalytic coefficients. This would help account for the similarity between k 2 values in methanol (in which the strong acid is almost completely dissociated) and in the azeotrope. It would also account for the observation of constant k 2 values in a range of strong acid concentrations over which the degree of dissociation is changing signi-ficantly. Preparative Experiments The methyl esters of benzoic acid, lactic acid and phenylalanine were prepared by the method described in the experimental section. In the case of lactic acid an 8510/o aqueous solution was used without removing the water. In all cases spectrophotometric methods indicated that the reactions went to com-pletion, and yields of ester plus boric acid after distilling away the solvent and the HCl were near quantitative. The yield of distilled methyl benzoate was 46 M. M. KREEVOY AND S . KANTNER 590/o, and that of methyl lactate was 24°!c>. Methyl lactate was distilled under vacuum, but polymerization in the pot nevertheless seems to have reduced the isolated yield. The product from phen ylalanine was discolored and was lost in attempted further purification without being weighed. Each preparation was carried out only once and it is clear that the isolated yields are not optimal. We believe that the present m ethod of methyl esterification can be made to compare favorably in cost, convenience, yield, and generality, with other available methods;,s. It appears to be particularly useful for hydroxy acids, like lactic. REFERENCES AND NOTES 1. (a) This research was supported by the Ventron Corporation through a research grant to the University of Minnesota, and by the U.S. National Science Foundation through grant 31360X to the University of Minnesota. (b) National Science Foun-dation Undergraduate Research Participant, Summer 1974. 2. M. M. Kr e e v o y, and S. S. Kant n er, Croat ica Cliem. Acta 49 (1977) 31. 3. A. V. W i 11 i, »SdurekataLytische Reaktionen der Organischen Chemie,« Friedr. Vieweg & Sohn, Braunschweig, 1965, pp 85-90. 4. A. A. Frost and R. G. Pe arson, »Kinetics and Mechanism« 2nd. ed., John Wiley & Sons, New York, N. Y., 1961, p. 30. 5. H. A. Smith and J. Burn, J. Amer. Chem. Soc, 6G (1944) 1494. 6. C. K. Ing o 1 d, »Structure and Mechanism in Organic Chemistry s< 2nd ed., Cornell University Press, Ithaca, N. Y., 1969, pp. 1153-1157. 7. E. Bowden, Org. Syn., Con. Vol. II (1943) 414. 8. J. K enyon, Org. Syn., Con. Vol. I (1941) 264. SAZETAK Azeotropna smjesa metanol-trimetoksiboran kao otapalo za kiselo katalizirane reakcije. Priprava metil estera. M. M. Kreevoy i S. S. Kantner Brza i potpuna kiselo katalizirana priprava metilnih estera karboksilnih kiselina moze se provesti u azeotropnoj smjesi metanol-trimetoksiboran. Reakcija je prvog reda s obzirom na karboksilnu kiselinu, i prvog reda obzirom na jaku kiselinu koja sluzi kao katalizator. Konstante brzine reakcije vrlo su slicne konstantama u cistom metanolu. Ta opafanja pokazuju da je mehanizam isti kao u metanolu -AAc2. Opisana reakcija moie sluziti kao osnova za prikladnu pripremu metilnih estera. Upotrijebljena je za pripravu metil-benzoata, metil-laktata i metil-estera fenilala-nina. Kiselo katalizirano nastajanje acetala i ketala u ovoj azeotropnoj smjesi je brzo, no ne tece do kraja. Priprava metilnih etera tercijarnih alkohola previse je ogranicena strukturom spoja da bi bila od opcenite koristi. Kiselo katalizirana adicija metanola na acetonitril ili akrilonitril nije opafona. CHEMICAL DYNAMICS LABORATORY DEPARTMENT OF CHEMISTRY UNIVERSITY OF MINNESOTA MINNEAPOLIS, MINN. 55455., U.S.A. Prispjelo 21. lipnja 1976. 

The Methanol-Trimethoxyborane Azeotrope as a Solvent for Acid-Catalyzed Reactions. Methyl Esterification

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