Hydrolysis and saponification of methyl benzoates A green procedure in high temperature water Pedro A. Alemán,† Carmen Boix* and Martyn Poliakoff* School of Chemistry University of Nottingham University Park Nottingham UK NG7 2RD. http://www.nottingham.ac.uk/supercritical/ Received 10th December 1998 In contrast hydrolysis in basic medium is highly effective because of the formation of a carboxylate ion which continuously shifts the reaction to the hydrolysed side. Hence hydrolysis in HT-H2O could be improved by performing the reaction under basic conditions and so far the saponification of carboxylic esters at high temperatures has not been studied. We report a fundamental study of the hydrolysis and saponification of methyl benzoates 1 in H2O and slightly alkaline solution at high temperature.We have verified the efficacy of the media in the difficult hydrolysis of sterically hindered esters such as methyl 2,4,6-trimethylbenzoate (1a) as well as the stability and influence on the rate of hydrolysis of other functional groups in the molecule. Summary We report a study of the hydrolysis and saponification of methyl benzoates 1 in both water and slightly alkaline solution (2% KOH) at high temperature (200–300 °C). In this green solventfree procedure we achieve partial hydrolysis or quantitative saponification of sterically hindered and p-substituted methyl benzoatesin 30 min. In addition methyl 2,4,6-trimethylbenzoate 1a and methyl p-aminobenzoate 1g can be selectively decarboxylated or hydrolyzed by changing the temperature and/or pH of the reaction medium.The enhancement of the nucleophilicity of diluted alkaline solution at high temperature is proved by the quantitative hydrolysis of the sterically hindered ester 1a and the partial hydrolysis of the trifluoromethyl group to a carboxylic acid in methyl p-trifluoromethylbenzoate 1e. Introduction Over the past five years the study of the reactivity of simple molecules in high temperature water (HT-H2O) has led to the development of solvent-free synthetic procedures in organic chemi s t r y .1 – 4 The application of these procedures to industrial processes will lead to a new environmentally friendly ‘green technology’ with minimised waste problems. This research has been encouraged by the change of the physical and chemical properties of water from room temperature to supercritical (374 °C).For instance the decrease of the relative permittivity of water implies an increasing solubility of the organic compounds, 5,6 and the increase of its dissociation constant7 can promote acid–base catalysed reactions that do not take place at lower temperatures. An example is the hydrolysis of carboxylic esters in HT-H2O,1,2 which has been applied to the hydrolysis of vegetable oils.8 Hydrolysis of carboxylic esters in water is a two-phase reaction and rates are usually slow due to the low solubility of the esters in the reaction medium. Although several procedures have been developed to overcome this problem including phase transfer catalysis9,10 and ultrasound 11 they present serious disadvantages due to high costs and the toxicity of solvents and catalysts.HT-H2O seems to be an environmentally friendly alternative. However only partial hydrolysis of carboxylic esters has been achieved in most examples so far.2,3 Hydrolysis in HT-H2O is a process acid-catalysed by the formation of soluble carboxylic acids during the reaction which eventually reaches equilibrium. † Permanent address Universidad de Valencia Departmento de Química Orgánica Avda. V. A. Estellés s/n E-46100 Burjassot Spain. Results and discussion Hydrolysis in high temperature water Water in the temperature range 250–300 °C promotes hydrolysis of methyl benzoates 1 (Scheme 1) recovering unreacted 1 at temperatures of 200 °C or below.The results are summarised in Table 1. HT-H2O is a powerful system able to hydrolyse sterically hindered esters such as 1a which usually undergoes acid hydrolysis only under extreme conditions e.g. in concentrated H2SO4 solution. 12 However decarboxylation of 2a is a secondary reaction in both H2SO4 and HT-H2O. Thus the reaction of 1a at 250 °C yielded the acid 2a (20%) after 0.5 h and a mixture of 2a (53%) and 1,3,5-trimethylbenzene 3a (20%) after 2 h. Reaction at 300 °C for 0.5 h gave only 3a (89%). These results indicate that hydrolysis and decarboxylation are competitive processes at 250 °C while decarboxylation is more favoured at 300 °C. Green Context Reactions in high temperature water represent a potentially green methodology.They avoid the extreme conditions required for supercritical water but the high temperatures used (>200 °C) are sufficient to render the water non-polar enough to allow good solubility of many organic compounds. This contribution describes the reactions of methyl esters of aromatics in this fascinating medium. Depending on the exact conditions chosen the methyl esters either hydrolyse to give the acids (basic conditions) or hydrolyse and decarboxylate (neutral conditions). C G DJM 65 Green Chemistry April 1999 Scheme 1 Table 1 Hydrolysis of methyl benzoates 1 in HT-watera Substrate T/°C (%)b Entry Conversion Product(s) (yield(%))c 2a (20) 2a (53) + 3a (20) 3a (89) 3a (40) 3a (76) 2b (28) 2c (59) 2d (66) 2e (64) 2f (46) 2f (70) + 3f (4) 2g (7) + 3g (51) 21 73 100 50 80 30 60 74 65 56 80 62 250 250d 300 250d 250d,e 250 250 250 250 250 300 250 1 2 3 4 5 6 7 8 9 10 11 12 1a 1a 1a 2a 2a 1b 1c 1d 1e 1f 1f 1g a H2O and 1 (or 2) were reacted for 0.5 h.Products were isolated by acid–base extraction and identified by GC and/ b d or NMR spectra in comparison with authentic samples. Isolated. c Gravimetric yield based on starting substrate. Reaction for 2 h. e Added CO2 (10 bar 20 °C). Furthermore the increase of the acidity of the water due to the CO2 evolved13 catalyses the decarboxylation process. Thus reaction of the acid 2a in H2O at 250 °C for 2 h underwent 50% decarboxylation and increased up to 80% by performing the reaction under an added pressure of CO2 (10 bar at 20 °C).As shown in the following experiments steric factors rather than polar ones control the rate of hydrolysis in HT-H2O. Therefore the nature of the substituent para to the ester group has less effect on the rate than the presence of ortho groups. Furthermore reduced hindrance of the ester moiety disfavours its decarboxylation. Thus methyl 2,4-dimethylbenzoate 1b underwent hydrolysis to 2b (28%) at 250 °C for 0.5 h without formation of xylene and p-benzoates 1c 1d 1e and 1f underwent hydrolyses (56–74%) under the same reaction conditions to the acids 2c 2d 2e and 2f.However amino-benzoate 1g gave largely aniline 3g. This is not unexpected considering that acidcatalysed decarboxylation can also be favoured by electronreleasing groups like NH2. However the methoxy group in 1f is not powerful enough to induce decarboxylation and only by forcing the reaction conditions (300 °C) was it possible to detect a small amount of anisole 3f. Although 2NH2 2OCH3 2NO2 and 2CF3 groups are stable under the reaction conditions their stability decreases with increasing temperature. Thus the nitro-ester 1d decomposed at 66 Green Chemistry April 1999 temperatures above 300 °C. In contrast to previous results,2,3 no significant cleavage of the methoxy group was observed for the methoxybenzoate 1f neither at 250 nor even at 300 °C.Finally acid catalysis for the hydrolysis of carboxylic esters in HT-H2O has been explained by the formation of soluble carboxylic acids during the reaction.2,3 However the temperature dependence of Kw plays a major role. As will be shown in the following section basic hydrolysis occurs readily at only 200 °C. Therefore if no hydrolysis is observed for a particular compound in HT-H2O at 200 °C the value of Kw must be too low to catalyse the hydrolysis rather than a problem of solubility. Saponification in alkaline water at high temperature Slightly alkaline H2O (2% KOH) promotes hydrolysis of methyl benzoates 1 in the temperature range 200 to 300 °C even though there is little conversion of 1 at 5 150 °C. The results are summarised in Table 2.Table 2 Saponification of methyl benzoates 1 in HTalkaline H2O (2 % KOH)a (%)b T/°C Ester Entry Conversion Product(s) (yield (%))c 2a (15) 2a (28) 2a (57) 2a (90) 2b (35) 2b (79) 2b (90) 2c (98) 2d (88) 2e (98) 2e (41) + 4 (20) 2f (90) 2f (87) 2f (86) 2g (84) 200 200d 250 300 200 250 300 200 200 200 375e 200 200f 220g 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1a 1a 1a 1a 1b 1b 1b 1c 1d 1e 1e 1f 1f 1f 1g a b d 17 30 60 100 36 81 100 100 100 100 100 92 98 97 100 2% KOH (aq) and 1 were reacted for 0.5 h. Products were isolated by acid–base extraction and identified by GC and/or NMR spectra in comparison with authentic samples.Isolated 1. c Gravimetric yield based on starting 1. Reaction for 2 h. e Black solid from thermal decomposition. f 3 M NH4OH (aq). g 2% Na2CO3 (aq). HT-alkaline H2O is an efficient medium to hydrolyse hindered esters like 1 a. Thus 1 a underwent hydrolysis to the acid 2 a a t 200 250 and 300 °C in 17 60 and 100% conversion after only 0.5 h without detectable decarboxylation. This relative high reactivity of 1 a at 300 °C is surprising. Indeed 1a is so difficult to hydrolyse owing to its steric hindrance that its hydrolysis is a classical test for evaluating the ability of a basic system to act as a strong nucleophile. Thus hydrolysis of 1 a has only been achieved with strongly nucleophilic reagents like ‘anhydrous h y d r o x i d e ’1 4 n- p r o p y l l i t h i u m1 5 or ‘solid KOH–Aliquat 336 syst e m .’1 0 Furthermore 1 a can not be hydrolysed in 20% NaOH (aq) neither after 1.5 h reflux nor after 1 h application of ultrasound used to increase the ester solubility in water.1 1 T h e r e f o r e alkaline H2O at 200–300 °C is an outstanding nucleophilic system. Proof of this is the hydrolysis of the CF3 group to COOH at 375 °C (i . e . under supercritical conditions) when terephthalic acid 4 was isolated in 20% yield in the reaction of trifluoromethyl ester 1 e. In contrast to the low reactivity of 1a 1b underwent 36% conversion and 1c was hydrolyzed quantitatively at 200 °C in 0.5 h. Also saponification of p-substituted esters 1d 1e 1f and 1g was quantitative under the same conditions.Their higher reactivity can be explained again in terms of hindrance on the COOMe moiety. As a control the hydrolysis of 1f was performed in 3 M NH4OH (aq) and 2% Na2CO3 (aq) at 200 °C for 30 min obtaining identical results to those for 2% KOH (aq). Conclusions In summary water or alkaline solution at high temperature provides an excellent medium for the green and selective hydrolysis or decarboxylation when possible of methyl benzoates 1. Decarboxylation takes place in HT-H2O on sterically hindered esters or esters with electron-releasing groups like 1a or 1g. Alkaline HT-H2O is a powerful nucleophilic system more efficient than HT-H2O for hydrolysis of carboxylic esters.The sterically hindered ester 1a is efficiently hydrolysed without decarboxylation. Experimental Materials Methyl benzoates 1c 1d 1e 1f and 1g (Aldrich or Lancaster) were used as received. Methyl esters 1a and 1b were prepared by reaction of the corresponding carboxylic acid 2 with methanol 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP).16 Water was purified by standard procedures. Analysis Reaction products were identified by GC and NMR spectra in comparison with authentic samples. GC analysis were performed on a non-polar capillary column [EC-5 (SE-54) Alltech 30 m film thickness 0.25 mm I.D. 0.32 mm]. High pressure/temperature batch reactor system SAFETY WARNING These reactions involve high pressures and must only be carried out in an apparatus with the appropriate pressure rating at the reaction temperature.Reactions were carried out in a batch reactor system consisting of a reactor vessel connected to a shut-off valve via a pressure transducer (Fig. 1). Fig. 1 Schematic view of the high T/p batch reactor system. The components are labelled as follows C high pressure vessel; O high temperature oven; P pressure monitor; T thermocouple; V high pressure valve. The high temperature/pressure stainless steel 316 reactor vessel (0.9 cm O.D. 0.5 cm I.D. 5.2 ml internal volume Keystone Scientific Inc.) had a maximum pressure rating of 690 bar at 400 °C. A chromel/alumel thermocouple monitored the temperature of the reactor wall. The pressure transducer (RDP electronics) had a pressure rating of 690 bar.The batch reactor was heated in an oven (PYE series 104). Overpressure could be avoided by releasing the pressure through the shut-off valve (HIP). No visible corrosion of the vessel was observed at the operating conditions. General procedure The reaction vessel was leak-tested with N2 charged with the appropriate amount of H2O and reagents sealed placed in the oven and connected to the pressure transducer and thermocouple. Reaction time was measured from the moment that the reaction temperature was reached and does not include the time required to reach the reaction temperature or to cool the system (10–15 min each). The appropriate amount of H2O was calculated for each temperature considering the density of the liquid as follows rw = mass of H2O/vessel volume.Safety The maximum amount of water which could be safely loaded without overpres - sure was calculated from the steam tables.17 Reactions were performed at liquid densities of the fluid (0.7–0.9 g cm23). Saponification/hydrolysis of methyl benzoates 1 Reactions were performed in H2O and in 2% KOH aqueous solution. The reaction vessel was charged with H2O (3.7–4.7 ml) and ester 1 (1.0–1.5 mmol). The system was heated for 0.5–2 h at 150–300 °C. The work-up of the reaction consisted of acid-base extraction of the aqueous reaction mixture with an organic solvent (methylene chloride or diethyl ether) and/or filtration of the carboxylic acid 2. The reaction products were analysed by NMR and yields determined gravimetrically.Acknowledgements We are grateful for support from EPSRC (Grant no. GR/K84929) the European Union for a Marie Curie TMR Fellowship (Contract no. ERBFMICT 972064) and Generalitat Valenciana for a grant (P. A. A.). We thank Dr. A. Kordikowski Dr. S. K. Ross Mr. M. Guyler and Mr. K. Stanley for their help and advice. References 1 J. An L. Bagnell T. Cablewski C. Strauss and R. W. Trainor J. Org. Chem. 1997 62 2505. 2 A. R. Katritzky S. M. Allin and M. Siskin Acc. Chem. Res. 1996 29 399. 3 B. Kulmann E. M. Arnett and M. Siskin J. Org. Chem. 1994 59 3098. 4 M. B. Korzenski and J. W. Kolis Tetrahedron Lett. 1997 38 5611. 5 J. F. Connoly J. Chem. Eng. Data 1966 11 13. 6 E. U. Franck J. Chem. Thermodyn. 1987 19 225. 7 W. L. Marshall and E. U. Franck J. Phys. Ref. Data 1981 10 295. 8 R. L. Holliday J. W. King and G. R. List Ind. Eng. Chem. Res. 1997 36 932. 9 N. Dehmlow J. Chem. Res. (S) 1979 238. 10 A. Loupy M. Pedoussaut and J. Sansoulet J. Org. Chem. 1986 51 740. 11 S. Moon L. Duchin and J. V. Cooney Tetrahedron Lett. 1979 41 3917. 12 H. P. Treffers and L. 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