Organic Process Research & Development 1999, 3, 357−362 Technical Notes A Kinetic Model of the Choline Chloride Synthesis Roman A. Kozlovsky,* Valery F. Shvets, and Mikhail G. Makarov D. MendeleyeV UniVersity of Chemical Technology of Russia, Chair of Basic Organic and Petrochemical Synthesis, 9 Miusskaya Square, Moscow, 125047, Russia Abstract: in ethylene glycol (EG) and ethylene chlorohydrin (EChG) The process of ethylene oxide interaction with trimethylamine formation hydrochloride, giving choline chloride, has been studied. The + f reactions that proceed in the system were established. A kinetic C2H4O H2O HOCH2CH2OH (II) model adequately describing the experimental data was devel- + f C2H4O HCl HOCH2CH2Cl (III) oped. Also in the system there is always free trimethylamine (TMA) present whose amount depends on the ratio of Introduction reactions I and III. The quality of the product is strongly Choline chloride (ChCh) is a biologically active species, influenced by the presence of these impurities (especially which plays a major role in cell metabolism, and is used in EChG, which is a harmful substance). many pharmaceuticals.1-3 It is also a base of many nutrition The general dependencies of EO reaction with amines are and feed additives.4-6 The simplest method of its manu- well known.18-21 The kinetics of EO hydrolysis also has been facture7-11 is a direct synthesis from trimethylamine hydro- described. However, these investigations were carried out chloride (TMAH) and ethylene oxide (EO) in an aqueous under different conditions, and the results could not be used medium to describe the choline chloride synthesis along reaction I without some corrections. Thus, to elucidate the reaction + f + - (CH3)3NHCl C2H4O [(CH3)3NCH2CH2OH] Cl (I) mechanism and obtain a valid model, we had to investigate This method is well-known and realized in industry, but the kinetics of processes running during the EO reaction with we cannot find a complete mathematical model of this TMAH in an aqueous solution. 12-21 process in the literature. We think that such a model would The Kinetic Model. It is known that the formation be useful to find the optimal technological conditions of the of the main products of the EO reaction with TMAH in an aqueous solution is the result of trimolecular reaction of synthesis of choline chloride. - - 12-17 nucleophiles (H2O, HO ,Cl, and (CH3)3N) with EO It is known that this reaction is accompanied by side- + processes of EO hydrolysis and hydrochlorination resulting activated by proton donors (H2O and (CH3)3NH ). The activation of EO is the result of the following (1) Watanabe, K. S.; Tuchida, T. S.; Schultz, D. R. Anti-inflammatory and equilibria: analgesic compounds, related compositions and methods for preparation and use thereof. U.S. Patent 5,180,743, 1993. K + y\1z (2) Simone, C. B. Rehydration drink. U.S. Patent 5,397,786, 1995. C2H4O H2O C2H4O-----HOH (IV) (3) Grischenko, V. I.; Kalugin, J. V. Method for low-temperature preservation of spermatozoa. U.S. Patent 4,965,186, 1990. K + + y\2z + (4) Kiefer, H. N.; Betz, R. N.; Bewert, W. F. Preparation of choline chloride- (CH3)3N H C2H4O C2H4O-----N H(CH3)3 containing powders, these powders, and their use. U.S. Patent 5,486,363, (V) 1996. (5) Nishimura, K. K.; Morita, T. K. Granular agent for ruminants and process These equilibria are established quite rapidly and values for producing the same. U.S. Patent 5,571,527, 1996. (6) Hyeon, S. B. Plant growth regulating composition. U.S. Patent 5,116,406, of K1 and K2 are low. So, the concentrations of activated 1992. (7) Kanetaka, J. Process for preparation of choline chloride. JP 52,014,708, (14) Lebedev, N. N.; Shvets, V. F.; Kondrotiev, L. T.; Romashkina, L. L. Kinet. 1977. Katal. 1976, 3, 576. (8) Bosche, H.; Soenksen, U. Continuous manufacture of an aqueous choline (15) Lebedev, N. N.; Shvets, V. F.; Romashkina, L. L. Kinet. Katal. 1976, 3, chloride solution. U.S. Patent 3,872,170, 1975. 583. (9) Yongjiang, Xu; Qin, Wang; Al Jiang Wenyu Et. Method for production of (16) Lebedev, N. N.; Shvets, V. F.; Romashkina, L. L. Kinet. Katal. 1976, 4, choline chloride. CN 1,078,231, 1993. 888. (10) Jemison, T. R.; Mathre, O. B.; Bellis, H. E. Process for the combined (17) Malinovsky, M. S. Okisi olefinoV i ikh proizVodnye. [Olefin oxides and synthesis of betaine and choline chloride. AU 5,156,098, 1998. their deriVatiVes]; Goskhimizdat: Moscow, 1961. (11) Xie, Z.; Zhong, F.; Haung, Q. Huaxue Shijie 1992, 33, 206. (18) Lebedev, N. N.; Smirnova, M. M. Tr. MChTI 1963, 42, 84. (12) Lebedev, N. N.; Savelianov, V. P.; Shvets V. F. Teor. Eksp. Khim. 1970, (19) Lebedev, N. N.; Smirnova, M. M. Tr. MChTI 1963, 42, 89. 6, 111. (20) Lebedev, N. N.; Smirnova, M. M. Kinet. Katal. 1965, 6, 457. (13) Lebedev, N. N.; Savelianov, V. P.; Baranov, U. I. Zh. Prikl. Khim. 1969, (21) Lebedev, N. N.; Pliuchinsky, Ya. K.; Smirnova, M. M. Zh. Org. Khim. 42, 1815. 1966, 2, 2108. 10.1021/op980080f CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry Vol. 3, No. 5, 1999 / Organic Process Research & Development • 357 Published on Web 07/29/1999 k EO can be described by the following equations: + 938 (CH3)3N C2H4O-----HOH [C H O-----HOH] ) K [C H O][H O] (1) + + - 2 4 1 2 4 2 (CH3)3N CH2CH2OH HO (XI) + ) + k [C2H4O-----N H(CH3)3] K2[C2H4O][(CH3)3N H] (2) + + 948 (CH3)3N C2H4O-----N H(CH3)3 + 22 + According to the literature, the TMA basicity constant (CH3)3N CH2CH2OH (CH3)3N (XII) determined by the equation Hydroxide ion formed in reaction XI regenerates free KB + - amine according to VI. So the sum of reactions IV, VI, and (CH ) N + H O y\z (CH ) N H + HO (VI) 3 3 2 3 3 XI together with V and XII yields the main reaction that is catalysed by the free amine -5 is KB ) 6.3 10 (pKB ) 4.2). Then pH of the 1 M aqueous (CH ) N solution of TMAH according to the equilibrium + 93 3 8 (CH3)3NHCl C2H4O + + h + + + - (CH3)3N H H2O (CH3)3N H3 O(VII) (VII) [(CH3)3NCH2CH2OH] Cl (XIII) is 4.9. During the EO reaction with TMAH the pH always Its rate is described by the following overall kinetic exceeds 7. It is the result of HCl binding by EO according equation: to the overall reaction ) + r34 K1k3[(CH3)3N][H2O][C2H4O] + f + + (CH3)3NHCl C2H4O (CH3)3N HOCH2CH2Cl (VIII) K2k4[(CH3)3N][HN (CH3)3][C2H4O] Ethylene chlorohydrine and free amine are formed as the or - result of the nucleophilic attack by Cl on EO activated r ) (k′ [H O] + k′ [TMAH])[TMA][C H O] (5) according to eqs IV and V 34 3 2 4 2 4 Free amine, catalysing the reaction XIII, can be obtained k - + 918 + - also by the equilibrium reaction VI adding NaOH before the Cl C2H4O-----HOH HOCH2CH2Cl HO (IX) reaction. Without adding NaOH free amine is formed only k - + + 928 in the reactions IX and X, and the equilibrium VI determines Cl C2H4O-----N H(CH3)3 the existence of the alkaline media in the course of the HOCH CH Cl + (CH3) N (X) 2 2 3 process. Concentrations of hydroxide ion and free amine can - be calculated from the equilibrium and balance equations: OH ion formed in the reaction IX yields a free amine reacting with TMAH according to VI. + - - [(CH ) N H][HO ] [TMAH] [HO ] The sum of the reactions IV, IX, and VI together with V K ) 3 3 ) B [(CH ) N] [TMA] and X gives VIII. The overall kinetic equation of the two 3 3 - EO parallel reactions IX and X is [EChG] ) [TMA] + [HO ] (6) - r ) K k [Cl ][H O][C H O] + 12 1 1 2 2 4 whereas - + K k [Cl ][HN (CH ) ][C H O] (3) 2 2 3 3 2 4 - ) + [HO ] KB[EChG]/([TMAH] KB) (7) According to experimental data (Table 2) the concentra- [TMA] ) [EChG][TMAH]/([TMAH] + K ) (8) tion of the EChG formed is negligible compared with sum B of concentrations of TMAH and ChCh. Thus, the Cl- Under alkaline conditions the reacting species undergo concentration in the course of the reaction can be assumed other transformations besides reactions VIII and XIII. The constant and equal to the initial TMAH concentration most significant of them are the reverse formations of EO [TMAH]0, also from EChG + k [HN (CH ) ] ) [TMAH] + - 958 + - + 3 3 HOCH2CH2Cl HO H2O Cl C2H4O (XIV) Then if K1k1 ) k′1 and K2k2 ) k′2, we obtain and choline chloride formation ) ′ + ′ HOCH CH Cl + (CH ) NH f r12 (k 1[H2O] k 2[TMAH])[TMAH]0 [C2H4O] (4) 2 2 3 3 + - [(CH3)3NCH2CH2OH] Cl (XV) The free amine formed in the reaction VIII is practically a catalyst of the main reaction and yields ChCh in the The free amine is spent in these reactions in equimolar reaction with the EO activated by eqs IV and V amounts. According to23,24 the rate of reaction XIV is (22) SpraVochnik khimika. [Chemists’ handbook]; Khimiya: Moscow, 1964, (23) Shvets, V. F.; Aleksanian, L. V. Arm. Khim. Zh. 1972, 25, 986. Vol. III. (24) Shvets, V. F.; Aleksanian, L. V. Zh. Org. Khim. 1972, 10, 2022. 358 • Vol. 3, No. 5, 1999 / Organic Process Research & Development Figure 1. The change of PEO with time: 1 and 2, without catalyst; 3, with catalyst ([NaOH] ) 0.028mol/L). described by the equation which according to dependence Summing up all the above we proposed the following kinetic model of the choline chloride synthesis: ) - ) - - r5 k5[EChG][HO ] exp(26.9 9444/T)[EChG][HO ] ) - - ) - 2 d[EChG]/dτ r12 r5 r6 r12 k5KB[EChG] / + - for concentration of a hydroxyl ion (eq 7) accepts the ([TMAH] KB) r6 (12) following kind: ) + ) ′ + ′ d[ChCh]/dτ r34 r6 (k 3[H2O] k 4[TMAH]) [C2H4O] + + ) - 2 + [EChG] [TMAH]/([TMAH] KB) r6 (13) r5 exp(26.9 9444/T)KB[EChG] /([TMAH] KB), )- - - mol/(L × s) (9) d[C2H4O]/dτ d[EChG]/dτ d[ChCh]/dτ r0 (14) d[TMAH]/dτ )-r + r - r (15) The rate of reaction XV is described by the equation 12 5 34 Experimental Section ) r6 k6[TMA][EChG] Materials.