Li Shufeng, Li Qian, Yang Xinlin, Huang Wenqiang
(State Key Laboratory of Functional Polymer Materials for Adsorption and Separation, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, China)

Abstract Polystyrene N-hydroxyl sulfonamide resin 1 and its derivative N-hydroxyl sulfonamide resins 2-5 were prepared and their corresponding N,O-diacetyl sulfonhydroxamate resins were used to synthesize the ester with n-butanol and acetic anhydride. The mechanism of esterification was that: O-H and N-H of N-hydroxyl sulfonamide resin reacted with acetic anhydride respectively to form the active intermediate polystyrene N,O-diacetyl sulfonhydroxamate, which was cleaved by n-butanol to produce n-butyl acetate. The characterization of the specificity of resins 1-5 was determined by the rate constant k₁ calculated according to a two-substrate reversible kinetic model. The results revealed that the activity of alkyl N-hydroxyl sulfonamide resin 4 and resin 5 with the rate constant k₁ of 3.74×10^-3 M^-1 min^-1 and 9.13×10^-3 M^-1 min^-1 were higher than those of the aryl N-hydroxyl sulfonamide resin 1 and resin 3. Resin 2 prepared from recycling resin 1 for 7 times showed a higher activity than resin 1. Resin 3 with the benzene ring substituted by the electron donating group gave the lowest activity with the k₁ of 0.75×10^-3 M^-1 min^-1.
Keywords polystyrene N-hydroxyl sulfonamide; N,O-diacetyl sulfonhydroxamate; esterification; double acyl transfer

1 INTRODUCTION
In recent years, polymeric reagents, containing a reactive functional group attached to a macromolecular backbone, have been utilized in many chemical reactions ^{[1, 2]}. The polymeric reagents could share both chemical and physical properties of the functional group and the polymeric matrix. Polymeric backbone could provide a specific microenvironment and played a decisive role in indicating the nature and reactivity of the attached functional group ^[3]. It could influence significantly on the selection of reaction solvent and the extent of functional group conversions in the subsequent reactions ^[4]. Introducing a new functional group to the polymeric matrix generally led to a variety of reactivity, selectivity ^[5-7]. A number of polymeric reagents have been prepared since the invention of Merrifield resin. Among them, the acylating reagents, such as polymer-bound nitrophenol ^{[8, 9]}, HOBT (1-hydroxybenzotriazole) ^[10], hydroxamic acid ^[11], oximino esters ^[12], N-hydroxysuccinimide ^[13], or oximino dithiocarbonic anhydride ^[14] were especially important for their wide application in the acylation of alcohols, amines, and in the synthesis of peptides.
    In this paper a new polymeric reagent  --  polystyrene N-hydroxyl sulfonamide resin 1 and its derivative resins 2-5 were prepared and the applications of their corresponding N,O-diacetyl sulfonhydroxamate in the preparation of ester from n-butanol and acetic anhydride were investigated. The mechanism of esterification by resin 1 was studied to be a double acyl process. Characterization of the specificity of resins 1- 5 was discussed by a kinetic method.

   Scheme 1   Resins 1-5

2 EXPERIMENTAL
2.1 General
Infrared spectra were recorded on a Bio-Rad FTS 13t spectrometer with KBr pellets. The CHN elementary analysis was recorded on Fess Heraes instrument and the Cl content of the resin was determined by the Volhard method. All the reagents were purified and dried following the literature. Polystyryl sulfonyl chloride resin (2.50 mmol/g, 1%DVB crosslinked, 100-200 mesh) and polystyryl chloromethyl resin (1.24 mmol/g, 1%DVB crosslinked, 100-200 mesh) were provided by Tianjin Nankai Hecheng Co., Tianjin, China.
2.2 Preparation of polystyrene N-hydroxyl sulfonamide resin 1
To polystyrene sulfonyl chloride resin (10 g, 25.2 mmol) in pyridine (200 mL) was added hydroxylamine hydrochloride (13.2 g, 0.252 mol). The mixture was stirred at room temperature for 8 h. Then the resin was collected by filtration, washed sequentially with DMF, DCM, Et₂O and dried in a vacuum oven for 24 h. The loading was 2.52 mmol/g by CHN elementary analysis.
2.3 Preparation of polystyrene N,O-diacetyl sulfonhydroxamate resin 2
Resin 1 was used to prepare n-butyl acetate from n-butanol and acetic anhydride at 50±0.5ºC for 4 h according to the reaction process mentioned in 2.7 section. After repeating this process for 7 times, resin 2 was obtained with the N content of 2.89%.
2.4 Preparation of 4-(polystyryl benzyloxyl) benzene N-hydroxyl sulfonamide resin 3
4-Hydroxybenzene sulfonate sodium salt was obtained by treating 4-hydroxybenzene sulfonic acid with NaOH. Sodium methoxide (1.0 g, 18.5 mmol) was added to a suspension of chloromethylated polystyrene resin (3.0 g, 3.7 mmol) and anhydrous 4-hydroxybenzene sulfonate sodium salt (3.6 g, 18.5 mmol) in N, N-dimethyl acetamide (DMAc, 50 mL) ^[15]. The mixture was stirred at 90ºC for 2 days. The resulted resin was collected by filtration, washed sequentially by DMAc, H₂O. The resin was acdified by 1 M HCl, then washed by H₂O, MeOH, DCM, Et₂O, and dried in vacuum oven at 25ºC for 24 h. The residual Cl content of the sulfonic acid resin was determined to be 0.6%. Pyridine (5 mL) was added to the sulfonic acid resin in DMF (10 mL) and the mixture was stirred at room temperature for 2 h. The resin was filtered, washed 3 times with DMF. Then the resin was suspended in DMF(15mL) and treated with thionyl chloride (5 mL) at 0ºC for 1 h, and the reaction was continued at room temperature for 20 h. The resin was filtered, washed with DMF, DCM, Et₂O and dried in vacuum. The sulfonyl chloride resin was converted to N-hydroxyl sulfonamide resin 3 by reacting with hydroxylamine hydrochloride at 50 ºC for 20 h. The elementary analysis showed the N content of resin 3 was 1.10 mmol/g.
2.5 Preparation of 2-(Polystyryl sulfonyloxyl) ethyl N-hydroxyl sulfonamide resin 4
2-Hydroxyl ethyl sulfonate sodium salt was prepared by refluxing 2-chloroethanol with sodium sulfite for 4 h ^[16]. To a suspension of polystyryl sulfonyl chloride resin (0.50g, 1.3 mmol) and 2-hydroxyl ethyl sulfonate sodium salt (2.2 g, 12.6 mmol) in DMF (30 mL) were added pyridine (0.36 mL) and deionized water (36 mL) and the mixture was stirred at 90ºC for 2 days. The resin was filtered, washed by H₂O, DMF, DCM, Et₂O and dried in a vacuum oven at 25ºC for 24 h to afford (2-polystyryl sulfonyloxyl) ethyl sulfonate sodium salt. The residual Cl of the resin was determined to be 0.32%. The resin was acidified by 1 M HCl, and then converted to the corresponding N-hydroxyl sulfonamide resin 4 in a similar way as resin 3. The N content of the resin 4 was 2.18 mmol/g.
2.6 Preparation of 6-(polystyryl sulfonyloxyl) hexyl N-sulfonamide resin 5
The resin 5 was prepared in a similar way as resin 4 with the N content of 1.92 mmol/g.
2.7 General procedure of esterification
The esterification of n-butanol (200 eq.) and acetic anhydride (200 eq.) was performed in a reactor containing polystyrene N-hydroxyl sulfonamide resin (1 eq.) at 50±0.5ºC for 7 h. A 100 ml of reaction solution was taken out from the system every 30 min interval. Esterification conversion was calculated by first adding enough standard sodium hydroxide aqueous solution into the 100 ml reaction mixture, then titrating the excess base by the standard HCl aqueous solution.
2.8 Kinetic model of a two-substrate reversible reaction mechanism ^[17]
The kinetic model based on the two-substrate reversible reaction was elaborated by Han et al ^[18].
          
    Where S_A and S_B denote the substrates (S_A being the limiting substrate), P_P and P_Q the products, and k₁ and k_-1 are the rate constants of the direct and reverse process.
    The rate P_P expression according to this model can be represented by Eq. (1):
         (1)
    Where A and B are the concentrations of the substrates, P and Q are the concentrations of the products at reaction time t.
    The integrated rate equation corresponding to this mechanism results in the parametric Eq. (2), containing two parameters (X_E and e) that can be determined by optimization:
           (2)
    where A₀ and B₀ are the initial concentrations of the two substrates, X is the fractional conversion of the limiting substrate [X = (A₀-A) / A₀] , X_E the equilibrium conversion, t the reaction time, and ε a parameter related to the rate constant k₁, as the results from Eq. (2). The rate constant of the direct reaction can be calculated using the following equation:
          (3)
    Optimization by using Origin 6.0 gives the values of parameters X_E and e that ensure the best fit of the model curve X = f(t) resulted from Eq. (2) with the experimental data points.
    Eq. (2) represents a kinetic model for reversible two-substrate reactions by resins 1-5, which does not take account of the consecutive intermediate. Consequently, it is not accurate to describe the intimate reaction mechanism, but could be useful for specificity determination. The kinetic constant k₁ is appropriate to be considered a measure of resin specificity under given reaction conditions, requiring one single measurement for each substrate.

3. RESULTS AND DISCUSSION
3. 1 Esterification by resins 1-5 and the acyl transfer mechanism               
Resins 1-5 were prepared in our experiment. Resin 1 is the polystyrene N-hydroxyl sulfonamide resin. Resin 2 is the polystyrene N,O-diacetyl sulfonhydroxamate resin by recycling resin 1 for 7 times to prepare the n-butyl acetate from n-butanol and acetic anhydride. Resin 3 is the 4-(polystyryl benzyloxyl) N-hydroxyl sulfonamide with the benzene ring substituted by an electron donating group. Resins 4 and 5 are the alkyl N-hydroxyl sulfonamide indirectly prepared through coupling the hydroxyl alkyl sulfonic acid sodium salt with the sulfonate ester linking to the polystyryl sulfonyl chloride resin. Though the sulfonate ester bond is not a good linker for its instability at basic reaction conditions, breakdown of the sulfonate ester was not observed by IR spectra in our experiment conditions.
    In the following experiments, an example of esterification by resin 1 was chosen to study the reaction mechanism. The esterification of n-butanol and anhydride by resin 1 was carried out at 50±0.5ºC for 7 h. IR spectra of resin 1 was showed in Figure 1. It was interestingly found that infrared absorption at 1792 cm^-1 first appeared at 75 min, corresponding to ester carbonyl group, then the infrared absorption appeared at 1716 cm^-1, corresponding to amide carbonyl group. These were in consistent with the reported IR spectra of N,O-diacetyl benzene sulfonhydroxamate ^[19], indicating the formation of the active intermediate polystyrene N,O-diacetyl sulfonyhydroxamate. With the time going on, both intensity of the infrared absorption at 1792 cm^-1 and 1716 cm^-1 increased.

Fig. 1 IR spectra of the resins 1-5 after the esterification. Curve 1: Used resin 1. Curve 2: Resin 2. Curve 3: Used resin 3. Curve 4: Used resin 4. Curve 5: Used resin 5.

Scheme 2 Mechanism of the esterification of n-butanol and acetic anhydride by resin 1

Table 1 Calculated kinetic constants for the esterification by resins 1-5 according to Eq.(2) and Eq.(3)

4. CONCLUSIONS
Polystyrene N-hydroxyl sulfonamide resin 1 and its derivative N-hydroxyl sulfonamide resin 2-5 were prepared and their corresponding N,O-diacetyl sulfonhydroxamate resins were used to synthesize the ester with n-butanol and acetic anhydride. During the esterification, polystyryl N-hydroxyl sulfonamide reacted with acetic anhydride to form the active intermediate polystyryl N,O-diacetyl sulfonhydroxamate, which was cleaved by n-butanol to form n-butyl acetate. Characterization of specificity of resins 1-5 was determined by a kinetic method. Alkyl N-hydroxyl sulfonamide resins 4 and 5 with the apparent rate k₁ of 3.74×10^-3 M^-1 min^-1 and 9.13×10^-3 M^-1 min^-1, respectively, have the higher activity than the aryl N-hydroxyl sulfonamide 1 and resin 3. To the aryl N-hydroxyl sulfonamide, resin 3 with an electron donating substitution on the benzene ring showed the lower rate constant k₁ of 0.75×10^-3 M^-1 min^-1, compared with resin 1 of k₁ = 0.80×10^-3 M^-1 min^-1. Resin 2 prepared from recycling resin 1 for 7 times showed an increasing rate constant k₁ of 3.87×10^-3 M^-1 min^-1 value, which was 4 fold over that of resin 1.

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