Esterification of Aryl/Alkyl Acids Catalysed by N-bromosuccinimide under Mild Reaction Conditions

N-halosuccinimides (NXSs) are well-known to be convenient, easily manipulable and low-priced halogenation reagents in organic synthesis. In the present work, N-bromosuccinimide (NBS) has been promoted as the most efficient and selective catalyst among the NXSs in the reaction of direct esterification of aryl and alkyl carboxylic acids. Comprehensive esterification of substituted benzoic acids, mono-, di- and tri-carboxy alkyl derivatives has been performed under neat reaction conditions. The method is metal-free, air- and moisture-tolerant, allowing for a simple synthetic and isolation procedure as well as the large-scale synthesis of aromatic and alkyl esters with yields up to 100%. Protocol for the recycling of the catalyst has been proposed.


Introduction
Esterification reaction is one of the most important synthetic routes in organic synthesis due to the significance of its products. It is an irreplaceable reaction step during the synthesis of pharmaceuticals, cosmetics, plasticizers, perfumes, flavour chemicals, fine chemicals, electronic materials, solvents and chiral auxiliaries [1] and together with transesterification, it is a transformation of major significance in the biodiesel production [2][3][4][5]. Aside from being among the most prevalent final products and/or intermediates in the fields of science and industry, esters also play a significant role in biology, as the ester bonds are key linking groups in many primary lipid metabolites as well as secondary cyclodepsipeptide and polyketide metabolites [6]. As a result, a plethora of approaches have been reported for ester preparation, one of the most common being the reaction of direct esterification between carboxylic acids and alcohols (Fischer esterification) [7]. Conventionally, it is performed with excessive amounts of reagents/dehydrating agents or with activated carboxylic acid derivatives in the presence of a stoichiometric base, which results in significant amounts of by products and waste at the end of the process as well as in energy-, time-and solvent-consuming purification [8]. Therefore, methods of catalytic direct condensation between carboxylic acids and alcohols, which lack these disadvantages, have recently become an attractive research subject, employing a broad spectra of different catalysts, such as Brønsted acids [9], metal catalysts [10,11], Lewis acids [12,13], solid-supported catalysts [14,15] and solid acids [16,17], ionic liquids [18,19], PPh 3 -based catalysts [20], enzymes [21,22], zeolites [23,24], etc. From the industrial and sustainability perspective, the ideal esterification method would include the use of easily manipulable, metal-free, low-cost, water- and air-tolerant recyclable catalyst and mild solvent-free reaction conditions without the need for stoichiometric amounts of activators, large excesses of reagents and simultaneous removal of water. It should also be applicable to a broad substrate scope with high selectivity; it should be suitable for large-scale synthesis and allow a simple purification procedure, providing high product yields. The majority of known methods do not comply with at least one of the mentioned criteria; therefore, the field of sustainable design of esterification methods remains an attractive research challenge. N-halosuccinimides (NXSs) belong to the class of N-halo reagents which are widely used in organic synthesis as halogenating, hydroxyhalogenating, oxidizing and condensing agents [25]. Their reactivity originates from the great lability of the N-X bond and various modes of its splitting [26]. Depending on the reaction conditions, different highly reactive species can be formed: N-radicals, N-cations, N-anions as well as their corresponding halogen counter particles, etc. [27]. Due to these convenient chemical properties, together with their metal-free character, low-cost, accessibility and higher stability relative to other N-halo reagents, NXSs have recently been attracting attention as mediators in substoichiometric amounts for different types of organic transformations [28][29][30][31]. The catalytic potential of N-bromosuccinimide (NBS) has recently been reviewed [32]; however, to the best of our knowledge, the use of N-bromosuccinimide as the only catalytic component in substoichiometric amounts for direct dehydrative esterification between alcohols and carboxylic acids has not been explored so far.
Molecules 2018, 23, x FOR PEER REVIEW  2 of 17   manipulable, metal-free, low-cost, water-and air-tolerant recyclable catalyst and mild solvent-free  reaction conditions without the need for stoichiometric amounts of activators, large excesses of  reagents and simultaneous removal of water. It should also be applicable to a broad substrate scope  with high selectivity; it should be suitable for large-scale synthesis and allow a simple purification procedure, providing high product yields. The majority of known methods do not comply with at least one of the mentioned criteria; therefore, the field of sustainable design of esterification methods remains an attractive research challenge. N-halosuccinimides (NXSs) belong to the class of N-halo reagents which are widely used in organic synthesis as halogenating, hydroxyhalogenating, oxidizing and condensing agents [25]. Their reactivity originates from the great lability of the N-X bond and various modes of its splitting [26]. Depending on the reaction conditions, different highly reactive species can be formed: N-radicals, N-cations, N-anions as well as their corresponding halogen counter particles, etc. [27]. Due to these convenient chemical properties, together with their metal-free character, low-cost, accessibility and higher stability relative to other N-halo reagents, NXSs have recently been attracting attention as mediators in substoichiometric amounts for different types of organic transformations [28][29][30][31]. The catalytic potential of N-bromosuccinimide (NBS) has recently been reviewed [32]; however, to the best of our knowledge, the use of N-bromosuccinimide as the only catalytic component in substoichiometric amounts for direct dehydrative esterification between alcohols and carboxylic acids has not been explored so far.

Results and Discussion
Previously, some advantages of N-bromosuccinimide (NBS) as a catalyst in reactions of transesterification have been observed, but the reaction was limited to transesterification of α-keto esters [46] or acetylation of alcohols using acetic anhydride [47]. In addition, esterification of carboxylic acids with alcohols in the presence of triphenylphosphine (PPh3) and N-bromo/iodosuccinimides has been reported as a method for ester preparation [48]. However, its significant drawback is posed by the by-product, phosphine oxide, formed in equimolar amounts, as it is difficult to remove during the purification step. Besides, the esterification was performed in halogenated solvent (dichloromethane) in the presence of equimolar amounts of base (pyridine) and NBS/NIS. Furthermore, molecular iodine has been presented as a convenient Lewis acid catalyst for direct dehydrative esterification, but attempts to prepare esters from corresponding aromatic acids have been found unsuccessful [49] or unselective [50,51]. Furthermore, bromine (Br2)-mediated esterification of carbocyclic acids with methanol has been reported [52], though this methodology carries handling safety risks due to the potentially hazardous effects of Br2/MeOH solution [53]. All the aforementioned provided us with an impetus to improve the reaction of direct esterification of aryl/alkyl acids. Since N-halosuccinimides have been widely used as more convenient and safer X2 substitutes in halogenation reactions, the catalytic activity of corresponding N-halosuccinimide derivatives in the reaction of direct condensation between various structurally different carboxylic acid and alcohols has been investigated and presented herein.
Initially, benzoic acid (1) has been chosen as an aromatic acid model molecule to verify expectations and optimize reaction protocols. In the typical experimental procedure, 1 has been refluxed with methanol (MeOH) in the presence of substoichiometric amounts of NXS: Scheme 1. Direct dehydrative esterification of carboxylic acids catalysed by substoichiometric amounts of NXSs.

Results and Discussion
Previously, some advantages of N-bromosuccinimide (NBS) as a catalyst in reactions of transesterification have been observed, but the reaction was limited to transesterification of α-keto esters [46] or acetylation of alcohols using acetic anhydride [47]. In addition, esterification of carboxylic acids with alcohols in the presence of triphenylphosphine (PPh 3 ) and N-bromo/iodosuccinimides has been reported as a method for ester preparation [48]. however, its significant drawback is posed by the by-product, phosphine oxide, formed in equimolar amounts, as it is difficult to remove during the purification step. Besides, the esterification was performed in halogenated solvent (dichloromethane) in the presence of equimolar amounts of base (pyridine) and NBS/NIS. Furthermore, molecular iodine has been presented as a convenient Lewis acid catalyst for direct dehydrative esterification, but attempts to prepare esters from corresponding aromatic acids have been found unsuccessful [49] or unselective [50,51]. Furthermore, bromine (Br 2 )-mediated esterification of carbocyclic acids with methanol has been reported [52], though this methodology carries handling safety risks due to the potentially hazardous effects of Br 2 /MeOH solution [53]. All the aforementioned provided us with an impetus to improve the reaction of direct esterification of aryl/alkyl acids. Since N-halosuccinimides have been widely used as more convenient and safer X 2 substitutes in halogenation reactions, the catalytic activity of corresponding N-halosuccinimide derivatives in the reaction of direct condensation between various structurally different carboxylic acid and alcohols has been investigated and presented herein.
Initially, benzoic acid (1) has been chosen as an aromatic acid model molecule to verify expectations and optimize reaction protocols. In the typical experimental procedure, 1 has been refluxed with methanol (MeOH) in the presence of substoichiometric amounts of NXS: N-chlorosuccinimide (NCS), NBS, or N-iodosuccinimide (NIS). The results presented in Table 1 reveal that NBS seems to be the most promising catalyst in reactions of esterification, while without the presence of any of the NXSs, no conversion of starting material has been observed. In search of optimal reaction conditions, the effect of catalyst NBS loading has been examined by changing the amount of catalyst from 3 mol% to 15 mol% ( Table 1). The amount below 7 mol% NBS furnished significantly lower conversion, while increasing the amount above 7 mol% did not significantly improve the yield of the corresponding ester. Therefore, further studies were carried out with 7 mol% of NBS. Moreover, the influence of temperature on the conversion of 1 to methyl benzoate (1a, Table 1) has been studied. The variation of temperature from 30 • C to 100 • C has been found to have a significant impact on the conversion of the acid to ester with the optimal temperature being 70 • C. Moreover, under dry reaction conditions (in the presence of Na 2 SO 4 ) the efficiency of the esterification dropped considerably (entry 8). The promoting activities of NXSs, halogen mineral acids and molecular bromine were compared in the present esterification reaction. In the case of both aqueous hCl (entry 12) and molecular Br 2 (entry 15), the conversions were comparable and their activity was similar to that of NBS (entry 6). On the other hand, the esterification efficiency in the case of both hBr and hI was considerably lower (entry 13 and 14) and resulted in the conversion yields of 84% and 68%, respectively. From the green-chemical point of view, NBS exhibited the highest catalytic activity among the examined catalysts. N-chlorosuccinimide (NCS), NBS, or N-iodosuccinimide (NIS). The results presented in Table 1 reveal that NBS seems to be the most promising catalyst in reactions of esterification, while without the presence of any of the NXSs, no conversion of starting material has been observed. In search of optimal reaction conditions, the effect of catalyst NBS loading has been examined by changing the amount of catalyst from 3 mol% to 15 mol% (Table 1). The amount below 7 mol% NBS furnished significantly lower conversion, while increasing the amount above 7 mol% did not significantly improve the yield of the corresponding ester. Therefore, further studies were carried out with 7 mol% of NBS. Moreover, the influence of temperature on the conversion of 1 to methyl benzoate (1a, Table 1) has been studied. The variation of temperature from 30 °C to 100 °C has been found to have a significant impact on the conversion of the acid to ester with the optimal temperature being 70 °C. Moreover, under dry reaction conditions (in the presence of Na2SO4) the efficiency of the esterification dropped considerably (entry 8). The promoting activities of NXSs, halogen mineral acids and molecular bromine were compared in the present esterification reaction. In the case of both aqueous HCl (entry 12) and molecular Br2 (entry 15), the conversions were comparable and their activity was similar to that of NBS (entry 6). On the other hand, the esterification efficiency in the case of both HBr and HI was considerably lower (entry 13 and 14) and resulted in the conversion yields of 84% and 68%, respectively. From the green-chemical point of view, NBS exhibited the highest catalytic activity among the examined catalysts. The optimal reaction conditions presented above (entry 6, Table 1) have been applied to 1-octanoic acid (2) as an alkyl acid model compound. As expected, 1-octanoic acid has been quantitatively converted to the corresponding methyl octanoate (2a, Figure 1), while in the absence of NBS, no conversion of the starting material was observed. The optimal reaction conditions presented above (entry 6, Table 1) have been applied to 1-octanoic acid (2) as an alkyl acid model compound. As expected, 1-octanoic acid has been quantitatively converted to the corresponding methyl octanoate (2a, Figure 1), while in the absence of NBS, no conversion of the starting material was observed.
To compare the reactivity of the aromatic and alkyl acids, the optimization of reaction time has been performed ( Figure 1). Relative to benzoic acid, significantly higher activity of alkyl acid (2) has been observed, which was in accordance with our expectations. Due to resonance stabilization of carboxyl group in aromatic acids, its lower activation resulted in longer reaction time and slightly lower conversion.
To compare the reactivity of the aromatic and alkyl acids, the optimization of reaction time has been performed ( Figure 1). Relative to benzoic acid, significantly higher activity of alkyl acid (2) has been observed, which was in accordance with our expectations. Due to resonance stabilization of carboxyl group in aromatic acids, its lower activation resulted in longer reaction time and slightly lower conversion. Encouraged by these promising results, the scope of the alcohols, suitable for esterification with acids 1 and 2, has been studied ( Table 2). It can be observed that almost in all cases, alkyl acid (2) is significantly more active than aromatic acid (1) and the conversions to the corresponding esters (2ai) are higher. Since nucleophilic characters, as well as steric properties, have been envisioned to have a considerable impact on reaction kinetics, different alcohols have been tested (a-i, Table 2). 2-Fluoro-1-ethanol (FCH2CH2OH, b) is a significantly weaker nucleophile than MeOH, therefore the reaction time for esterification of 1 as well as of 2 had to be prolonged. The elongation of the alcohol alkyl chain (a, d, f) had a stronger impact on esterification efficiency of benzoic acid than on esterification efficiency of octanoic acid, resulting in higher yields of octanoate esters (2a, 2d, 2f) relative to benzoate esters (1a, 1d, 1f). Moreover, the effect of increased steric hindrance of the nucleophilic alcohol component was followed by varying the bulkiness of alcohol from primary to tertiary structure (a, c and g, e and i). Interestingly, the esterification of octanoic acid was considerably less affected by the structural change from primary (MeOH, 2a) to secondary alcohol (i-PrOH and cyclopentanol, 2c and 2g) than the transformation of benzoic acid, where low (i-PrOH, 1a) or no conversion (cyclopentanol, 1g) was detected. Unfortunately, the limitation of the method was observed in reactions with bulky tertiary alcohols t-BuOH (e) and adamantanol (i), where no product was detected. Similarly, when phenol (h) has been used as the nucleophile, no reaction products were noticed, which can be assigned to the low nucleophilicity originating from the relatively high acidity of phenol molecule.
Due to the commercial importance of certain methyl esters in biodiesel production (fatty acid methyl esters, FAME) and perfumery (methyl benzoate), esterification of different types of carbocyclic acids with MeOH under optimal reaction conditions has been furtherly investigated ( Table 3). As can be noticed, electronic effects of substituents, as well as their position on the phenyl ring of the investigated aromatic acids have exhibited a significant influence on the conversion of acids (3-12) to their corresponding methyl esters. Encouraged by these promising results, the scope of the alcohols, suitable for esterification with acids 1 and 2, has been studied ( Table 2). It can be observed that almost in all cases, alkyl acid (2) is significantly more active than aromatic acid (1) and the conversions to the corresponding esters (2a-i) are higher. Since nucleophilic characters, as well as steric properties, have been envisioned to have a considerable impact on reaction kinetics, different alcohols have been tested (a-i, Table 2). 2-Fluoro-1-ethanol (FCH 2 CH 2 OH, b) is a significantly weaker nucleophile than MeOH, therefore the reaction time for esterification of 1 as well as of 2 had to be prolonged. The elongation of the alcohol alkyl chain (a, d, f) had a stronger impact on esterification efficiency of benzoic acid than on esterification efficiency of octanoic acid, resulting in higher yields of octanoate esters (2a, 2d, 2f) relative to benzoate esters (1a, 1d, 1f). Moreover, the effect of increased steric hindrance of the nucleophilic alcohol component was followed by varying the bulkiness of alcohol from primary to tertiary structure (a, c and g, e and i). Interestingly, the esterification of octanoic acid was considerably less affected by the structural change from primary (MeOH, 2a) to secondary alcohol (i-PrOH and cyclopentanol, 2c and 2g) than the transformation of benzoic acid, where low (i-PrOH, 1a) or no conversion (cyclopentanol, 1g) was detected. Unfortunately, the limitation of the method was observed in reactions with bulky tertiary alcohols t-BuOH (e) and adamantanol (i), where no product was detected. Similarly, when phenol (h) has been used as the nucleophile, no reaction products were noticed, which can be assigned to the low nucleophilicity originating from the relatively high acidity of phenol molecule.
Due to the commercial importance of certain methyl esters in biodiesel production (fatty acid methyl esters, FAME) and perfumery (methyl benzoate), esterification of different types of carbocyclic acids with MeOH under optimal reaction conditions has been furtherly investigated (Table 3). As can be noticed, electronic effects of substituents, as well as their position on the phenyl ring of the investigated aromatic acids have exhibited a significant influence on the conversion of acids (3-12) to their corresponding methyl esters.

Methyl Alkyl Esters and Methyl Esters of Cholic Acid Derivatives
Molecules 2018, 23, x FOR PEER REVIEW 6 of 17
Furthermore, the applicability of the method on more complex structural backbones has been demonstrated by performing the esterification of two significant steroidal carboxylic acids: cholic acid as one of the most common bile acids, formed as an end product of cholesterol metabolism in the liver [54], and its derivative dehydrocholic acid, which is the main component in many drugs against cholestatic liver disease and for dissolution of cholesterol gallstones [55]. In both cases, an excellent conversion of the starting material was achieved already after 1 h. Although in the crude reaction mixture obtained after esterification of dehydrocholic acid, partial conversion to ketal was observed, it was quantitatively converted into the corresponding ester during the isolation step by washing the mixture with 10% hCl (aq) .
Moreover, to confirm the synthetic value of the presented methodology, synthesis of methyl benzoate (1a), methyl stearate (13a) and methyl citrate (16a) has been performed on 10-40 mmol scale with high to excellent yields (85-100%).

General Information
All reactions were performed in Mettler-Toledo Easymax 102 Advanced Synthesis Workstation using 25 mL reactor tubes. NMR spectra were recorded on Varian Inova 300 spectrometer (300 MHz 1 H, 75 MHz 13 C, 285 MHz 19 F) at 25 • C. 1 H-NMR spectra were obtained as solutions in CDCl 3 with TMS as the internal standard. 19 F-NMR spectra were obtained as solutions in CDCl 3 with CFCl 3 as the internal standard. N-bromosuccinimide was freshly recrystallized before use. All other chemicals used for synthetic procedures were obtained from commercial sources and were of reagent grade purity or better (Merck, Sigma Aldrich, Carlo Erba, Fluka, Fisher Scientific, Apollo Scientific, etc.). Reactions were monitored by TLC with silica gel coated plates Silica gel/TLC cards, DC-Alufolien-Kieselgel with 60 Å medium pore diameter (Sigma Aldrich) and detection was conducted by UV absorption (254 nm). Purification of certain products was conducted on preparative silica gel glass plates PLC Kieselgel 60 F254 with 2 mm layer thickness. Succinimide, isolated at the end of the reaction, can easily be recycled back to N-bromosuccinimide according to the standard procedure by NaOH, as elaborated in other reports [56]. Copies of 1 H-NMR, 13 C-NMR and 19 F-NMR spectra of isolated final products are available in Supplementary material file online.

General Procedure for the Esterification between Carboxylic Acids and Alcohols
The mixture of carboxylic acid, alcohol and N-bromosuccinimide was stirred in a 25 mL reactor tube at 70 • C for 2-40 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The isolation procedure was as follows, except where noted differently in Section 3.2.6. The residue was dissolved in ethyl acetate and consecutively washed with 10 mL of 10% Na 2 S 2 O 3 (aq) , 5 mL of saturated NaHCO 3 (aq) and 10 mL of distilled water. The water phase was extracted with ethyl acetate (3 × 5 mL). The organic layers were combined, dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure.

Scale-Up Procedure for Preparation of Methyl Benzoate (1a) and Isolation of Succinimide
The mixture of benzoic acid (40 mmol, 4.88 g), MeOH (20 mL) and N-bromosuccinimide (2.80 mmol, 0.50 g) was stirred in a 25 mL reactor tube at 70 • C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The residue was washed with distilled water (20 mL) and the water phase was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined and washed with the mixture of 10 mL of saturated NaHCO 3 (aq) , 10 mL of 10% Na 2 S 2 O 3 (aq) and 15 mL of distilled water. The water layer was again extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure to furnish methyl benzoate as colourless oil. The water layer from the first washing of the crude reaction mixture was evaporated under the reduced pressure to give succinimide as a white solid.

Scale-Up Procedure for Preparation of Trimethyl Citrate (16a)
The mixture of citric acid (11 mmol, 2.11 g), MeOH (20 mL) and N-bromosuccinimide (0.77 mmol, 0.138 g) was stirred in a 25 mL reactor tube at 70 • C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with the mixture of 10 mL of saturated NaHCO 3 (aq) , 10 mL of 10% Na 2 S 2 O 3 (aq) and 25 mL of distilled water and the water phase was extracted with ethyl acetate (2 × 25 mL). The organic layers were combined, dried with Na 2 SO 4 and the solvent was evaporated under reduced pressure to furnish methyl citrate as a white solid. Yield: 2.55 g, 99%.

Scale-Up Procedure for Preparation of Methyl Stearate (13a)
The mixture of stearic acid (10 mmol, 2.85 g), MeOH (20 mL) and N-bromosuccinimide (0.70 mmol, 0.125 g) was stirred in a 25 mL reactor tube at 70 • C for 20 h. After the completion of the reaction, the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with the mixture of 10 mL of saturated NaHCO 3 (aq) , 10 mL of 10% Na 2 S 2 O 3 (aq) and 15 mL of distilled water and the water phase was extracted with ethyl acetate (2 × 25 mL). The organic layers were combined, washed with distilled water (2 × 20 mL), dried with Na 2 SO 4 and the solvent was evaporated under reduced pressure to furnish methyl stearate as a white solid. Yield: 2.99 g, 100%.
3.2.5. Procedure for Recycling of N-bromosuccinimide (NBS) from Waste Succinimide Succinimide (0.272 g, 2.75 mmol) was dissolved in a mixture of 1.36 g (3.29 mmol) NaOH, 0.5 g crushed ice and 1.5 mL of cold water. To this mixture, 0.156 mL (3.02 mmol, 0.483 g) of Br 2 was added while stirring. It was stirred for five minutes and then the product was filtered, washed with cold water and dried in a desiccator to isolate 0.348 g (71%) of NBS.

Conclusions
In conclusion, a convenient and selective metal-free method for direct dehydrative esterification of free aromatic and aliphatic acids with different alcohols has been developed, using inexpensive and easy-to-handle N-bromosuccinimide as a moisture-and air-tolerant recyclable catalyst. The synthesis has been performed under neat reaction conditions without the need for simultaneous removal of water and excessive reagents. In spite of some scope limitations, the method provides good to excellent product yields and in the majority of cases, enables simple isolation procedure only by extraction. Even in the case of di-and tri-carboxy aliphatic acids, esterification has been successfully accomplished with the same amount of NBS catalyst as in the case of mono-carboxy alkyl acids. The applicability of the method has been successfully demonstrated also on steroidal carboxylic acids. The large-scale synthesis of methyl benzoate, methyl stearate and trimethyl citrate as examples of commercially significant esters has been performed with high to excellent yields (85-100%).