Atom-efficient chlorination of benzoic acids with PCl 3 generating acyl chlorides

Abstract

By using PCl₃ as the chlorinating reagent, various carboxylic acids are converted into the corresponding acid chlorides in good yields. This method features high atom efficiency in which nearly all three chlorine atoms of PCl₃ are used in the chlorination. Moreover, the work-up procedure is simple since the major side product is phosphonic acid [HP(O)(OH)₂] which is non-toxic and easily removed by filtration. A possible mechanism is proposed in this paper.

Introduction

Acyl chlorides (RCOCl) are fundamental reagents in organic synthesis for acylating reactions and are widely used in medicines, agricultural chemicals, dye industries, and so on.^1–3 Generally, RCOCls are prepared from reactions of the corresponding carboxylic acids or anhydrides with chlorinating reagents (Scheme 1).^4,5–12 For example, thionyl chloride (1 equiv.), phosgene (2 equiv.), oxalyl chloride (3 equiv.), and phosphorus pentachloride (4 equiv.) are generally used in reactions with carboxylic acids to produce the corresponding acyl chlorides. However, with these chlorinating reagents, the reaction has relatively low atom efficiency regarding the chlorine atom. Thus, with thionyl chloride, oxalyl chloride, and phosgene, the maximum utilization ratio of the chlorine atoms in the product is no more than 50% because one equivalent of HCl is concomitantly generated. With PCl₅, the utilization of the chlorine is even less (20%). Therefore, at least one equivalent of the chlorinating reagents has to be employed. Moreover, these reactions also unavoidably produce toxic by-products SO₂, CO, HCl, and P(O)Cl₃.

Scheme 1.

Methods for preparing acyl chlorides (chemicals in red are toxic side-products).

We required a straightforward method for the preparation of ArCOCls for our ongoing project. Literature searches revealed the chlorination of carboxylic acids with phosphorus trichloride (PCl₃), a cheap and readily available industrial chemical (5 equiv.).^13–15 We were fascinated by the remarkable potential that one molecule of PCl₃ may possibly produce three molecules of the RCOCl (100% Cl utilization), without producing toxic by-products! Furthermore, since the HP(O)(OH)₂ by-product is sparingly soluble in an organic solvent, the isolation of the acyl chloride product becomes very easy. Although a few examples of the use of PCl₃ could be found in the literature,^13,16–24 a detailed study on the scope, limitations, and mechanism of the chlorination of carboxylic acids with PCl₃ are clearly desirable.

Results and discussion

We began this work with the reaction of benzoic acid (1a) with PCl₃. As shown in Table 1, a trace amount of benzoyl chloride was generated at room temperature by mixing benzoic acid (1a) and PCl₃ overnight (entry 1). A 63% yield of 2a was generated upon heating the mixture at 60 °C (entry 2), and a 66% GC yield of 2a was generated at 100 °C (entry 3). Similar results were obtained by using other solvents such as hexane (entry 4) and dioxane (entry 5). However, only a trace amount of the product was obtained in dimethylformamide (DMF) at 100 °C (entry 6). With CH₃CN, a 75% yield of 2a was obtained (entry 7), indicating that more than two Cl atoms from PCl₃ were utilized for the chlorination. By lowering the reaction temperature from 100 to 80 °C (entry 8) and 60 °C (entry 9), better yields of 2a were obtained (78% and 85%, respectively). The reaction can even take place at 40 °C (entry 10) and room temperature (entry 11), although the yields of 2a decreased. The reaction is well-reproducible, as a large-scale experiment under the same conditions gave a similar yield of 2a (entry 12). As shown in entry 13, the reaction time of 6 h was sufficient.

Table 1.

Optimization of the reaction conditions. ^a

Entry	Solvent	Temperature (°C)	Time (h)	Yield (%) b
1	Toluene	25	24	Trace
2	Toluene	60	24	63
3	Toluene	100	24	66
4	Hexane	100	24	65
5	Dioxane	100	24	64
6	DMF	100	24	Trace
7	CH3CN	100	24	75
8	CH3CN	80	24	78
9	CH3CN	60	24	85
10	CH3CN	40	24	64
11	CH3CN	25	24	43
12 c	CH3CN	60	24	88
13	CH3CN	60	6	86

DMF: dimethylformamide.

a

Conditions: 1a (1.0 mmol), PCl₃ (0.33 mmol), solvent (0.6 mL).

b

GC yield based on 1a using n-decane as an internal standard.

c

10 mmol of 1a and 3.3 mmol of PCl₃ in 6 mL of MeCN.

It was observed that a slightly yellowish solid precipitated in the bottom of the glass tube during the reaction. We expected that the majority of this solid would be phosphonic acid since most of the Cl atoms of PCl₃ were utilized for chlorination. Next, we decided to confirm the structure of this solid. We removed the reaction solution and washed the solid with toluene several times. After it was dried under vacuum, the solid obtained was dissolved in dimethyl sulfoxide (DMSO)-d6 and analyzed by ³¹P NMR and ¹H spectrascopy. As depicted in Figure 1, two signals were observed at δ 2.16 and δ 0.09, respectively (ratio: 2.8/1.0), that accounted for phosphorus. The signal at 2.16 ppm was assigned to HP(O)(OH)₂ by comparing with an authentic sample of phosphonic acid, while the signal at 0.09 ppm was tentatively assigned to H₃PO₄ (H₃PO₄ appeared at around here; however, we are not sure how it was generated in this reaction). Further supporting the assignment was the result of ¹H NMR spectroscopy, in which the H-P(O) group was clearly observed as a doublet at 7.49 and 5.88 ppm, and the OH groups appeared as a broad peak at 6.39 ppm. This experiment clearly confirmed that the major by-product was H₃PO₃ which is in good agreement with the fact that most of the Cl was utilized to generate 2a (entry 13).

Figure 1.

³¹P and ¹H NMR spectra of the crude solid.

With optimized conditions in hand, we next examined the generality of this reaction. As shown in Scheme 2, various functional groups were well tolerated in this system. Electron-rich aryl acids bearing methyl, OMe, and SMe groups at the para-position of the benzene rings were compatible under the present reaction conditions, producing the corresponding aroyl chlorides in good to high yields (2b–d). 4-Vinylbenzoic acid was also applicable to this chlorination reaction, giving the desired product 2e in 81% yield. Substrates with electron-withdrawing groups such as F, CF₃, CN, and C(O)OMe on the benzene ring also reacted with PCl₃ smoothly, furnishing the expected products (2f–i) in good yields at 80 °C. However, 4-acetylbenzoic acid only gave a 49% yield of the desired product (2j) with major starting material recovered, partly due to the poor solubility of the substrate. The substrate scope was then extended to 2-naphthoic acid, and the corresponding product, 2-naphthoyl chloride (2k), was obtained in 95% yield under similar conditions. Notably, an important industrial intermediate, 2,4,6-trimethylbenzoyl chloride (2l), could also be generated in 78% yield.

Scheme 2.

Reaction of aryl acids with PCl₃.^a

Another remarkable feature of this reaction is its simple work-up procedure for the isolation of the product. As shown in Figure 2, a mixture of 4-(methylthio)benzoic acid (3 mmol) and PCl₃ (1 mmol) in MeCN (3.0 mL) was heated at 60 °C for 6 h, and from the initial clear solution (Figure 2(a)), H₃PO₃ precipitated out (Figure 2(b)). By simple decantation, a clear solution containing 2d was obtained (Figure 2(c) right), and spectroscopically, pure 2d was obtained by removal of the solvent under vacuum (96% yield).

Figure 2.

Photographs of the reaction process: (a) 8 min, (b) after reaction, and (c) after decanting solid (L); solution (R).

It is known that PCl₃ can react with an aliphatic carboxylic acid at room temperature. ¹³ To elucidate the difference in reactivity between an aliphatic acid and an aromatic acid, a series of control experiments were conducted. As shown in Scheme 3, only a trace amount of benzoyl chloride was detected when benzoic acid and PCl₃ were stirred in CH₃CN (0.6 mL) at room temperature for 30 min. In comparison, hexanoic acid was chlorinated by PCl₃ successfully, giving the desired product in 73% yield. Very surprisingly, bulky 2-ethylhexanoic acid gave a 97% yield of product 2n under similar conditions. Furthermore, a more sterically hindered 2,2-dimethylpentanoic acid gave a 31% yield of product 2o under similar conditions. Therefore, it appears that both steric and electronic effects of the substituents affect the reaction. Thus, sterically, a hindered α carbon hampers the chlorination, while electronically, an electron-rich α carbon accelerates the reaction.

Scheme 3.

Reactions of different acids with PCl₃ at room temperature (yields are isolated yields based on benzoic acids).

To gain further insight into the reaction, the reactions of benzoic acids bearing different substituents on the benzene ring (CF₃, F, H, and MeO) were also carried out (Scheme 4). Electron-deficient 4-(trifluoromethyl)benzoic acid gave only a trace amount of the product 2g. 4-Fluorobenzoic acid reacted with PCl₃; however, the yield was low (21%) compared to PhCO₂H (52% yield). In contrast, compared with benzoic acid, 4-methoxybenzoic acid with an electron-donating OMe group gave the product 2c in a higher yield (78%). Thus, the reactivity of the benzoic acids follows an increasing order of CF₃ < F < H < OMe, that is, an electron-rich acid was more rapidly chlorinated by PCl₃ than an electron-deficient acid.

Scheme 4.

Electronic effects (reactions for 3 h; yields are isolated yields based on benzoic acids).

Although the detailed mechanism was not clear, a possible mechanism is proposed in Scheme 5. Thus, the first step should be a reaction of the acid with PCl3, probably via a four-center transition state A, with carbonyl oxygen attacks the electron-deficient P(Cl) while Cl attacking the electronically deficient carbonyl carbon. Formation of a Cl-C bond and P-O bond (A’), further C-O bond cleavage and hydrogen transfer took place to give the products B and C. Product C then reacts further with the acid to give the corresponding chlorides and HP(O)(OH)2.

Scheme 5.

Plausible mechanism of the reaction.

Conclusion

In summary, we have studied the chlorination of carboxylic acids with PCl₃ which afford the corresponding acyl chlorides in good yields under simple conditions. Unlike other approaches, nearly all the chlorines of PCl₃ are used for the chlorination. Moreover, it is easy to isolate the products because the main by-product is phosphonic acid, which is insoluble in the solvents. Electronic effect study revealed that electron-rich acids have higher reaction activity than electron-deficient acids.

Experiment

All reactions were carried out in oven-dried Schlenk tubes under argon. Reagents and solvents were obtained from TCI and were purified according to standard methods. Distillation was performed using a glass tube oven (GTO-350RD; SIBATA). The pure products were obtained by distillation under reduced pressure. A Shimadzu GC-2010 equipped with flame ionization detector (FID) was used to analyze the reaction mixtures. ¹H NMR and ¹³C NMR spectra were recorded on a JEOL JNM-ECS400 spectrometer (400 MHz for ¹H and 100 MHz for ¹³C) in CDCl₃. Chemical shifts for ¹H NMR are referred to internal Me₄Si (0 ppm). Gas chromatograph–mass spectrometry (GC-MS) was conducted on a Shimadzu GCMS-QP2010 Plus equipped with an EI ion source.

Typical procedure for the reaction of acids with PCl₃ (yield based on three parallel reactions)

Under argon, acid (1.0 mmol) and PCl₃ (0.333 mmol) were added to a 10-mL dried Schlenk tube, followed by the solvent (0.6 mL). The tube was heated at 60 °C. The reaction mixture was cooled to room temperature and the solid was filtered off. Evaporation of the solvent under vacuum and distillation of the residue under reduced pressure gave analytically pure acid chlorides.

Benzoyl chloride (2a): ²⁵ Colorless oil, yield 83%, 349.8 mg (75 °C, 2 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.12–8.10 (m, 2H), 7.70–7.66 (m, 1H), 7.53–7.49 (m, 2H); ¹³C NMR (100 MHz CDCl₃): δ: 168.47, 135.47, 133.30, 1131.50, 129.08; GC-MS (EI, 70 eV): m/z = 140 (M⁺, 4), 105 (100), 77 (68), 63 (8), 51 (46), 50 (33).

4-Methylbenzoyl chloride (2b): ²⁶ Colorless oil, yield 84%, 389.4 mg (90 °C, 4 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.01–7.98 (m, 2H), 7.31–7.29 (m, 2H), 2.44 (s, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 168.17, 146.93, 131.66, 130.65, 129.79, 21.89; GC-MS (EI, 70 eV): m/z = 156 ([M+2]⁺, 2), 154 (M⁺, 7), 119 (100), 91 (58), 65 (21), 63 (12).

4-Methoxybenzoyl chloride (2c): ²⁶ Colorless oil, yield 94%, 480.9 mg (90 °C, 2 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.09–8.05 (m, 2H), 6.98–6.94 (m, 2H), 3.90 (s, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 167.22, 165.48, 134.09, 125.53, 114.33, 55.84; GC-MS (EI, 70 eV): m/z = 172 ([M+2]⁺, 3), 170 (M⁺, 9), 135 (100), 107 (12), 92 (20), 77 (28), 63 (13).

4-(Methylthio)benzoyl chloride (2d): ²⁷ White solid, yield 95%, 531.9 mg (130 °C, 2 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 7.99–7.95 (m, 2H), 7.27–7.24 (m, 2H), 2.52 (s, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 167.63, 149.88, 131.74, 128.96, 124.94, 14.66; GC-MS (EI, 70 eV): m/z = 188 ([M+2]⁺, 6), 186 (M⁺, 16), 151 (100), 123 (11), 108 (12), 79 (12), 45 (23).

4-Vinylbenzoyl chloride (2e): ²⁸ Colorless oil, yield 81%, 404.7 mg (75 °C, 2 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.07–8.05 (m, 2H), 7.52–7.50 (m, 2H), 6.80–6.72 (m, 1H), 5.96–5.91 (m, 1H), 5.50–5.47 (m, 1H); ¹³C NMR (100 MHz CDCl₃): δ: 167.98, 144.44, 135.49, 132.21, 131.95, 126.68, 118.55; GC-MS (EI, 70 eV): m/z = 168 ([M+2]⁺, 4), 166 (M⁺, 11), 131 (100), 103 (38), 77 (32), 51 (19).

4-Fluorobenzoyl chloride (2f): ²⁶ Colorless oil, yield 72%, 342.3 mg (45 °C, 6 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.18–8.13 (m, 2H), 7.22–7.16 (m, 2H); ¹³C NMR (100 MHz CDCl₃): δ: 167.21 (d, J_C-F = 258.0 Hz), 167.11, 134.31 (d, J_C-F = 10.0 Hz), 129.62 (d, J_C-F = 3.0 Hz), 116.40 (d, J_C-F = 22.0 Hz); GC-MS (EI, 70 eV): m/z = 160 ([M+2]⁺, 2), 158 (M⁺, 5), 123 (100), 95 (60), 75 (25), 69 (6), 50 (10).

4-(Trifluoromethyl)benzoyl chloride (2g): ²⁹ Colorless oil, yield 72%, 450.6 mg (45 °C, 6 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.24 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H); ¹³C NMR (100 MHz CDCl₃): δ: 167.66, 137.04–136.06 (m), 136.33, 131.67, 126.17–126.07 (m), 123.25 (q, J_C-F = 271.0 Hz); GC-MS (EI, 70 eV): m/z = 208 (M⁺, 1), 173 (100), 145 (70), 125 (9), 95 (14), 75 (14), 50 (14).

4-Cyanobenzoyl chloride (2h): ²⁶ White solid, yield 76%, 377.4 mg (100 °C, 4 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.23–8.20 (m, 2H), 7.84–7.81 (m, 2H); ¹³C NMR (100 MHz CDCl₃): δ: 167.39, 136.65, 132.80, 131.59, 118.67, 117.34; GC-MS (EI, 70 eV): m/z = 165 (M⁺, 1), 130 (100), 102 (47), 75 (18), 50 (15).

Methyl 4-(chlorocarbonyl)benzoate (2i): ³⁰ White solid, yield 79%, 470.4 mg (150 °C, 2 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.18–8.13 (m, 4H), 3.95 (s, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 167.99, 165.69, 136.66, 135.95, 131.26, 130.07, 52.80; GC-MS (EI, 70 eV): m/z = 198 (M⁺, 2), 163 (100), 135 (18), 103 (15), 76 (17).

4-Acetylbenzoyl chloride (2j): ²⁶ White solid, yield 49%, 268.2 mg (110 °C, 2 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.20–8.17 (m, 2H), 8.06–8.03 (m, 2H), 2.65 (s, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 197.03, 167.95, 141.84, 136.58, 131.60, 128.68, 27.07; GC-MS (EI, 70 eV): m/z = 184 ([M+2]⁺, 2), 182 (M⁺, 7), 167 (17), 147 (100), 139 (14), 104 (15), 91 (18), 76 (17), 50 (15).

2-Naphthoyl chloride (2k): ³¹ White solid, yield 95%, 543.3 mg (140 °C, 4 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 8.71–8.71 (m, 1H), 8.04–7.97 (m, 2H), 7.69–7.65 (m, 1H), 7.62–7.58 (m, 1H); ¹³C NMR (100 MHz CDCl₃): δ: 168.48, 136.51, 134.86, 132.35, 130.43, 130.11, 129.99, 128.92, 127.92, 127.51, 125.39; GC-MS (EI, 70 eV): m/z = 192 ([M+2]⁺, 6), 190 (M⁺, 20), 155 (100), 127 (83), 77 (14), 63 (19).

2,4,6-Trimethylbenzoyl chloride (2l): ³² Colorless oil, yield 78%, 427.4 mg (40 °C, 9 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 6.96 (s, 2H), 2.46 (s, 6H), 2.38 (s, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 170.62, 140.73, 136.37, 132.98, 128.73, 21.22, 19.43.

Hexanoyl chloride (2m): ³³ Colorless oil, yield 73%, 294.6 mg (40 °C, 9 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 2.87 (t, J = 8.0 Hz, 2H), 1.74–1.67 (m, 2H), 1.35–1.29 (m, 4H), 0.91–0.87 (m, 2H); ¹³C NMR (100 MHz CDCl₃): δ: 173.93, 47.15, 30.62, 24.82, 22.23, 13.84; GC-MS (EI, 70 eV): m/z = 106 ([M-28]⁺, 13), 99 (100), 91 (21), 78 (53), 71 (60), 63 (13), 57 (74).

2-Ethylhexanoyl chloride (2n): ³⁴ Colorless oil, yield 97%, 473.1 mg (45 °C, 9 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 2.73–2.66 (m, 1H), 1.80–1.50 (m, 4H), 1.38–1.25 (m, 4H), 0.95 (t, J = 8.0 Hz, 3H), 0.92–0.87 (m, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 177.41, 58.80, 31.35, 29.13, 25.19, 22.56, 13.88, 11.39; GC-MS (EI, 70 eV): m/z = 162 (M⁺, 2), 106 (20), 99 (11), 70 (15), 57 (100), 55 (22).

2,2-Dimethylpentanoyl chloride (2o): ³⁵ Colorless oil, yield 31%, 151.2 mg (45 °C, 9 × 10 Pa); ¹H NMR (400 MHz CDCl₃): δ: 1.62–1.58 (m, 2H), 1.32–1.24 (m, 8H), 0.94–0.90 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz CDCl₃): δ: 180.28, 52.97, 42.67, 25.25, 18.05, 14.45; GC-MS (EI, 70 eV): m/z = 106 ([M-42]⁺, 3), 85 (100), 69 (7), 57 (18).

Supplemental material

Supporting_information_PDF – Supplemental material for Atom-efficient chlorination of benzoic acids with PCl₃ generating acyl chlorides

Supplemental material, Supporting_information_PDF for Atom-efficient chlorination of benzoic acids with PCl₃ generating acyl chlorides by Jing Xiao and Li-Biao Han in Journal of Chemical Research