Introduction

The ester condensation reaction is among the most fundamental organic transformations, and more environmentally benign alternative synthetic approaches to the ones currently used are in strong demand by the chemical industry1. Conventionally, the ester condensation reaction of carboxylic acids with alcohols is catalyzed by Brønsted acids such as HCl, H2SO4, p-toluenesulfonic acid and so on for acid-resistance substrates. For acid-sensitive substrates, weak Brønsted acids such as pyridinium p-toluenesulfonate should be used. However, these have lower catalytic activities and the reactants that can be used are rather limited. With regard to green chemistry, in particular with respect to atom economy and E-factor, several catalytic methods for the ester condensation reaction between equimolar amounts of carboxylic acids and alcohols have been developed2,3,4,5,6. Conventionally, in fact, esterifications are conducted with an excess of carboxylic acids or alcohols against its reaction counterpart in the presence of an acid catalyst, or with a stoichiometric dehydrating reagent or activated carboxylic acid derivative in the presence of a stoichiometric amount of base. The use of excess amounts of substrates is a wasteful practice in itself. Furthermore, the use of stoichiometric dehydrating reagents or activated carboxylic acid derivatives leads to the formation of significant amounts of undesired by-products. Purifying the crude products from (excess) substrates or from reaction by-products is a rather demanding task—also in financial terms—requiring additional apparati and additional amounts of materials, energy (e.g., for azeotropic reflux) and time. It is therefore evident why the direct catalytic condensation between equimolar amounts of carboxylic acids and alcohols that does not require the presence of dehydrating agents is, at least in principle, such an attractive synthetic goal. Among these 'green' catalytic condensations, metal-free organocatalytic methods are particularly desirable, especially for industrial processes. In 2000, Tanabe and co-workers2 reported that diphenylammonium triflate ([Ph2NH2]+[OTf]−, 1.0–10 mol%) efficiently catalyzed the ester condensation reaction at 80 °C without the need for removal of water. Unfortunately, however, as [Ph2NH2]+[OTf]− is the salt of a superacid (trifluoromethansulfonic acid (TfOH)) and a weak base (Ph2NH), it is a strong Brønsted acid, and as such is difficult to use in the reaction of sterically demanding and acid-sensitive alcohols.

In the course of our continuing study on environmentally benign dehydration catalysts, we have developed N,N-dimesitylammonium pentafluorobenzenesulfonate (3) and N-(2,6-diisopropylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate (4) as mild and selective ester condensation catalysts7,8,9. A scheme for the synthesis of ammonium catalysts 3 and 4 is shown in Figure 1. N,N-Dimesitylamine (1) is prepared from 2,4,6-trimethylaniline by palladium-catalyzed cross-coupling with 2,4,6-mesitylbromide10,11. The reaction of 1 with an equimolar amount of pentafluorobenzenesulfonic acid (C6F5SO3H), which is prepared from pentafluorobenzenesulfonyl chloride by hydrolysis, gives ammonium salt 3. This catalyst 3 has been commercially available from Tokyo Chemical Industry Co., Ltd (TCI) since January 2007. Catalyst 4 can be prepared from 2,6-diisopropylaniline by an analogous procedure. It is, in particular, the synthesis of catalyst 4 that is detailed in the PROCEDURE section.

Figure 1: Scheme for the synthesis of ammonium catalysts 3 and 4.
figure 1

(a) 2,4,6-mesitylbromide, Pd(dba)2, BINAP, t-Bu ONa, toluene, reflux, (b) C6F5SO3H, toluene.

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C6F5SO3H (pKa(CD3CO2D) = 11.1, H0 = −3.98) is a weaker acid than TfOH (pKa(CD3CO2D) = −0.74, H0 = −14.00), concentrated H2SO4 (pKa(CD3CO2D) = 7.5, H0 = −11.93) and p-toluenesulfonic acid (pKa(CD3CO2D) = 8.5, H0 = −4.5). This means that 3 and 4 are milder acids than the corresponding ammonium triflates, sulfates and tosylates. Nevertheless, 3 and 4 have much higher catalytic activities than Tanabe catalyst ([Ph2NH2]+[OTf]−) (see data in Fig. 2), owing to the hydrophobic environment created around the ammonium protons in the catalyst12. Even though the ester condensation was performed under heating without the removal of water, the reaction proceeded well without any deceleration owing to the generated water.

Figure 2: Ester condensation of 4-phenylbutyric acid with cyclododecanol (5).
figure 2

The proportions of 5 (green line), 6 (blue line) and 7 (red line) in the reaction mixture over time are shown. The reactions were catalyzed by [Ph2NH2]+[OTf]− (a) [Mes2NH2]+[OTf]− (b), or 3 (c).

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The X-ray single-crystal structures of 3 and [Ph2NH2]+[OTf]− are shown in Figure 3. The crystals obtained were dimeric cyclic ion pairs composed of two diarylammonium cations and two arenesulfonate anions. Interestingly, the dimeric cyclic ion pair of 3 was stabilized by two intermolecular π–π interactions as well as four hydrogen bondings, whereas there was no intermolecular π–π interaction in the ion pair of [Ph2NH2]+[OTf]−. It is conceivable that a 'hydrophobic wall' prevents polar water molecules from gaining access to the active site of the catalysts and thus inhibits the inactivation of the catalyst by water (Fig. 3). Furthermore, the steric bulkiness of the mesityl and pentafluorophenyl groups in the catalyst suppressed the dehydrative elimination of secondary alcohols to produce alkenes.

Figure 3: Structures of the catalysts.
figure 3

Top: ORTEP diagrams of X-ray single-crystal structure of 3 (a) and [Ph2NH2]+[OTf]− (b). F = green, N = blue, O = red, S = yellow. Bottom: Schematic representation of the active sites (yellow) and 'hydrophobic wall' (green).

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When the ester condensation of 4-phenylbutyric acid with cyclododecanol (5; see Fig. 2) was conducted in the presence of Tanabe catalyst (5 mol%) in heptane under reflux conditions (bath temperature 115 °C), a significant amount of the undesired cyclododecene (7) was produced along with cyclododecyl 4-phenylbutyrate (6) (Fig. 2, graph a). The use of dimesitylammonium triflate ([Mes2NH2]+[OTf]−) showed higher catalytic activity than [Ph2NH2]+[OTf]− and reduced the production of 7 (Fig. 2, graph a). Furthermore, the ester condensation catalyzed by 3 (5 mol%) proceeded more rapidly, and the production of 7 decreased (Fig. 2, graph a). The use of less-polar solvents such as heptane is important. The catalytic activities of 3 and 4 increased in such less-polar solvents, to produce esters in high yields. One of the limitations of the present method is the need for less-polar solvents: it is difficult to perform ester condensation of hydrophilic substrates that cannot dissolve in less-polar solvents.

Typically, the ester condensations of 1:1 mixtures of carboxylic acids and alcohols are carried out in the presence of 3 or 4 (1–5 mol%) in heptane by heating at 80 °C without the removal of water. Sterically demanding alcohols are condensed to produce the corresponding esters in high yields. For example, when the ester condensation of 4-phenylbutyric acid with 6-undecanol (1.0 equiv.) was performed in the presence of 4 (5 mol%) in heptane under heating conditions without the removal of water, the corresponding ester was obtained in 88% yield along with 5-undecene (3%) (Fig. 4). In Box 1, a detailed protocol for this reaction is reported. Esterification with 1,2-diols proceeded well to give the corresponding diesters in high yields, while Lewis acidic metal salts were not suitable for use with these diols owing to tight chelation with metal ions13. For example, the condensation between cis-1,2-cyclohexanediol and 4-phenylbutyric acid with 4 gave the corresponding diester in 90% yield, while no esterification product was obtained by heating a mixture of 1,2-butanediol and 1-adamantanecarboxylic acid in toluene in the presence of HfCl4·(THF)2. In addition, we have been able to recover and reuse the bulky diarylammonium pentafluorobenzenesulfonate catalyst immobilized on a polystyrene support without any loss of catalytic activity more than 10 times7,8. On the contrary, a polystyrene-supported diarylammonium triflate could not be prepared, as the polymer support decomposed with superacidic TfOH.

Figure 4
figure 4

Ester condensation of 4-phenylbutyric acid with 6-undecanol.

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Ester condensation reactions with more reactive primary alcohols proceeded even at ambient temperature (22 °C) without solvents. Several carboxylic acids were esterified with 1.1 equiv. of methanol in good yield in the presence of 3 (1 mol%). For example, when condensation between 4-phenylbutyric acid and methanol (1.1 equiv.) was carried out in the presence of 3 (1 mol%) without the removal of water for 24 h, the corresponding ester was obtained in 95% yield (Fig. 5). This reaction can be carried out by the same protocol as that of the reaction in Figure 4 but without the use of solvent (heptane) and heating. 1-Octanol was also reactive, albeit slightly less reactive than methanol8. Octyl methoxyacetate was obtained in 74% yield under the same conditions described in Figure 5.

Figure 5
figure 5

Ester condensation under solvent-free conditions.

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Materials

Reagents

  • N,N-Dimesitylammonium pentafluorobenzenesulfonate (TCI, cat. no. D3293)

  • Mesityl bromide (TCI, cat. no. B1261)

  • 2,6-Diisopropylaniline (TCI, cat. no. D1755)

  • Bis(dibenzylidene acetone)palladium(0) (Pd(dba)2; Sigma-Aldrich, cat. no. 227994)

  • (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene ((±)-BINAP; Sigma-Aldrich, cat. no. 481084)

  • Sodium tert-butoxide (Wako, cat. no. 196-10922)

  • Pentafluorobenzenesulfonyl chloride (TCI, cat. no. P0934)

  • Toluene (Kanto, dehydrated, cat. no. 40500)

  • Distilled water (Wako, cat. no. 042-16973)

  • Silica gel (Merck, silica gel 60 (0.040–0.063 mm), 230–400 mesh ASTM, cat. no. 109385)

  • Thin-layer silica gel plates (Merck, silica gel 60GF254, 0.25 mm, cat. no. 105715)

  • Saturated NaCl aqueous solution

  • Anhydrous sodium sulfate

  • Diethyl ether

  • Hexane

  • Ethyl acetate

Equipment

  • Stirring hotplate with temperature controller

  • Oil bath (15 cm diameter × 6.5 cm depth) and silicone oil (Dow Corning Toray, SRX310)

  • Teflon-coated magnetic stir bars

  • Glass syringes and syringe needles

  • Vacuum pump (ULVAC)

  • Rotary evaporator (EYELA)

Procedure

Synthesis of N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)amine (2)

Timing ∼2–3 days

  1. 1

    Place 9.6 g (100 mmol) sodium tert-butoxide, 575 mg (1.0 mmol) Pd(dba)2 (10 mol%), 934 mg (1.5 mmol) (±)-BINAP (15 mol%) and 50 ml toluene (dehydrated) in a 200 ml round-bottomed flask containing a Teflon-coated magnetic stir bar, and cap the flask with a three-way stopcock with a 24/40 joint.

  2. 2

    Fit the three-way stopcock with a balloon and a dual bank manifold connected to a vacuum pump and a nitrogen tank. Turn the magnetic stirrer on.

  3. 3

    Evacuate the flask using a vacuum pump via the three-way stopcock (∼0.5 min), and fill the flask and the balloon with nitrogen.

  4. 4

    Successively add 5.0 ml (33 mmol) mesityl bromide and 1.89 ml (10 mmol) 2,6-diisopropylaniline, and recap with the three-way stopcock.

  5. 5

    Fit a reflux condenser between the flask and the three-way stopcock.

  6. 6

    Evacuate the flask using a vacuum pump via the three-way stopcock (∼0.5 min), and fill the flask and the balloon with nitrogen. Repeat this operation three times.

  7. 7

    Have tap water flow through the reflux condenser.

  8. 8

    Heat the flask in an oil bath (∼120 °C) under reflux conditions.

    Pause point

    Stir the reaction mixture vigorously at this temperature for 48–60 h.

  9. 9

    Remove the flask from the oil bath and allow the reaction mixture to cool to ambient temperature.

  10. 10

    Add 50 ml of water to the flask, and stir the mixture vigorously for 15 min.

  11. 11

    Transfer the aqueous layer to a separatory funnel and extract it with three 50 ml portions of diethyl ether.

  12. 12

    Combine the organic layer and the extracts, and wash them with brine (saturated NaCl aqueous solution, 50 ml).

  13. 13

    Dry the solution with the addition of anhydrous sodium sulfate (∼50 g) until sodium sulfate no longer adsorbs water (it will appear powdery instead of gelatinous), and keep it for ∼10 min.

  14. 14

    Filter the mixture under an aspirator vacuum through a glass filter (G3) to remove sodium sulfate and collect the filtrate in a flask.

  15. 15

    Evaporate solvents from the filtrate using a rotary evaporator at ∼30 °C under vacuum (10–20 Torr).

  16. 16

    Pack a chromatography glass column (4.2 cm diameter × 50 cm length) with ∼400 ml silica gel using hexane.

  17. 17

    Load a solution of the crude product in ∼20 ml hexane on top of the silica gel using a pipette.

  18. 18

    Elute the column under pressure, initially with hexane, then with 100:1 (vol/vol) hexane/ethyl acetate, and collect 200 ml fractions.

  19. 19

    Identify fractions containing N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)amine by thin-layer chromatography (silica gel plates) using 10:1 (vol/vol) hexane/ethyl acetate (Rf = 0.5).

  20. 20

    Evaporate solvents from the pooled fractions containing N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)amine using a rotary evaporator at ambient temperature under an aspirator vacuum (∼20 Torr), and dry the colorless solid using a vacuum pump (∼1 Torr) for ∼0.5–1 h. The colorless solid can be stored under nitrogen at ambient temperature for more than 6 months.

    Troubleshooting

Synthesis of pentafluorobenzenesulfonic acid

Timing ∼1.5 days

  1. 21

    Place 3.0 ml (20 mmol) pentafluorobenzenesulfonyl chloride in a 200 ml round-bottomed flask containing a Teflon-coated magnetic stir bar.

  2. 22

    Add 50 ml distilled water. Turn the magnetic stirrer on.

  3. 23

    Fit the flask with a reflux condenser and have tap water flow through the reflux condenser.

  4. 24

    Heat the flask in an oil bath (80 °C).

    Pause point

    Stir the mixture vigorously at this temperature overnight (∼12 h).

    Caution

    The reaction should be conducted in a well-ventilated hood, as hydrogen chloride vapors, which are toxic and corrosive, are evolved.

  5. 25

    Remove the flask from the oil bath and allow the reaction mixture to cool to ambient temperature.

  6. 26

    Transfer the reaction mixture to a separatory funnel, and wash with three 10 ml portions of hexane.

  7. 27

    Transfer the aqueous solution to an appropriately sized round-bottomed flask and evaporate solvents using a rotary evaporator at ∼30 °C under vacuum (∼5 Torr).

  8. 28

    Add toluene (∼10 ml) to the residue, which is colorless solid and/or oil, and evaporate solvents from the mixture using a rotary evaporator at ∼30 °C under vacuum (∼10 Torr).

    Pause point

    Dry the resulting colorless solid using a vacuum pump (∼1 Torr) overnight (∼12 h). The dry solid pentafluorobenzenesulfonic acid can be stored under nitrogen in a −20 °C freezer for more than a month.

    Critical Step

    The colorless solid must be obtained as monohydrate form. As pentafluorobenzenesulfonic acid is hygroscopic, store the compound under nitrogen in a −20 °C freezer.

Synthesis of N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)ammonium pentafluorobenzenesulfonate (4)

Timing ∼1 day

  1. 29

    Place 131 mg (0.53 mmol) pentafluorobenzenesulfonic acid in a 50 ml round-bottomed flask containing a Teflon-coated magnetic stir bar and dissolve in 5 ml toluene. Turn the magnetic stirrer on.

  2. 30

    Add 156 mg (0.53 mmol) of 2. Maintain stirring during the addition, and continue stirring for an additional hour.

  3. 31

    Evaporate toluene from the mixture using a rotary evaporator at ∼30 °C under vacuum (∼10 Torr).

  4. 32

    Add hexane (∼3 ml) to wash the resulting white solid. Remove hexane using a Pasteur pipette.

    Pause point

    Dry the now colorless solid under vacuum (∼1 Torr) at ambient temperature for ∼12 h.

    Critical Step

    The initially colorless solid obtained gradually turns green at room temperature during prolonged storage. Therefore, store the compounds under argon in a −20 °C freezer for up to a month to avoid coloration.

    Troubleshooting

Troubleshooting

Troubleshooting advice can be found in Table 1.

Table 1 Troubleshooting table.
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Timing

Synthesis of N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)amine (2): Steps 1–7, 1 h; Step 8, 24–48 h; Step 9, 30 min; Step 10, 20 min; Steps 11–15, 2 h; Steps 16–18, 2 h; Steps 19 and 20; 1 h

Synthesis of pentafluorobenzenesulfonic acid: Steps 22 and 23, 1 h; Step 24, ∼12 h; Step 25, 30 min; Step 26, 30 min; Steps 27 and 28, ∼14 h

Synthesis of N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)ammonium pentafluorobenzenesulfonate (4): Steps 29 and 30, 1.5 h; Step 31, 30 min; Step 32, 30 min; Step 5, ∼12 h

Anticipated results

Analytical data

N -(2,6-Diisopropylphenyl)- N -(2,4,6-mesityl)amine (2)

Typical isolated yield, ∼70–95%. 1H NMR (300 MHz, CDCl3) δ 7.10 (s, 3H), 6.76 (s, 2H), 4.68 (br s, 1H), 3.12 (septet, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.95 (s, 6H), 1.11 (d, J = 6.9 Hz, 12H); 13C NMR (75 MHz, CDCl3) δ 143.3 (s, 1C), 140.4 (s, 1C), 139.1 (s, 1C), 130.0 (s, 2C), 129.0 (s, 1C), 126.3 (s, 2C), 124.2 (s, 2C), 123.2 (s, 2C), 27.9 (s, 2C), 23.4 (s, 4C), 20.4 (s, 1C), 19.3 (s, 2C); IR (KBr, cm−1) 1,484, 1,466, 1,442, 1,340, 1,270. HRMS (FAB) (m/z) [M + H+] calculated for C21H29N 295.2300, found 295.2308.

N -(2,6-Diisopropylphenyl)- N -(2,4,6-mesityl)ammonium pentafluorobenzenesulfonate (4)

Typical yield, >90%. 1H NMR (300 MHz, CDCl3) δ 7.36 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.73 (s, 2H), 3.11 (septet, J = 6.8 Hz, 2H), 2.20 (s, 3H), 2.15 (s, 6H), 1.07 (d, J = 6.6 Hz, 12H); 13C NMR (125 MHz, CDCl3) δ 143.7 (t, J = 7.8 Hz, 2C), 143.3 (s, 1C), 142.0 (d, J = 255 Hz, 1C), 137.7 (s, 1C), 137.2 (d, J = 252 Hz, 2C), 134.1 (s, 1C), 132.3 (s, 1C), 131.4 (s, 2C), 130.9 (s, 2C), 129.2 (s, 2C), 125.0 (s, 2C), 118.7 (s, 1C), 28.6 (s, 2C), 23.5 (s, 4C), 20.3 (s, 1C), 19.1 (s, 2C); 19F NMR (282 MHz, CDCl3) δ −138.3 (dd, J = 6.2, 21.2 Hz, 2F), −153.0 (t, J = 21.2 Hz, 1F), −162.4 (dt, J = 6.2, 21.2 Hz, 2F). IR (KBr, cm−1) 1,489, 1,247, 1,227, 1,115.