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. 2020 Apr 30;85(11):6959–6969. doi: 10.1021/acs.joc.0c00235

Kinetic Analysis as an Optimization Tool for Catalytic Esterification with a Moisture-Tolerant Zirconium Complex

Piret Villo 1, Oscar Dalla-Santa 1, Zoltán Szabó 1, Helena Lundberg 1,*
PMCID: PMC7304901  PMID: 32352291

Abstract

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This work describes the use of kinetics as a tool for rational optimization of an esterification process with down to equimolar ratios of reagents using a recyclable commercially available zirconocene complex in catalytic amounts. In contrast to previously reported group IV metal-catalyzed esterification protocols, the work presented herein circumvents the use of water scavengers and perfluorooctane sulfonate (PFOS) ligands. Insights into the operating mechanism are presented.

Introduction:

Esterification of alcohol and carboxylic acid with the release of water is one of the most fundamental organic reactions. In synthesis, the Brønsted acid-catalyzed Fischer esterification reaction has served the community well since 1895.1 However, this equilibrium process typically requires high excess of one reagent and/or removal of water to drive the reaction to high yields, and is unsuitable for many applications. As a result, techniques that rely on stoichiometric activation of the carboxylic acid are often utilized, such as Steglich esterification and the Schotten–Baumann reaction.2 A breakthrough was seen in the early 2000s when Yamamoto and co-workers demonstrated that Lewis acids efficiently catalyze dehydrative esterification using equimolar ratios of the starting materials,3 and the field expanded rapidly to include homogeneous, heterogeneous, and micellar protocols.4 The seminal papers by Yamamoto identified chloride and alkoxide complexes based on hafnium and zirconium as the most efficient catalysts in refluxing toluene with azeotropic water removal. The required use of a dehydration technique is a common feature for protocols using early transition metal catalysts with halide and alkoxide ligands, due to their tendency to undergo hydrolytic decomposition.5 In contrast, analogous fluoroalkyl sulfonate complexes render moisture-tolerant catalysts for a variety of applications.6,7 Despite the benefits that water-stable catalysts present, particularly in the context of dehydrative reactions, Lewis acidic fluoroalkyl sulfonate metal complexes remain a surprisingly understudied catalyst class with respect to (re)activity and mechanistic action.8 While the use of the one-carbon trifluoromethane sulfonate (triflate) unit is unrestricted, its longer chain analogue perfluorooctane sulfonate (PFOS) displays bioaccumulative and toxic properties9 and is regulated by, e.g., the European Chemicals Regulation (REACH EC no. 1907/2006) and the United States Environmental Protection Agency’s (EPA) PFOA Stewardship Program.10 As a result, the use of PFOS in early transition metal catalysis is hampered despite its recently demonstrated efficiency as a ligand in, e.g. zirconium-catalyzed esterification.11

During the last decades, modern and user-friendly methods for intuitive visual kinetic analysis of organic reactions have been developed, starting with Blackmond’s pioneering reaction progress kinetic analysis (RPKA),12 and recently complemented with Burés’ variable time normalization analysis (VTNA).13 These methodologies enable facile extraction of kinetic data by the utilization of full reaction profiles for a minimal number of experiments under synthetically relevant conditions to generate an in-depth understanding of a chemical system, and have been successfully employed for the mechanistic elucidation of a wide variety of organic transformations.14 While valuable from a fundamental perspective, mechanistic insights can also be converted into strategic modifications of reaction conditions to improve yields and selectivities.15 In this work, integrated use of kinetics enables rational optimization of zirconium-catalyzed esterification to provide more insight compared to traditional screening relying on single data points, typically yield at a specified time. In addition, insight into the operating mechanism is provided based on kinetics and NMR spectroscopy.

Results and Discussion

Based on previous work using zirconocene triflate,6i we expected that the complex would display catalytic activity for dehydrative ester condensation in tetrahydrofuran (THF). Indeed, a first attempt using an equimolar ratio of benzyl alcohol and benzoic acid with a 2 mol % loading of the zirconium complex resulted in 6% benzyl benzoate after 24 h at 80 °C. Taking off from this starting point, an assessment of solvents was carried out (Supporting Information (SI)) that indicated byproduct formation at high reactant concentrations. This prompted a switch to 2-phenylethanol as the new benchmark alcohol and a lower reactant concentration for further screenings. By plotting product concentration as a function of time, it became clear that aromatic hydrocarbons, and benzotrifluoride in particular,16 were favorable for ester formation, whereas the reaction rate decreased with increasing polarity and coordination capability of the solvent (Figure 1, left). Despite low to moderate yields after 24 h in ethers and sulfolane, continuous build-up of product indicated that decomposition or irreversible inhibition of the catalyst was not taking place, suggesting that these solvents may be used as co-solvents. As expected, the reaction rate was shown to be temperature dependent, with virtually no reaction occurring at room temperature (Figure 1, right). At 60 °C, a steady accumulation of product was observed, whereas reactions at 80 and 100 °C had increasingly faster rates. An approximate 70% yield of 2-phenylethyl benzoate (3a) for the 0.5 M equimolar reaction of 1a and 2a was reached at different reaction times depending on the temperature, whereas higher yields were not observed at any of the evaluated temperatures even with prolonged reaction times. For further assessments, a reaction temperature of 80 °C was chosen to allow for compatibility with a wider range of functionalized substrates.

Figure 1.

Figure 1

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Left: solvent evaluation at 80 °C. Right: temperature evaluation. Conditions: 0.5 M benzoic acid 1a, 0.5 M 2-phenylethanol 2a, 2 mol % Zr(Cp)2(CF3SO3)2·THF, benzotrifluoride, and ambient atmosphere.

The rate dependencies on reactant concentrations were assessed with different excess experiments12 and determined to be close to zero by comparison with standard conditions (equimolar ratios of starting materials) (Figure 2, top). Furthermore, no reaction took place in the absence of zirconium. The order in [Zr(Cp)2(CF3SO3)2·THF] was estimated to be 0.75 (Figure 2, middle) for different global reaction concentrations.13 The less than first order in [Zr] suggests that the zirconium is partitioned between catalytically active species and inactive forms of higher order, similar to what has previously been described for other catalytic systems.17 The catalyst stability was probed with two same excess experiments (Figure 2, bottom),12 where the equimolar esterification of 1a and 2a (0.5 M) (circles) was compared to two separate reactions simulating 25% conversion (0.375 M 1a and 2a) in the absence (squares) and presence (triangles) of the corresponding amount of water (0.125 M). As evident, the time-adjusted profiles for the same excess experiments overlay very well with that of standard conditions, indicating that the catalyst does not undergo significant inhibition or decomposition under standard conditions.

Figure 2.

Figure 2

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Top: different excess experiments and blank experiments. Middle: determination of order in [Zr] (0.2 M equimolar substrate concentration). Bottom: same excess experiments in the absence and presence of added water.

The combined kinetic results suggested that the reaction would tolerate an increase in zirconium and reactant concentrations by a decrease in solvent volume for the formation of ester 3a, without the risk of catalyst deactivation. This was indeed found to be the case (SI) and concentrations of 1 M and 0.02 M for substrates and Zr(Cp)2(CF3SO3)2·THF, respectively, were chosen as the starting points for the substrate evaluation. Under these conditions, the turnover number (TON) for the first 6 h of the reaction time was estimated to be 19.7, corresponding to a turnover frequency (TOF) of around 3.3 h–1 (SI).18

The catalyst was found to be moisture stable, as assessed by the addition of water at the outset of the reaction (Figure 3, top left). Similar reaction rates compared to standard conditions were observed for reactions with 25 and 50 equiv of water relative to zirconium, whereas the addition of 250 molar equiv of water quenched catalysis. It has previously been demonstrated that hydrolytic decomposition of titanocene triflate and other Lewis acidic trifluoromethane sulfonate complexes can occur under certain conditions to release triflic acid,19 which can be used as a Brønsted acid catalyst for Fischer esterification.20 To probe the nature of the active catalyst in our system, a set of experiments was performed using 2 mol % of either zirconocene triflate or triflic acid (Figure 3, top right). The use of the latter resulted in a slightly faster reaction compared to the zirconium complex, hence reaching a higher yield of 3a over 24 h under standard conditions at 0.5 M. The addition of 250 equiv of water relative to the catalyst resulted in the product in 37% yield in the presence of triflic acid after 24 h, whereas only traces of 3a were observed in the presence of the zirconocene complex. Interestingly, the addition of molecular sieves (MS) suppressed the reaction rate of the zirconium-containing reaction significantly and almost completely quenched triflic acid catalysis, resulting in only trace amounts of product 3a after 24 h (Figure 3, top right; for additional information, see SI). This decelerating behavior stands in contrast to what is typically observed for dehydrative transformations, where water removal shifts the equilibrium toward product formation.6i While the origin of catalytic inhibition by molecular sieves was not the subject of further investigations, the different responses from triflic acid and zirconocene triflate suggest that the esterification is indeed zirconium-catalyzed under our conditions.21 Further support for zirconium catalysis was obtained by 13C NMR spectroscopy. While a sharp carbonyl peak was observed at 169.3 ppm for 13C(1)-labeled benzoic acid, introduction of Zr(Cp)2(CF3SO3)2·THF resulted in a downfield shift to 171.18 ppm and considerable broadening of the carbonyl peak (Figure 3, bottom), suggesting carbonyl coordination to zirconium in a fashion reminiscent of what has been observed for similar systems.17a,22 The line broadening indicates exchange between the free and coordinated carboxylic acid.

Figure 3.

Figure 3

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Top left: assessment of the effect of water. Conditions: 2 mol % Zr(Cp)2(CF3SO3)2·THF, 1 M benzoic acid, 1 M benzyl alcohol, 80 °C, toluene (dry, inert), and N2 atmosphere. Top right: comparison between zirconium catalysis and triflic acid catalysis in the presence of water and molecular sieves. Conditions: 2 mol % Zr(Cp)2(CF3SO3)2·THF or 2 mol % TfOH, 0.5 M benzoic acid, 0.5 M 2-phenylethanol, H2O (2.5 M), or 3 Å molecular sieves (MS) (0.1 g/1 mmol benzoic acid). Rates are plotted as percent of Zr-catalyzed standard conditions. Bottom: effect on carbonyl peak shift for 13C(1)-benzoic acid in the absence (left) and presence (right) of Zr(Cp)2(CF3SO3)2·THF (toluene-d8, 80 °C, 100 MHz).

A tentative catalytic cycle is depicted in Figure 4. The positive rate dependence on [Zr] and close to zero order in [benzoic acid] and [2-phenylethanol] suggest that the turnover-limiting step is found late in the catalytic cycle. Since the same excess experiments indicated insignificant product inhibition, the release of ester and water is likely not turnover-limiting under the examined conditions. Hence, our data suggest that the slow step in the catalytic cycle is the collapse of the tetrahedral intermediate resulting from nucleophilic attack by the alcohol on the coordinated carboxylic acid. This corresponds to a barrier of approximately 16.7 ± 0.5 kcal/mol (SI) and is of the same order of magnitude as what has previously been estimated by density functional theory (DFT) calculations for collapse of the tetrahedral intermediate in zirconium-catalyzed amidation.17a

Figure 4.

Figure 4

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Proposed catalytic cycle.

Using the optimized conditions, a range of carboxylic acids and alcohols were evaluated as substrates. Our model product, 2-phenylethyl benzoate (3a), was formed in a 78% yield, whereas excess alcohol or carboxylic acid resulted in increased yields, as expected for an equilibrium process (Figure 5). Benzoic acid derivatives with electron-withdrawing or electron-donating groups resulted in good to moderate yields (3b–i), tolerating ketone and aldehyde substituents. Heteroaromatic carboxylic acids delivered the expected products 3j and 3k in moderate yields, whereas carboxylic acids with pyridine, imidazole, and indazole backbones failed to form esters (vide infra). Aliphatic carboxylic acids were smoothly converted into their corresponding esters 3l–u in good to excellent yields using equimolar amounts of alcohol, including fatty acids 3m and 3n, sterically congested substrates 3o and 3p as well as diacids 3q and 3r. The anti-inflammatory drug indomethacin was converted into its respective ester 3s in a good yield, and we were pleased to see that the corresponding 2-phenethyl ester 3t of Boc-protected l-alanine retained >99% enantiomeric excess (ee), similar to what has previously been described for zirconium-catalyzed amidation.23 In contrast to the corresponding PFOS complex,11 zirconocene triflate in catalytic amounts preferentially mediates esterifications over transesterifications (SI). Gratifyingly, this differentiation in carbonyl activation allowed for selective synthesis of the unsymmetric diester 3u from the corresponding methyl ester-substituted phenylacetic acid without any transesterification product observed. The catalyst can be recycled and used for at least four consecutive cycles with negligible loss of activity for the formation of ester 3l (SI).

Figure 5.

Figure 5

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Carboxylic acid scope for esterification. Standard conditions: 2 mol % Zr(Cp)2(CF3SO3)2·THF, 1 M carboxylic acid, 1 M alcohol, benzotrifluoride, 80 °C, 24 h, and ambient atmosphere. aHigh-performance liquid chromatography (HPLC) yield, b2 equiv of alcohol, c2 equiv of acid, dtoluene as solvent, e3 equiv of alcohol, and f1:2 ratio of alcohol to carboxylic acid moieties (1:1 molar ratio of starting materials). g 1H-NMR yield.

A range of aliphatic alcohols proved to be suitable esterification coupling partners (Figure 6), including oleyl alcohol and allyl alcohol, which smoothly yielded esters 3v and 3w with both aryl and alkyl carboxylic acids. The electron-poor benzylic alcohol and the heteroaromatic 2-thiophene ethanol were acylated to form 3x and 3y in high yields. Trifluoroethanol formed the corresponding phenylacetate 3z in moderate yield, as did the sterically hindered adamantyl alcohol and cholesterol, rendering 3aa and 3ab, respectively. The corresponding benzoic and phenylacetic esters of 1-phenyl-2-propanol formed in different yields, giving benzoic ester 3ac in a moderate yield, whereas the use of (R)-(−)-1-phenyl-2-propanol (>98% ee) furnished phenylacetic ester 3ad in an excellent yield and retained enantiomeric excess.

Figure 6.

Figure 6

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Alcohol scope for esterification. Standard conditions: 2 mol % Zr(Cp)2(CF3SO3)2·THF, 1 M carboxylic acid, 1 M alcohol, benzotrifluoride, 80 °C, 24 h, and ambient atmosphere; a2 equiv of alcohol, b100 °C.

Aromatic alcohols and N-heterocyclic carboxylic acids and alcohols with a basic nitrogen failed to form esters, and the starting materials could be recovered in near-quantitative amounts. To probe the origin of this observation, nicotinic acid and phenol were added separately to standard reactions after 3 h of reaction time (Figure 7). Interestingly, whereas the effect of phenol addition on the formation rate of 3a lies within the variability for the standard reaction (SI), the addition of nicotinic acid completely quenched the catalysis, indicating that the inability of aromatic alcohols and basic heteroaromatic compounds to form esters has different origins. The inhibiting effect of nicotinic acid, occurring already at a nearly 1:1 ratio to zirconium (SI), may be explained by the formation of catalytically inactive zirconium species that could form by N-coordination of the pyridine or by coordination of a negatively charged carboxylate species after deprotonation by pyridine. On the contrary, 2-phenylethyl benzoate 3a continued to form at a similar rate after the addition of 50 equiv of phenol relative to zirconium with only traces of phenyl ester formation (see SI). As secondary and tertiary alcohols perform well as coupling partners (Figure 6), the low reactivity of the phenol is likely not a function of steric hindrance; rather, its poor nucleophilicity under non-basic conditions is expected to be the main reason for the sluggish performance.

Figure 7.

Figure 7

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Addition of phenol/nicotinic acid to esterification of benzoic acid and 2-phenylethanol. Conditions: 2 mol % Zr(Cp)2(CF3SO3)2·THF, 0.5 M carboxylic acid, 0.5 M alcohol, benzotrifluoride, 80 °C, and ambient atmosphere. Addition of 1 equiv of phenol/nicotinic acid relative to carboxylic acid after 3 h. Yields obtained by HPLC analysis.

As suggested from Figure 7, the low reactivity of phenols under standard conditions would allow for esterification of substrates substituted with unprotected aromatic alcohols. Indeed, acylation of 2-(4-hydroxyphenyl)ethanol proceeded with full selectivity for the aliphatic over the aromatic alcohol to form ester 3ae (Scheme 1).

Scheme 1. Selective Monoacylation of a Diol.

Scheme 1

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Conditions: 2 mol % Zr(Cp)2(CF3SO3)2·THF, 1 M carboxylic acid, 1 M alcohol, benzotrifluoride, 80 °C, and ambient atmosphere. Isolated yield.

In summary, this work demonstrates the use of kinetics as an integrated tool in the optimization of dehydrative esterification using a moisture-tolerant zirconium complex in catalytic amounts. The insights from the kinetic assessment of reaction parameters allowed for rational tuning of conditions and enabled an understanding of why certain substrate classes fail to form products. Furthermore, kinetics and spectroscopy were used to assess catalyst properties and provide support for the proposed mechanism. The present work adds to the general understanding of the reactivity of the understudied moisture-tolerant group (IV) metal complexes, a highly interesting compound class for future use in dehydrative catalyzed reactions.

Experimental Section

General Information

All reagents were purchased from commercial suppliers and used without further purification. Reactions were carried out in 4 mL screw neck glass vials furnished with screw caps equipped with poly(tetrafluoroethylene) (PTFE)/rubber septa, and stir bars under ambient atmosphere unless otherwise noted. Silica gel 60 Å (40–60 μm, 230–400 mesh) was used for column chromatography. All NMR spectra were recorded in CDCl3 using a Bruker AVANCE II 400 MHz or Bruker Avance 500 MHz. Chemical shifts are given in ppm relative to the residual solvent peak (1H NMR: CDCl3 δ 7.26, 13C NMR: CDCl3 δ 77.16) with multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (in hertz), and integration. Kinetic data was analyzed by Agilent 1260 Infinity Quaternary LC (Eclipse Plus 18C column, 3.5 μm, 4.6 × 100 mm2; UV detector, 265 nm) with a gradient of acetonitrile and 0.1% formic acid in Milli-Q water at a flow rate of 1 mL/min. The analytes were calibrated using a five-point calibration curve with threefold dilution between each sample in the series. HPLC with a chiral stationary phase was performed on an Agilent 1100 series instrument. High-resolution mass spectrometry analyses were performed by Thermo Scientific Q Exactive HF Hybrid Quadrupole-Orbitrap HESI or Bruker microTOF ESI, and low-resolution mass analyses by Bruker Daltonics amaZon speed no 06052 ESI.

General Esterification Procedure A for Kinetic Analysis

For 1 M reaction mixture Zr(Cp)2(CF3SO3)2·THF (0.02 mmol, 11.8 mg), benzoic acid (1 mmol, 122.1 mg), internal standard (IS) 4,4′-di-tert-butylbiphenyl (0.02 mmol, 5.3 mg), benzotrifluoride (1 mL, nondried), and 2-phenylethanol (1 mmol, 120 μL) were added into the reaction vessel under an air atmosphere. The screw cap was tightened and the vial was placed in an oil bath at 80 °C. At indicated times, 20 μL of the reaction mixture was removed with a microliter syringe and mixed with 0.5 mL of 10% v/v aqueous acetonitrile (HPLC gradient grade), filtered in a filter vial (polypropylene housing, PTFE membrane), and subjected to HPLC analysis, after which the analyte concentrations were integrated against the internal standard 4,4′-di-tert-butylbiphenyl.

Different Excess Experiments

Different excess experiments followed general esterification procedure A, where (a) 0.5 M benzoic acid, 1 M 2-phenylethanol (0.5 M excess), 0.01 M (2 mol %) Zr(Cp)2(CF3SO3)2·THF, benzotrifluoride, 80 °C, ambient atmosphere; (b) 1 M benzoic acid (0.5 M excess), 0.5 M 2-phenylethanol, 0.01 M (2 mol %) Zr(Cp)2(CF3SO3)2·THF, benzotrifluoride, 80 °C, ambient atmosphere.

Same Excess Experiments

Same excess experiments followed general esterification procedure A, where (a) standard conditions: 0.5 M benzoic acid, 0.5 M 2-phenylethanol, 0.01 M (2 mol %) Zr(Cp)2(CF3SO3)2·THF, benzotrifluoride, 80 °C, and ambient atmosphere; (b) same excess conditions mimicking 25% conversion of benzoic acid: 0.375 M benzoic acid, 0.375 M 2-phenylethanol, 0.01 M (2 mol %) Zr(Cp)2(CF3SO3)2·THF, benzotrifluoride, 80 °C, and ambient atmosphere; and (c) same excess conditions mimicking 25% conversion of benzoic acid with addition of the corresponding amount of water at the outset of the reaction: 0.125 M Milli-Q water, 0.375 M benzoic acid, 0.375 M 2-phenylethanol, 0.01 M (2 mol %) Zr(Cp)2(CF3SO3)2·THF, benzotrifluoride, 80 °C, and ambient atmosphere.

Addition Reactions

Addition reactions followed general esterification procedure A, where either (a) water 25:1 H2O/Zr (9 μL, 0.5 mmol H2O), 50:1 H2O/Zr (18 μL, 1.0 mmol H2O), or 250:1 H2O/Zr (90 μL, 5.0 mmol H2O) was added at the outset of three separate reactions (1 M equimolar ratios of benzyl alcohol and 2-phenylethanol, 1 mmol scale); (b) powdered molecular sieves (100 mg, 3 Å, flame-dried under high vacuum) were added at the outset of the reaction (0.5 M equimolar reactants, 0.5 mmol scale); (c) phenol (1 equiv, 0.5 mmol, 47 mg) was added 3 h after the onset of the reaction (0.5 M equimolar, 0.5 mmol scale); and (d) nicotinic acid (2 mol %, 3 mg, 0.02 mmol; 10 mol %, 14 mg, 0.1 mmol; 1 equiv, 123 mg, 1.0 mmol) was added 3 h after the onset of three separate reactions (0.5 M equimolar reactants, 1.0 mmol scale).

TfOH-Catalyzed Esterification

TfOH-catalyzed esterification followed general esterification procedure A for 0.5 M equimolar reaction on a 0.5 mmol scale with TfOH (1 μL, 0.02 mmol) instead of Zr(Cp)2(CF3SO3)2. For the TfOH-catalyzed reaction in the presence of molecular sieves (0.5 M equimolar reaction, 0.5 mmol scale), MS (3 Å, 50 mg) and TfOH (1 μL, 0.02 mmol) were used.

Recycling Experiments

Recycling experiments were carried out as follows. The reaction was started in accordance with general esterification procedure B on a 0.5 mmol scale. After 24 h, the vial was removed from the heated oil bath and the solvent was evaporated. The reaction mixture was thereafter extracted with 1 mL of petroleum ether (40–65 °C bp) and decanted. The opaque solution was injected into an Eppendorf tube (2 mL) and subjected to centrifugation (3000 rpm, 3 min), after which the yellow solution was removed from the black catalyst residue. This procedure was repeated for a total of three extractions. The combined product/substrate fractions were evaporated, weighed, and subjected to 1H NMR analysis using MeOD-d4 as the solvent. The black catalyst residue was dissolved in a minimal amount of dichloromethane and added to the original reaction vial and the solvent was evaporated. To the dried catalyst residue, phenylacetic acid, 2-phenylethanol, and benzotrifluoride were then added in accordance with general esterification procedure B and the reaction was stirred at 80 °C for another 24 h, after which the recycling procedure was repeated.

General Esterification Procedure B for Product Isolation

For 1 M reaction mixture, Zr(Cp)2(CF3SO3)2·THF (0.02 mmol, 11.8 mg), carboxylic acid (1 mmol), benzotrifluoride (1 mL, nondried), and alcohol (1 mmol) were added into the reaction vessel under an air atmosphere. The screw cap was tightened and the vial was placed in an oil bath at 80 °C (or the indicated temperature). After 24 h, the reaction mixture was brought to room temperature and purified by column chromatography (silica gel 60, 2–10% EtOAc/petroleum ether) unless otherwise stated.

2-Phenylethyl Benzoate (3a)

3a was synthesized according to the esterification procedure B on a 1 mmol scale using 2 equiv of 2-phenylethanol (2 mmol, 240 μL). The product was isolated as a yellow oil in 89% yield (0.89 mmol, 200.7 mg). Analytical data matches with the reported literature.24,253a: 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 2H), 7.61–7.13 (m, 8H), 4.49 (m, 2H), 3.04 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.7, 138.0, 133.0, 130.4, 129.7, 129.1, 128.7, 128.5, 126.7, 65.6, 35.4.

2-Phenylethyl 4-Nitrobenzoate (3b)

3b was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a yellow oil in 51% yield (0.511 mmol, 138 mg). Analytical data matches with the reported literature.26,273b: 1H NMR (400 MHz, CDCl3) δ 8.29–8.18 (m, 2H), 8.18–8.07 (m, 2H), 7.37–7.16 (m, 5H), 4.57 (t, J = 6.9 Hz, 2H), 3.08 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.7, 150.6, 137.5, 135.7, 130.7, 128.9, 128.7, 126.9, 123.6, 66.4, 35.2. High-resolution mass spectrometry (HRMS) (heated electrospray ionization (HESI)) m/z: [M + Na]+ calcd for C15H13NNaO4 294.0737; found 294.0761.

2-Phenylethyl 4-Cyanobenzoate (3c)

3c was synthesized according to the general esterification procedure B on a 0.5 mmol scale with toluene as the solvent. The product was isolated as a yellow solid in 40% yield (0.20 mmol, 50.8 mg). Analytical data matches with the reported literature.283c: 1H NMR (400 MHz, CDCl3) δ 8.16–8.04 (m, 2H), 7.79–7.68 (m, 2H), 7.41–7.21 (m, 5H), 4.57 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.9, 137.6, 134.2, 132.4, 130.2, 129.03, 128.8, 126.9, 118.1, 116.5, 66.3, 35.2.

2-Phenylethyl 4-Iodobenzoate (3d)

3d was synthesized according to the general esterification procedure B on a 0.5 mmol scale with toluene as the solvent. The product was isolated with minor inseparable impurities as a yellow liquid (28.8 mg). NMR-yield 13% for 3d was determined by 1H NMR with 1,4-dimethoxybenzene as the internal standard. Analytical data matches with the reported literature.273d: 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 2H), 7.69 (m, 2H), 7.35–7.20 (m, 5H), 4.51 (t, J = 6.9 Hz, 2H), 3.06 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 137.8, 137.8, 131.1, 129.9, 129.1, 128.7, 126.8, 100.8, 65.8, 35.3.

2-Phenylethyl 4-Methoxybenzoate (3e)

3e was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a yellow oil in 37% yield (0.374 mmol, 96 mg). Analytical data matches with the reported literature.293e: 1H NMR (400 MHz, CDCl3) δ 7.89 (m, 2H), 7.30–7.09 (m, 5H), 6.82 (m, 2H), 4.42 (t, J = 7.0 Hz, 2H), 3.75 (s, 3H), 2.98 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 163.4, 138.1, 131.7, 129.1, 128.6, 126.6, 122.8, 113.7, 65.3, 55.5, 35.4.

2-Phenylethyl 4-Formylbenzoate (3f)

3f was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated with minor byproducts as a yellow waxy solid (110 mg). 30% NMR-yield for 3f was obtained by 1H NMR analysis of a crude reaction mixture with 1,4-dimethoxybenzene as the internal standard. After a 24 h reaction time, the reaction mixture was dried under vacuum to remove benzotrifluoride; then, the internal standard (IS) was added (7.6 mg, 0.055 mmol), as well as CDCl3. The resulting slurry was filtered through a cotton plug, followed by immediate recording of the 1H NMR spectrum. Aromatic signals for 3f and the standard were used for the NMR-yield calculation (SI). Further purification using preparative thin-layer chromatography using an eluent of 1:15 ethyl acetate/petroleum ether (bp 40–65 °C) afforded the pure compound. 3f: 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.07 (m, 2H), 7.84 (m, 2H), 7.29–7.11 (m, 5H), 4.49 (t, J = 7.0 Hz, 2H), 3.01 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 191.7, 165.5, 139.2, 137.7, 135.2, 130.2, 129.5, 128.9, 128.6, 126.8, 66.1, 35.2. MS (electrospray ionization (ESI)) m/z: [M + Na]+ calcd for C16H14NaO3 277.08; found 277.08.

2-Phenylethyl 3-Acetylbenzoate (3g)

3g was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a yellow oil in 73% yield (0.728 mmol, 195 mg). 3g: 1H NMR (500 MHz, CDCl3) δ 8.51 (m, 1H), 8.15 (m, 1H), 8.10 (m, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.32–7.16 (m, 5H), 4.52 (t, J = 7.0 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 2.59 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 197.2, 165.7, 137.8, 137.3, 133.9, 132.3, 130.9, 129.6, 129.0, 128.9, 128.6, 126.7, 65.9, 35.2, 26.7. HRMS (HESI) m/z: [M + Na]+ calcd for C17H16NaO3 291.0992; found 291.0987.

2-Phenylethyl 2-Bromo-5-methoxybenzoate (3h)

3h was synthesized according to the general esterification procedure B on a 0.5 mmol scale. The product was isolated as a beige, waxy solid in 59% yield (0.297 mmol, 100 mg). 3h: 1H NMR (400 MHz, CDCl3) δ 7.44 (m, 1H), 7.34–7.11 (m, 6H), 6.80 (m, 1H), 4.50 (m, 2H), 3.70 (s, 3H), 3.03 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.9, 158.6, 137.7, 135.1, 132.8, 129.1, 128.6, 126.7, 119.2, 116.2, 112.0, 66.1, 55.7, 35.1. HRMS (HESI) m/z: [M + Na]+ calcd for C16H15BrNaO3 357.0097; found 357.0093.

2-Phenylethyl 2-Methoxybenzoate (3i)

3i was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a yellow oil in 71% yield (0.714 mmol, 183 mg). 3i: 1H NMR (500 MHz, CDCl3) δ 7.73 (dd, J = 7.9, 1.7 Hz, 1H), 7.42 (m, 1H), 7.32–7.25 (m, 4H), 7.24–7.19 (m, 1H), 6.97–6.90 (m, 2H), 4.50 (t, J = 7.0 Hz, 2H), 3.84 (s, 3H), 3.05 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 166.1, 159.2, 138.1, 133.5, 131.6, 129.0, 128.5, 126.5, 120.1, 120.1, 112.0, 65.3, 55.9, 35.2. HRMS (HESI) m/z: [M + H]+ calcd for C16H17O3 257.1172; found 257.1167.

2-Phenylethyl 1H-Indole-2-carboxylate (3j)

3j was synthesized according to the general esterification procedure B on a 0.5 mmol scale using 3 equiv of 2-phenylethanol (1.5 mmol, 180 μL). The product was isolated as a pale yellow solid in 34% yield (0.17 mmol, 45.1 mg). 3j: 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.55–7.19 (m, 9H), 4.65 (m, 2H), 3.18 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.0, 137.8, 136.9, 129.1, 128.7, 127.6, 127.4, 126.8, 125.6, 122.8, 120.9, 112.0, 108.9, 65.7, 35.4. HRMS (HESI) m/z: [M + H]+ calcd for C17H16NO2 266.1176; found 266.1173.

2-Phenylethyl Thiophene-2-carboxylate27 (3k)

3k was synthesized according to the general esterification procedure B on a 0.5 mmol scale. The product was isolated as a yellow oil in 61% yield (0.306 mmol, 71 mg). 3k: 1H NMR (400 MHz, CDCl3) δ 7.70 (m, 1H), 7.46 (m, 1H), 7.31–7.11 (m, 5H), 7.01 (m, 1H), 4.42 (t, J = 7.0 Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.3, 137.9, 133.9, 133.6, 132.5, 129.2, 128.7, 127.8, 126.8, 65.7, 35.4. MS (ESI) m/z: [M + Na]+ calcd for C13H12NaO2S 255.04; found 255.04.

2-Phenylethyl 2-Phenylacetate (3l)

3l was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a yellow liquid in 95% yield (0.949 mmol, 228 mg). Analytical data matches with the reported literature.303l: 1H NMR (400 MHz, CDCl3) δ 7.46–7.29 (m, 8H), 7.23 (m, 2H), 4.40 (t, J = 7.0 Hz, 2H), 3.69 (s, 2H), 3.00 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 137.7, 134.0, 129.3, 128.9, 128.5, 128.5, 127.1, 126.5, 65.3, 41.4, 35.0.

2-Phenylethyl Octadecanoate (3m)

3m was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a pale yellow solid in 90% yield (0.90 mmol, 348.6 mg). 3m: 1H NMR (400 MHz, CDCl3) δ 7.39–7.17 (m, 5H), 4.29 (m, 2H), 2.94 (m, 2H), 2.28 (m, 2H), 1.64–1.50 (m, 2H), 1.26 (s, 28H), 0.88 (t, J = 6.7 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.9, 138.0, 129.0, 128.6, 126.7, 64.8, 35.3, 34.5, 32.1, 29.84–29.80 (overlapping signals, 7C), 29.75, 29.6, 29.5, 29.4, 29.3, 25.1, 22.8, 14.3. HRMS (HESI) m/z: [M + Na]+ calcd for C26H44NaO2 411.3234; found 411.3230.

2-Phenylethyl (Z)-Octadec-9-enoate (3n)

3n was synthesized according to the general esterification procedure B on a 0.5 mmol scale. The product was isolated as a colorless oil in 92% yield (0.46 mmol, 177.7 mg). 3n: 1H NMR (400 MHz, CDCl3) δ 7.46–7.15 (m, 5H), 5.38 (m, 2H), 4.31 (t, J = 7.1 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H), 2.04 (m, 4H), 1.60 (m, 2H), 1.48–1.22 (m, 20H), 0.91 (t, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.9, 138.0, 130.2, 129.9, 129.0, 128.6, 126.7, 64.8, 35.3, 34.5, 32.1, 29.92–29.24 (overlapping signals, 8C), 27.4, 27.3, 25.1, 22.8, 14.3. HRMS (HESI) m/z: [M + Na]+ calcd for C26H42NaO2 409.3077; found 409.3070.

2-Phenylethyl Cyclohexanecarboxylate (3o)

3o was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a colorless oil in 51% yield (0.51 mmol, 118.8 mg). Analytical data matches with the reported literature.313o: 1H NMR (400 MHz, CDCl3) δ 7.53–7.01 (m, 5H), 4.31 (t, J = 7.0 Hz, 3H), 2.96 (t, J = 7.0 Hz, 3H), 2.30 (m, 1H), 1.89 (m, 2H), 1.83–1.71 (m, 2H), 1.70–1.55 (m, 2H), 1.52–1.37 (m, 2H), 1.36–1.17 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 176.1, 138.1, 129.0, 128.5, 126.6, 64.7, 43.3, 35.3, 29.1, 25.9, 25.5.

2-Phenylethyl 2,2-Dimethylpropanoate (3p)

3p was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a colorless oil in 91% yield (0.91 mmol, 187.6 mg). Analytical data matches with the reported literature.323p: 1H NMR (400 MHz, CDCl3) δ 7.38–7.17 (m, 5H), 4.28 (t, J = 6.9 Hz, 2H), 2.94 (t, J = 6.9 Hz, 2H), 1.16 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 178.6, 138.2, 129.1, 128.5, 126.6, 64.9, 38.8, 35.3, 27.3.

Diphenethyl Propanedioate (3q)

3q was synthesized according to the general esterification procedure B on a 1 mmol scale using 2 equiv of 2-phenylethanol (2 M, 2 mmol, 241 μL). The product was isolated as a colorless oil in 72% yield (0.72 mmol, 225.1 mg). Analytical data matches with the reported literature.333q: 1H NMR (400 MHz, CDCl3) δ 7.46–7.11 (m, 10H), 4.38 (m, 4H), 3.39 (s, 2H), 2.97 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.5, 137.6, 129.0, 128.7, 126.8, 66.1, 41.7, 35.0.

2-Phenethyl 4-(2-Oxo-2-phenethoxyethyl)benzoate (3r)

3r was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a yellow oil in 77% yield (0.387 mmol, 150 mg). 3r: 1H NMR (400 MHz, CDCl3) δ 8.02 (m, 2H), 7.44–7.24 (m, 10H), 7.19 (m, 2H), 4.60 (t, J = 6.9 Hz, 2H), 4.38 (t, J = 6.9 Hz, 2H), 3.70 (s, 2H), 3.14 (t, J = 6.9 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.7, 166.3, 139.2, 137.9, 137.6, 129.9, 129.4, 129.2, 129.0, 128.9, 128.6, 128.6, 126.7, 126.6, 65.6, 65.5, 41.4, 35.3, 35.0. HRMS (HESI) m/z: [M + Na]+ calcd for C25H24NaO4 411.1567; found 411.1563.

Phenethyl 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-Indol-3-yl)acetate (3s)

3s was synthesized according to the general esterification procedure B on a 0.5 mmol scale. The product was isolated as a yellow oil in 70% yield (0.352 mmol, 163 mg). 3s: 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 8.5, 2.2 Hz, 2H), 7.55 (dd, J = 8.5, 2.2 Hz, 2H), 7.31 (m, 3H), 7.21 (m, 2H), 7.08–6.95 (m, 2H), 6.78 (m, 1H), 4.43 (m, 2H), 3.91 (s, 3H), 3.74 (s, 2H), 3.01 (m, 2H), 2.42 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.8, 168.3, 156.1, 139.2, 137.7, 135.9, 134.0, 131.2, 130.9, 130.7, 129.2, 128.9, 128.5, 126.6, 115.0, 112.6, 111.7, 101.4, 65.5, 55.7, 35.1, 30.4, 13.4. HRMS (HESI) m/z: [M + Na]+ calcd for C27H24ClNaNO4 484.1286; found 484.1281.

(S)-Phenethyl 2-[(tert-Butoxycarbonyl)amino]propanoate (3t)

3t was synthesized according to the general esterification procedure B on a 0.5 mmol scale with 2 equiv of 2-phenylethanol (1 mmol, 120 μL). The product was isolated as a white crystalline solid in 40% yield (0.20 mmol, 59 mg). 3t: 1H NMR (400 MHz, CDCl3) δ 7.48–7.05 (m, 5H), 5.00 (s, 1H), 4.46–4.24 (m, 3H), 2.96 (d, J = 7.0 Hz, 2H), 1.44 (s, 9H), 1.32 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, MeOD) δ 174.89, 157.83, 139.19, 129.99, 129.49, 127.55, 80.47, 66.72, 50.64, 35.99, 28.71, 17.64. HRMS (HESI) m/z: [M + H]+ calcd for C16H24NO4 294.1699; found 294.1696. HPLC analysis was used to determine ee > 99% for 3t (Chiralcel OD-H column 250 × 4.6 mm2, 10% 2-propanol in hexane, 1.0 mL/min, λ = 225 nm, 10 μL injection volume, S isomer t(1) = 5.8 min. Compared against racemic mixture: S isomer t(1) = 5.8 min, R isomer t(2) = 6.6 min).

Methyl 4-(2-Oxo-2-phenethoxyethyl)benzoate (3u)

3u was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a colorless waxy solid in 57% yield (0.566 mmol, 169 mg) with two minor, unidentified impurities. 3u: 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.25–7.12 (m, 5H), 7.07 (m, 2H), 4.26 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 3.58 (s, 2H), 2.84 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.8, 167.0, 139.2, 137.7, 129.9, 129.5, 129.2, 129.0, 128.6, 126.7, 65.6, 52.2, 41.5, 35.1. HRMS (ESI) m/z: [M + Na]+ calcd for C18H18NaO4 321.1097; found 321.1094.

[(E)-Octadec-9-enyl] Benzoate34 (3v)

3v was synthesized according to the general esterification procedure B on a 0.5 mmol scale with 2 equiv of oleyl alcohol (1 mmol, 316 μL). The product was isolated as a colorless oil in 77% yield (0.385 mmol, 143.5 mg). 3v: 1H NMR (400 MHz, CDCl3) δ 8.05 (m, 2H), 7.55 (m, 1H), 7.44 (m, 2H), 5.36 (m, 2H), 4.32 (t, J = 6.9 Hz, 3H), 2.01 (m, 4H), 1.77 (m, 2H), 1.51–1.17 (m, 20H), 0.88 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.8, 132.9, 130.7, 130.1, 129.9, 129.7, 128.5, 65.3, 32.1 (overlapping signals, 2C), 29.8–29.4 (overlapping signals, 7C), 28.9, 27.4, 26.2, 22.8, 14.2. HRMS (HESI) m/z: [M + Na]+ calcd for C25H40NaO2 395.2921; found 395.29205.

Prop-2-enyl Octadecanoate35 (3w)

3w was synthesized according to the general esterification procedure B on a 0.25 mmol scale using 2 equiv of allyl alcohol (0.5 mmol, 34 μL). The product was isolated as a white crystalline mass in 93% yield (0.25 mmol, 81.6 mg). 3w: 1H NMR (400 MHz, CDCl3) δ 5.92 (m, 1H), 5.27 (m, 2H), 4.57 (m, 2H), 2.33 (t, J = 7.6 Hz, 2H), 1.63 (m, 2H), 1.25 (s, 26H), 0.87 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.7, 132.5, 118.2, 65.1, 34.4, 32.1, 29.84–29.83 (overlapping signals, 4C), 29.82, 29.80, 29.79, 29.74, 29.6, 29.5, 29.4, 29.3, 25.1, 22.8, 14.3. HRMS (HESI) m/z: [M + Na]+ calcd for C21H40NaO2: 347.2921; found 347.2903.

3-Methyl-4-nitrobenzyl 2-Phenylacetate (3x)

3x was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a yellow oil in 88% yield (0.877 mmol, 250 mg). 3x: 1H NMR (400 MHz, CDCl3) δ 8.16 (m, 1H), 7.66–7.38 (m, 7H), 5.41 (s, 2H), 3.97 (s, 2H), 2.79 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.0, 148.6, 141.4, 133.9, 133.6, 131.5, 129.3, 128.6, 127.3, 125.7, 124.9, 64.9, 41.3, 20.4. HRMS (ESI) m/z: [M + Na]+ calcd for C16H15NNaO4 [M + Na]+ 308.0893; found 308.0895.

2-(Thiophen-2-yl)ethyl 2-Phenylacetate36 (3y)

3y was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a clear, colorless liquid in 91% yield (0.914 mmol, 225 mg). 3y: 1H NMR (400 MHz, CDCl3) δ 7.37–7.21 (m, 5H), 7.15 (d, J = 5.2 Hz, 1H), 6.92 (m, 1H), 6.79 (m, 1H), 4.32 (m, 2H), 3.64 (s, 2H), 3.14 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.5, 139.9, 133.9, 129.4, 128.7, 127.2, 126.9, 125.7, 124.1, 65.1, 41.5, 29.3. HRMS (HESI) m/z: [M + Na]+ calcd for C14H14NaO2S 269.0607; found 269.0603.

2,2,2-Trifluoroethyl 2-Phenylacetate (3z)

3z was synthesized according to the general esterification procedure B on a 1 mmol scale with 2 equiv of 2,2,2-trifluoroethanol (2 mmol, 145 μL) at 100 °C. The product was isolated as a pale yellow oil in 32% yield (0.321 mmol, 70 mg). At 80 °C, under the same conditions, only traces of the product were isolated (ca. 1%). Analytical data matches with the reported literature.373z: 1H NMR (400 MHz, CDCl3) δ 7.33–7.07 (m, 5H), 4.37 (m, 2H), 3.62 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 132.9, 129.4, 128.9, 127.6, 123.0 (q, J = 277.2 Hz), 60.7 (q, J = 36.7 Hz), 40.7. 19F NMR (377 MHz, CDCl3) δ −73.80 (t, J = 8.5 Hz).

(3S,5S,7S)-Adamantan-1-yl 2-Phenylacetate (3aa)

3aa was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a beige oil in 29% yield (0.291 mmol, 79 mg). When the reaction was carried out at 100 °C instead of 80 °C, the product was isolated in 40% yield (0.402 mmol, 109 mg). 3aa: 1H NMR (400 MHz, CDCl3) δ 7.41–7.18 (m, 5H), 3.54 (s, 2H), 2.26–2.03 (m, 9H), 1.66 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.6, 134.9, 129.3, 128.5, 126.9, 80.9, 42.9, 41.4, 36.3, 30.9. HRMS (HESI) m/z: [M + H]+ calcd for C18H23O2 271.1693; found 271.1688.

Cholesterol Phenylacetate (3ab)

3ab was synthesized according to the general esterification procedure B on a 0.5 mmol scale. The product was isolated as a yellow solid in 49% yield (0.244 mmol, 123 mg). 3ab: 1H NMR (400 MHz, CDCl3) δ 7.42–7.20 (m, 5H), 5.37 (d, J = 5.0 Hz, 1H), 4.64 (m, 1H), 3.60 (s, 2H), 2.32 (m, 2H), 2.08–1.91 (m, 2H), 1.85 (m, 3H), 1.67–1.22 (m, 10H), 1.23–0.80 (m, 23H), 0.68 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 139.7, 134.5, 129.3, 128.6, 127.1, 122.8, 74.6, 56.8, 56.3, 50.1, 42.4, 41.8, 39.9, 39.7, 38.2, 37.1, 36.7, 36.3, 35.9, 32.0, 31.9, 28.4, 28.2, 27.9, 24.4, 23.9, 22.9, 22.7, 21.2, 19.5, 18.9, 11.9. HRMS (HESI) m/z: [M + Na]+ calcd for C35H52NaO2 527.3860; found 527.3864.

1-Phenylpropan-2-yl Benzoate (3ac)

3ac was synthesized according to the general esterification procedure B on a 1 mmol scale with 2 equiv of alcohol (138 μL, 1 mmol). The product was isolated as a yellow oil in 41% yield (0.21 mmol, 49.4 mg). Analytical data matches with the reported literature.383ac: 1H NMR (400 MHz, CDCl3) δ 8.13–7.92 (m, 2H), 7.63–7.49 (m, 1H), 7.50–7.38 (m, 2H), 7.38–7.14 (m, 5H), 5.37 (m, 1H), 3.08 (m, 1H), 2.90 (m, 1H), 1.35 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.2, 137.7, 132.9, 130.9, 129.7 (overlapping signals, 2C), 128.5, 128.4, 126.6, 72.3, 42.5, 19.6.

(R)-1-Phenylpropan-2-yl 2-Phenylacetate (3ad)

3ad was synthesized according to the general esterification procedure B on a 0.5 mmol scale. The product was isolated as a beige oil in 93% yield (0.466 mmol, 119 mg). 3ad: 1H NMR (400 MHz, CDCl3) δ 7.42–7.09 (m, 10H), 5.21 (m, 1H), 3.62 (s, 2H), 2.96 (m, 1H), 2.81 (m, 1H), 1.29 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 137.5, 134.2, 129.5, 129.3, 128.6, 128.4, 127.0, 126.5, 77.5, 77.2, 76.8, 72.0, 42.2, 41.8, 19.5. HRMS (HESI) m/z: [M + Na]+ calcd for C17H18NaO2 277.1199; found 277.1194. Enantiomeric ratio (er) 99.18:0.82 (98.4% ee) for 3ad was determined by HPLC analysis (ReproSil Chiral-NR 250 × 4.6 mm2, 5% 2-propanol in hexane, 1.0 mL/min, λ = 225 nm, 10 μL injection volume), R isomer t(1) = 10.2 min, S isomer and t(2) = 11.4 min, compared against the racemic mixture. Starting material (R)-(−)-1-phenyl-2-propanol 98.7% ee was confirmed by HPLC (Chiralcel OD-H column 250 × 4.6 mm2, 0.5% 2-propanol in hexane, 0.5 mL/min, λ = 225 nm, 10 μL injection volume, S isomer t(1) = 12.5 min, R isomer t(1) = 12.9 min, compared against the racemic mixture).

4-Hydroxyphenethyl 2-Phenylacetate (3ae)

3ae was synthesized according to the general esterification procedure B on a 1 mmol scale. The product was isolated as a colorless oil in 43% yield (0.434 mmol, 111 mg). Analytical data matches with the reported literature.393ae: 1H NMR (500 MHz, CDCl3) δ 7.39–7.22 (m, 5H), 7.03–6.95 (m, 2H), 6.77–6.71 (m, 2H), 4.31 (t, J = 7.0 Hz, 2H), 3.65 (s, 2H), 2.86 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 154.6, 133.7, 130.0, 129.32, 129.28, 128.6, 127.2, 115.5, 65.9, 41.5, 34.1.

Acknowledgments

The authors gratefully acknowledge Prof. Donna G. Blackmond for valuable comments on this work. The authors thank Merle Plassman, Joakim Romson, Jonas Ståhle and Carin Larsson for assistance with mass spectroscopy measurements. The Swedish Research Council (2015-06466), Stiftelsen Olle Engkvist Byggmästare and Magnus Bergvalls Stiftelse are gratefully acknowledged for research funding.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.0c00235.

  • 1H NMR and 13C{1H} NMR spectra of all new compounds; all known compounds made by a new route not reported in previous studies; 13C{1H} NMR analysis of Zr(Cp)2(CF3SO3)2·THF; HPLC chromatograms for esters 3t and 3ad; additional data for the kinetic evaluation of solvents, reproducibility, VTNA analysis, concentration effects, addition of water and molecular sieves, transesterification with Zr(Cp)2(CF3SO3)2·THF, and incompatible substrates; and calculations for TON/TOF, Arrhenius equation, and recycling experiments (PDF)

The authors declare no competing financial interest.

Supplementary Material

jo0c00235_si_001.pdf (4.3MB, pdf)

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