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

Article abstract of DOI:10.1021/acs.joc.0c00235

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.

Full text of DOI:10.1021/acs.joc.0c00235

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Article
Kinetic Analysis as an Optimization Tool for Catalytic
Esterification with a Moisture Tolerant Zirconium Complex
Piret Villo, Oscar Dalla-Santa, Zoltán Szabó, and Helena Lundberg
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Apr 2020
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Kinetic Analysis as an Optimization Tool for
Catalytic Esterification with a Moisture Tolerant
Zirconium Complex
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Piret Villo, Oscar Dalla-Santa, Zoltán Szabó, Helena Lundberg*
KTH Royal Institute of Technology, School of Engineering Sciences in Chemistry,
Biotechnology and Health, Teknikringen 30, S-100 44 Stockholm, Sweden.
Keywords: esterification, zirconocene, kinetics, mechanistic studies, moisture tolerant catalyst
Abstract: 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-
catalyzed esterification protocols the herein presented work circumvents the use of water
scavengers and PFOS ligands. Insights into the operating mechanism is presented.
Introduction: Esterification of an alcohol and a 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
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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 2000’s 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 ligand in e.g. zirconium-catalyzed esterification.11
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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
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by utilization of full reaction profiles for a minimal number of experiments under synthetically
relevant conditions to generate in-depth understanding of a chemical system, and have been
successfully employed for mechanistic elucidation of a wide variety of organic transformations.14
While valuable from a fundamental perspective, mechanistic insights can also be converted into
strategic modification 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.
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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 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 hours at 80 °C. Taking off from
this starting point an assessment of solvents was carried out (SI) that indicated by-product
formation at high reactant concentrations. This prompted a switch to 2-phenylethanol as 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 hours 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
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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 °C and 100 °C had increasingly faster rates. Approximately 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.
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O
O
Zr(Cp)2(CF3SO3)2 THF
(2 mol%)
O
Bn
OH
HO
Bn
+
1a
2a
3a
0.5
0.5
0.4
0.4
Benzotrifluoride
0.3
0.3
Benzotrifluoride
Toluene
Toluene
0.2
0.2
Sulfolane
Sulfolane
THF
THF
0.1
0.1
1,4-Dioxane
1,4-Dioxane
0
0
0
0
5
5
10
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15
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20
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25
25
time (h)
time (h)
Figure 1. 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,
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 0.75 (Figure 2,
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middle) for different global reaction concentrations.13 The less than 1st 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 profile for the same
excess experiments overlay very well with standard conditions, indicating that the catalyst does
not undergo significant inhibition or decomposition under standard conditions.
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Figure 2. 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.
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These 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, respectively, were chosen as starting point for the
substrate evaluation. Under these conditions, the turnover number (TON) for the first six hours of
reaction time was estimated to 19.7, corresponding to a turnover frequency (TOF) around 3.3 h-1
(SI).18
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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 equivalents of water relative to zirconium, whereas addition
of 250 molar equivalents 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 hours under standard conditions
at 0.5 M. The addition of 250 equivalents of water relative to catalyst resulted in 37% product in
the presence of triflic acid after 24 hours whereas only traces of 3a were observed in the presence
of the zirconocene complex. Interestingly, addition of molecular sieves 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 hours (Figure 3, top right; for
additional information see SI). This decelerating behavior stands in contrast to what is typically
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observed for dehydrative transformations, where water removal shifts the equilibrium towards
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 suggests
that the esterification is indeed zirconium-catalyzed under our conditions.21 Further support for
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zirconium catalysis was obtained by C-NMR spectroscopy. While a sharp carbonyl peak was
13
observed at 169.3 ppm for C(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.
1
120
100
80
60
40
20
0
0.8
0.6
0.4
0.2
0
standard conditions
25:1 [H2O]:[Zr]
50:1 [H2O]:[Zr]
TfOH
Zr
250:1 [H2O]:[Zr]
24 h
yield
24 h relative 24 h relative
yield
rate
yield
standard
6000
rate
0
2
4
6
time (h)
3Å MS
[H2O]:[Zr] 250:1
2000
1500
1000
500
0
5000
4000
3000
2000
1000
0
O
O
C13
C13
OH
OH
+ Zr(Cp)2(CF3SO3)2·THF
175 174 173 172 171 170 169 168 167 166 165
f1 (ppm)
175 174 173 172 171 170 169 168 167 166 165
f1 (ppm)
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Figure 3. Top left: Assessment of the effect of water. Conditions: 2 mol% Zr(Cp)2(CF3SO3)2 ･
5
6
7
8
THF, 1 M benzoic acid, 1 M benzyl alcohol, 80 °C, toluene (dry, inert), 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
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acid, 0.5 M 2-phenylethanol, H2O (2.5 M) or 3 Å molecular sieves (MS) (0.1 g/1 mmol benzoic
acid). Rates plotted as percent of Zr-catalyzed standard conditions. Bottom: The effect on carbonyl
peak shift for 13C(1)-benzoic acid in the absence (left) and presence (right) of Zr(Cp)2(CF3SO3)2･
THF (d8-toluene, 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, release of
Figure 4. Proposed catalytic cycle
ester and water is likely not turnover limiting under the examined conditions. Hence, our data
suggest that the slow step in the catalytic cycle may be 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 DFT calculations for collapse of the
tetrahedral intermediate in zirconium-catalyzed amidation.17a
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 78% yield whereas
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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 to 3i), 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 to their corresponding esters 3l
to 3u 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 to its respective ester 3s in good yield and we were pleased to
see that the corresponding 2-phenethyl ester 3t of Boc-protected L-Alanine retained >99% 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).
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Figure 5. 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, ambient atmosphere. a
HPLC yield, b 2 equiv. alcohol, c 2 equiv. acid, d toluene as solvent, e 3 equiv. alcohol, f 1:2 ratio of
alcohol to carboxylic acid moieties (1:1 molar ratio of starting materials).
A range of aliphatic alcohols proved to be suitable esterification coupling partners (Figure 6),
including oleyl alcohol and allyl alcohol that smoothly yielded esters 3v and 3w with both aryl and
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alkyl carboxylic acids. The electron-poor benzylic alcohol and the heteroaromatic 2-
thiopheneethanol were smoothly acylated to form 3w and 3y in high yields. Trifluoroethanol
formed the corresponding phenylacetate 3z in moderate yield, as did the sterically hindered
adamantly 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 moderate yield whereas the use of (R)-(-)-1-phenyl-2-propanol (>98% ee) furnished
phenylacetic ester 3ad in excellent yield and retained enantiomeric excess.
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Figure 6. 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, ambient atmosphere; a 2 equiv.
alcohol, b 100 °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 three hours 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), addition of
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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 near 1:1 ratio to zirconium (SI), may be explained by 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. To the
contrary, 2-phenylethyl benzoate 3a continued to form with a similar rate after the addition of 50
equivalents 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.
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0.5
0.4
0.3
0.2
0.1
0
Addition experiments
O
O
[Zr]
+ phenol
Ph
O
Bn
HO
OH +
Bn
Ph
3a: 24% (3 h)
addition (3 h)
standard
conditions
O
additive (1 equiv.)
Ph
O
Bn
Yield (24 h)
additive
+ nicotinic acid
O
60% - no additive
67% - phenol
OH
OH
0
10
20
30
24% - nicotinic acid
N
time (h)
Figure 7. 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, ambient atmosphere. Addition of 1 equiv. phenol/nicotinic acid relative
to carboxylic acid after 3 h. Yields obtained by HPLC analysis.
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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).
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Scheme 1. Selective monoacylation of a diol.
Conditions: 2 mol% Zr(Cp)2(CF3SO3)2 ･ THF, 1 M carboxylic acid, 1 M alcohol,
benzotrifluoride, 80 °C, 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 use in future catalyzed dehydrative transformations.
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 PTFE/rubber septa, and stir bars under ambient atmosphere unless
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otherwise noted. Silica gel 60 Å (40-60 μm, 230-400 mesh) was used for column chromatography.
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All NMR spectra were recorded in CDCl3 using a Bruker AVANCE II 400 MHz or Bruker Avance
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500 MHz. Chemical shifts are given in ppm relative to the residual solvent peak ( H NMR: CDCl3
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δ 7.26, C NMR: CDCl3 δ 77.16) with multiplicity (br = broad, s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), coupling constants (in Hz) and integration. Kinetic data was analyzed
by Agilent 1260 Infinity Quaternary LC (Eclipse Plus 18C column, 3.5 µm, 4.6x100mm; 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 three-fold
dilution between each sample in the series. HPLC with a chiral stationary phase was performed on
Agilent 1100 Series instrument. High resolution mass spectrometry analyses were obtained by
Thermo Scientific Q Exactive HF Hybrid Quadrupole-Orbitrap HESI or Bruker microTOF ESI,
low resolution mass analyses by Bruker Daltonic 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
4,4’-di-tert-butylbiphenyl (0.02 mmol, 5.3 mg), benzotrifluoride (1 mL, non-dried) and 2-
phenylethanol (1 mmol, 120 µL) were added into the reaction vessel under air atmosphere. The
screw cap was tightened and the vial placed in an oil bath at 80 °C. At indicated times, 20 µL
reaction mixture was removed with a microliter syringe and mixed with 0.5 mL 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 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,
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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.
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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, 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, ambient atmosphere; 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, ambient atmosphere.
Addition reactions followed general esterification procedure A, where either a) water [25:1 H2O:Zr
(9 휇L, 0.5 mmol H2O), 50:1 H2O:Zr (18 휇L, 1.0 mmol H2O), 250:1 H2O:Zr (90 휇L, 5.0 mmol
H2O) was added at the outset of three separate reactions (1 M equimolar reactants, 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 onset of reaction (0.5 M equimolar, 0.5 mmol scale); 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 onset of three separate reactions (0.5 M equimolar reactants, 1.0 mmol scale).
TfOH catalyzed esterification followed general esterification procedure A for 0.5 M equimolar
reaction in 0.5 mmol scale with TfOH (1 휇L, 0.02 mmol) instead of Zr(Cp)2(CF3SO3)2. For TfOH
catalyzed reaction in the presence of molecular sieves (0.5 M equimolar reaction, 0.5 mmol scale)
was used MS (3 Å, 50 mg) and TfOH (1 휇L, 0.02 mmol).
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Recycling experiments were carried out as follows. Reaction was started in accordance with
General esterification procedure B on a 0.5 mmol scale. After 24 hours the vial was removed from
the heated oil bath and the solvent was evaporated. The reaction mixture was thereafter extracted
with 1 mL petroleum ether (40-65 oC 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 3
extractions. The combined product/substrate fractions were evaporated, weighed and subjected to
1H-NMR analysis using d4-MeOD as 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 was then added phenylacetic acid, 2-phenylethanol and
benzotrifluoride in accordance with General esterification procedure B and the reaction was stirred
at 80 oC for another 24 hours, after which the recycling procedure was repeated.
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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,
non-dried) and alcohol (1 mmol) were added into the reaction vessel under air atmosphere. The
screw cap was tightened and the vial 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) was synthesized according to the esterification procedure B in 1
mmol scale, using 2 equiv. of 2-phenylethanol (2 mmol, 240 µL). The product was isolated as a
yellow oil in 89% (0.89 mmol, 200.7 mg). Analytical data matches with reported literature.24, 25
3a: 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 2H), 7.61–7.13 (m, 8H), 4.49 (m, 2H), 3.04 (m, 2H).
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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.
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2-Phenylethyl 4-nitrobenzoate (3b) was synthesized according to the general esterification
procedure B in 1 mmol scale. The product was isolated as yellow oil in 51% (0.511 mmol, 138
mg). Analytical data matches with reported literature.26, 27 3b: 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. HRMS (HESI) m/z: [M+Na]+ Calcd for C15H13NNaO4 294.0737; Found
294.0761
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2-Phenylethyl 4-cyanobenzoate (3c) was synthesized according to the general esterification
procedure B in 0.5 mmol scale with toluene as solvent. The product was isolated as yellow solid
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in 40% (0.20 mmol, 50.8 mg). Analytical data matches with reported literature.28 3c: H 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) was synthesized according to the general esterification
procedure B in 0.5 mmol scale with toluene as 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 internal standard. Analytical data matches with reported
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literature.27 3d: H 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.
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2-Phenylethyl 4-methoxybenzoate (3e) was synthesized according to the general esterification
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procedure B in 1 mmol scale. The product was isolated as a yellow oil in 37% (0.374 mmol, 96
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mg). Analytical data matches with reported literature.29 3e: H NMR (400 MHz, CDCl3) δ 7.89
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(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
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Hz, 2H). C{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) was synthesized according to the general esterification
procedure B in 1 mmol scale. The product was isolated with minor by-products as a yellow waxy
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solid (110 mg). 30% NMR-yield for 3f was obtained by H-NMR analysis of a crude reaction
mixture with 1,4-dimethoxybenzene as internal standard. After 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 1H-NMR spectrum. Aromatic signals for 3f and
standard were used for NMR-yield calculation (SI). Further purification using preparative thin
layer chromatography using an eluent of 1:15 ethyl acetate:petroleum ether (bp 40-65 oC) 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 (ESI)
m/z: [M+Na]+ Calcd for C16H14NaO3 277.08; Found 277.08.
2-Phenylethyl 3-acetylbenzoate (3g) was synthesized according to the general esterification
procedure B in 1 mmol scale. The product was isolated as yellow oil in 73% (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}
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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.
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2-Phenylethyl 2-bromo-5-methoxybenzoate (3h) was synthesized according to the general
esterification procedure B in 0.5 mmol scale. The product was isolated as beige, waxy solid in
59% (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) was synthesized according to the general esterification
procedure B in 1 mmol scale. The product was isolated as yellow oil in 71% (0.714 mmol, 183
1
mg). 3i: H 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) was synthesized according to the general
esterification procedure B in 0.5 mmol scale using 3 equiv. of 2-phenylethanol (1.5 mmol, 180
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μL). The product was isolated as pale yellow solid in 34% (0.17 mmol, 45.1 mg). 3j: H 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
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(m, 2H). C{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.
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2-Phenylethyl thiophene-2-carboxylate27 (3k) was synthesized according to the general
esterification procedure B in 0.5 mmol scale. The product was isolated as yellow oil in 61% (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.
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2-Phenylethyl 2-phenylacetate (3l) was synthesized according to the general esterification
procedure B in 1 mmol scale. The product was isolated as yellow liquid in 95% (0.949 mmol, 228
mg). Analytical data matches with reported literature.30 3l: 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) was synthesized according to the general esterification
procedure B in 1 mmol scale. The product was isolated as pale yellow solid in 90% (0.90 mmol,
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348.6 mg). 3m: H 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) was synthesized according to the general esterification
procedure B on a 0.5 mmol scale. The product was isolated as colourless oil in 92% (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
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(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) was synthesized according to the general
esterification procedure B in 1 mmol scale. The product was isolated as colourless oil in 51% (0.51
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mmol, 118.8 mg). Analytical data matches with reported literature.31 3o: H 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) was synthesized according to the general
esterification procedure B in 1 mmol scale. The product was isolated as colourless oil in 91% (0.91
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mmol, 187.6 mg). Analytical data matches with reported literature.32 3p: H 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) was synthesized according to the general esterification
procedure B in 1 mmol scale, using 2 equiv. of 2-phenylethanol (2 M, 2 mmol, 241 μL). The
product was isolated as colourless oil in 72% (0.72 mmol, 225.1 mg). Analytical data matches with
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reported literature.33 3q: H 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) was synthesized according to the
general esterification procedure B in 1 mmol scale. The product was isolated as yellow oil in 77%
(0.387 mmol, 150 mg). 3r: 1H NMR (400 MHz, CDCl3) δ 8.02 (m, 2H), 7.44–7.24 (m, 10H), 7.19
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(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),
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2.97 (t, J = 6.9 Hz, 2H). C{1H} NMR (101 MHz, CDCl3) δ 170.7, 166.3, 139.2, 137.9, 137.6,
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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.
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Phenethyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate (3s) was
synthesized according to the general esterification procedure B in 0.5 mmol scale. The product
was isolated as yellow oil in 70% (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) was synthesized according to
the general esterification procedure B in 0.5 mmol scale with 2 equiv. of 2-phenylethanol (1 mmol,
120 μL). The product was isolated as white crystalline solid in 40% (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
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Hz, 2H), 1.44 (s, 9H), 1.32 (d, J = 7.0 Hz, 3H). C{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 250x4.6 mm, 10% 2-propanol in hexane, 1.0
mL/min, 휆=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).
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Methyl 4-(2-oxo-2-phenethoxyethyl)benzoate (3u) was synthesized according to the general
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esterification procedure B in 1 mmol scale. The product was isolated as colourless waxy solid in
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57% (0.566 mmol, 169 mg) with two minor, unidentified impurities. 3u: H NMR (400 MHz,
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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),
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3.58 (s, 2H), 2.84 (t, J = 6.9 Hz, 2H). C{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) was synthesized according to the general esterification
procedure B in 0.5 mmol scale with 2 equiv. of oleyl alcohol (1 mmol, 316 μL). The product was
isolated as colourless oil in 77% (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) was synthesized according to the general esterification
procedure B in 0.25 mmol scale, using 2 equiv. allyl alcohol (0.5 mmol, 34 µL). The product was
isolated as white crystalline mass in 93% (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),
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0.87 (m, 3H). C{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.
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3-Methyl-4-nitrobenzyl 2-phenylacetate (3x) was synthesized according to the general
esterification procedure B in 1 mmol scale. The product was isolated as yellow oil in 88% (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.
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2-(Thiophen-2-yl)ethyl 2-phenylacetate36 (3y) was synthesized according to the general
esterification procedure B in 1 mmol scale. The product was isolated as clear, colourless liquid in
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91% (0.914 mmol, 225 mg). 3y: H 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) was synthesized according to the general esterification
procedure B in 1 mmol scale with 2 equiv. of 2,2,2-trifluoroethanol (2 mmol, 145 μL) at 100 °C.
The product was isolated as pale yellow oil in 32% (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 reported
1
literature.37 3z: H 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) was synthesized according to the general
esterification procedure B in 1 mmol scale. The product was isolated as beige oil in 29% (0.291
mmol, 79 mg). When the reaction was carried out at 100 °C instead of 80 °C, the product was
1
isolated in 40% (0.402 mmol, 109 mg). 3aa: H NMR (400 MHz, CDCl3) δ 7.41–7.18 (m, 5H),
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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.
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Cholesterol phenylacetate (3ab) was synthesized according to the general esterification
procedure B in 0.5 mmol scale. The product was isolated as yellow solid in 49% (0.244 mmol, 123
1
mg). 3ab: H 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
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(m, 23H), 0.68 (s, 3H). C{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) was synthesized according to the general esterification
procedure B in 1 mmol scale with 2 equiv. of alcohol (138 μL, 1 mmol). The product was isolated
as yellow oil in 41% (0.21 mmol, 49.4 mg). Analytical data matches with reported literature.38
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3ac: H 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) was synthesized according to the general
esterification procedure B in 0.5 mmol scale. The product was isolated as beige oil in 93% (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
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(HESI) m/z: [M+Na]+ Calcd for C17H18NaO2 277.1199; Found 277.1194. Er 99.18:0.82 (98.4%
ee) for 3ad was determined by HPLC analysis (ReproSil Chiral-NR 250x4.6 mm, 5% 2-propanol
in hexane, 1.0 mL/min, 휆=225 nm, 10 µL injection volume), R isomer t(1)= 10.2 min, S isomer
t(2)= 11.4 min; compared against racemic mixture. Starting material (R)-(-)-1-phenyl-2-propanol
98.7% ee was confirmed by HPLC (Chiralcel OD-H column 250x4.6 mm, 0.5% 2-propanol in
hexane, 0.5 mL/min, 휆=225 nm, 10 µL injection volume, S isomer t(1)= 12.5 min, R isomer t(1)=
12.9 min; compared against racemic mixture.
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4-Hydroxyphenethyl 2-phenylacetate (3ae) was synthesized according to the general
esterification procedure B in 1 mmol scale. The product was isolated as colourless oil in 43%
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(0.434 mmol, 111 mg). Analytical data matches with reported literature.39 3ae: H 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.
Supporting Information Available: [PDF] This material is available free of charge at
http://pubs.acs.org
13
1H NMR and C{1H} NMR spectra of all new compounds, all known compounds made by a
new route not reported in previous literature, and 13C{1H} NMR analysis of
Zr(Cp)2(CF3SO3)2·THF. HPLC chromatograms for esters 3t and 3ac. 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. Calculations for TON/TOF, Arrhenius equation and recycling experiments.
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Corresponding Author
* hellundb@kth.se
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Acknowledgements
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The authors gratefully acknowledge Prof. Donna G. Blackmond for valuable comments on this
work. We thank Merle Plassmann, Joakim Romson and Carin Larsson for assistance with mass
spectroscopy measurements and the Swedish Research Council (2015-06466) and Stiftelsen Olle
Engkvist Byggmästare for funding the research.
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