Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols and Hydroxide Catalyzed by a Ruthenium N-Heterocyclic Carbene Complex

Article abstract of DOI:10.1021/acs.joc.6b02105

Primary alcohols have been reacted with hydroxide and the ruthenium complex [RuCl₂(IiPr)(p-cymene)] to afford carboxylic acids and dihydrogen. The dehydrogenative reaction is performed in toluene, which allows for a simple isolation of the products by precipitation and extraction. The transformation can be applied to a range of benzylic and saturated aliphatic alcohols containing halide and (thio)ether substituents, while olefins and ester groups are not compatible with the reaction conditions. Benzylic alcohols undergo faster conversion than other substrates, and a competing Cannizzaro reaction is most likely involved in this case. The kinetic isotope effect was determined to be 0.67 using 1-butanol as the substrate. A plausible catalytic cycle was characterized by DFT/B3LYP-D3 and involved coordination of the alcohol to the metal, β-hydride elimination, hydroxide attack on the coordinated aldehyde, and a second β-hydride elimination to furnish the carboxylate.

Full text of DOI:10.1021/acs.joc.6b02105

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Article
Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols
and Hydroxide Catalyzed by a Ruthenium N-Heterocyclic Carbene Complex
Carola Santilli, Ilya S. Makarov, Peter Fristrup, and Robert Madsen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02105 • Publication Date (Web): 29 Sep 2016
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Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols and
Hydroxide Catalyzed by a Ruthenium N-Heterocyclic Carbene Complex
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Carola Santilli, Ilya S. Makarov, Peter Fristrup and Robert Madsen*
Department of Chemistry, Technical University of Denmark, DKꢀ2800 Lyngby, Denmark
Eꢀmail: rm@kemi.dtu.dk
_____________________________________________________________________________
Abstract
Primary alcohols have been reacted with hydroxide and the ruthenium complex [RuCl2(IiPr)(pꢀ
cymene)] to afford carboxylic acids and dihydrogen. The dehydrogenative reaction is performed
in toluene which allows for a simple isolation of the products by precipitation and extraction.
The transformation can be applied to a range of benzylic and saturated aliphatic alcohols
containing halide and (thio)ether substituents while olefins and ester groups are not compatible
with the reaction conditions. Benzylic alcohols undergo faster conversion than other substrates
and a competing Cannizzaro reaction is most likely involved in this case. The kinetic isotope
effect was determined to be 0.67 by using 1ꢀbutanol as the substrate. A plausible catalytic cycle
was characterized by DFT/B3LYPꢀD3 and involved coordination of the alcohol to the metal, βꢀ
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hydride elimination, hydroxide attack on the coordinated aldehyde and a second βꢀhydride
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elimination to furnish the carboxylate.
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INTRODUCTION
The oxidation of a primary alcohol to a carboxylic acid constitutes one of the fundamental
textbook reactions in organic chemistry. The oxidation is usually carried out with a
stoichiometric metal oxide or by a catalytic procedure where either a metal, a metal complex or
an organic molecule serves as the catalyst in the presence of a cheap stoichiometric oxidant such
as dioxygen, periodate or hypochlorite.1
In recent years, dehydrogenation with the liberation of dihydrogen has gained significant
attention as an alternative method for the oxidation of alcohols. This has led to very efficient
syntheses of amides, imines, esters and acetals from primary alcohols where no stoichiometric
additive or oxidant is employed and with dihydrogen as the only byproduct.2 The
transformations are usually carried out in the presence of various ruthenium complexes which
dehydrogenate the primary alcohol to the corresponding aldehyde. Subsequent reaction with an
amine or an alcohol furnishes imines and acetals while amides and esters are obtained when the
transformation is accompanied by another dehydrogenation.2
If water is employed as the nucleophile the dehydrogenation from a primary alcohol may
form the corresponding carboxylic acid. The development of this transformation, however, has
been more slow. First, several rhodium complexes with a diolefin amido ligand were shown to
catalyze the oxidation, but the reaction required a ketone, an alkene, dioxygen or nitrous oxide
as a hydrogen scavenger.3 In 2013, 0.2% of a ruthenium PNN pincer complex was employed to
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catalyze the oxidation in aqueous solution in the absence of a hydrogen scavenger4 and the
reaction has recently been extended to the synthesis of amino acids from amino alcohols.5 The
mechanism of this transformation has been studied computationally and the reaction was shown
to proceed through the aldehyde which reacts with water to form a gemꢀdiol followed by
dehydrogenation to the carboxylic acid.6 Since then, 1% of a ruthenium benzimidazolylidene
complex7 and 0.1 – 1% of several ruthenium PNP pincer complexes8 were presented as catalysts
for the oxidation under analogous conditions and it was shown that ruthenium carbonyl
complexes may be formed during the reaction by decarbonylation of the aldehyde.8b In the same
way, aqueous ethanol has been subjected to the catalytic dehydrogenation with similar
ruthenium PNP pincer complexes in order to produce dihydrogen from a renewable alcohol.9
Palladium on carbon has also been applied as a catalyst with a 5 mol% palladium loading for the
carboxylic acid synthesis where a reduced pressure was necessary in order to achieve a good
yield.10 In all these oxidations of primary alcohols to carboxylic acids a stoichiometric amount
of sodium hydroxide is included and the immediate product is therefore the sodium salt of the
acid. This makes the overall transformation energetically more favored and prevents
deactivation of the catalyst by the acid as well as formation of the ester by a competing
pathway.6 Furthermore, the dehydrogenations are all performed with water as the solvent which
in some cases constitute a limitation in the oxidation of more lipophilic alcohols.7,8
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Figure 1. Structure of complex 1.
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In 2008 we introduced ruthenium Nꢀheterocyclic carbene complexes for the dehydrogenation
of primary alcohols and complex 1 has been used as a (pre)catalyst for the synthesis of amides,11
esters12 and imines (Figure 1).13 The mechanism for the formation of amides has been studied in
detail by experimental and theoretical methods where it has been shown that both the aldehyde
and the hemiaminal intermediate stay coordinated to the metal during the catalytic cycle.14 We
envisioned that this transformation could be extended to the formation of carboxylic acids by
performing the dehydrogenation in the presence of water or hydroxide. Herein, we report a full
account on the dehydrogenative synthesis of carboxylic acids with complex 1 and describe a
theoretical investigation of the reaction mechanism.
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RESULTS AND DISCUSSION
The formation of a carboxylic acid was first observed during our optimization of the ester
synthesis from primary alcohols. The optimized conditions for this transformation required 1 –
5% of 1, 1 – 5% of PCy3, 3 – 15% of KOtBu and a strong base (Mg3N2 or K3PO4) in refluxing
toluene,12a but when the bases were replaced by a stoichiometric amount of KOH the
corresponding carboxylic acid was obtained. In this way, 2ꢀphenylethanol was converted into
phenylacetic acid in 75% yield (Scheme 1).
Scheme 1. Conditions for Dehydrogenative Oxidation of Primary Alcohols
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The yield deteriorated to only 20% when the same reaction was performed in refluxing
xylene. With more polar solvents such as dioxane, diglyme and tertꢀamyl alcohol, the
transformation did not go to completion in 24 h. This is most likely due to inhibition of the
ruthenium catalyst by the formed carboxylate which is soluble in more polar solvents, but
precipitates as the potassium salt in toluene. Lower conversion of 2ꢀphenylethanol was also
observed when the base was changed to LiOH or NaOH, or when the phosphine was replaced by
PPh3 or dppp. A stoichiometric amount of the base is important since the reaction only gave
52% conversion of the alcohol with 0.5 equiv. of KOH. The ruthenium (pre)catalyst 1 could be
used in loadings ranging from 0.1 to 2%, but a loading of 1% was often necessary to secure full
conversion in 24 h. The conditions were also investigated with benzyl alcohol as the substrate
since the oxidation in this case is faster and gave a 79% isolated yield of benzoic acid in only 6
h. However, the yield decreased with a lower catalyst loading or when a higher amount of KOH
was used. Attempts to use water as a coꢀsolvent were unsuccessful since the oxidation of a 1 M
aqueous solution of benzyl alcohol or 1ꢀbutanol in both cases only gave 15% yield of the
carboxylic acid. Therefore, the optimized conditions for the oxidation employ 1% of 1, 1% of
PCy3·HBF4 and 1.2 equiv. of KOH in refluxing toluene under a flow of argon. The organic
solvent allows for an easy isolation of the carboxylic acids which are first precipitated as the
potassium salts and then converted into the acids with hydrochloric acid.
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With these conditions in hand a number of primary alcohols were subjected to the oxidation
to investigate the substrate scope and limitations. First, several paraꢀsubstituted benzyl alcohols
were converted into the corresponding benzoic acids (Table 1). The oxidation of pꢀmethylꢀ and
pꢀchlorobenzyl alcohol proceeded smoothly and gave the carboxylic acids in high yields (entries
1 and 2). The same transformation with pꢀbromoꢀ and pꢀiodobenzyl alcohol gave slightly lower
yields due to a competing dehalogenation to benzoic acid (entries 3 and 4). When pꢀ
hydroxybenzyl alcohol was submitted to the conditions the oxidation stopped at the aldehyde
level and produced pꢀhydroxybenzaldehyde (result not shown). This was also observed with two
equiv. of KOH and is presumably due to deprotonation of the phenol. With an ether or a
thioether in the para position the oxidation again went to the carboxylic acid level (entries 5 and
6). pꢀPhenylꢀ and pꢀ(trifluoromethyl)benzyl alcohol also furnished the corresponding carboxylic
acids although in a more moderate yield with the former (entries 7 and 8). In entries 5 – 8 traces
of the aldehyde and the corresponding decarbonylation product were also observed by GCꢀMS.
In all the reactions in Table 1 the starting alcohol was fully converted after 6 h. Methyl pꢀ
(hydroxymethyl)benzoate was also subjected to the oxidation conditions, but in this case only
hydrolysis of the ester occurred to produce pꢀ(hydroxymethyl)benzoic acid and no oxidation of
the alcohol was observed even with an excess of KOH. This is most likely due to precipitation
of the potassium salt of pꢀ(hydroxymethyl)benzoic acid.
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Table 1. Dehydrogenative Oxidation of Benzyl Alcohols to Benzoic Acidsa
entry
1
substrate
product
isolated yield (%)
88
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a
Conditions: Alcohol (2.5 mmol), KOH (3 mmol), 1 (0.025 mmol), PCy3·HBF4 (0.025 mmol),
b
c
toluene, reflux, 6 h, then aq. HCl. Benzoic acid also formed in 5% yield. Benzoic acid also
formed in 12% yield.
A number of aliphatic primary alcohols were also converted to the corresponding carboxylic
acids (Table 2) and in this case a reaction time of 18 h was necessary to secure full conversion
since these alcohols are less reactive than the benzylic substrates. Linear alcohols gave good
yields (entries 1 and 2) and the same was observed with substituents in the 3 position (entries 3
and 4). Alcohols with substituents in the 2 position gave slightly lower yields (entries 5 – 7)
while the dehydrogenation of hexꢀ5ꢀenꢀ1ꢀol was accompanied by hydrogenation of the olefin
(entry 8). Primary alcohols with a chiral center in the 2 position are intriguing substrates since
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the stereochemistry may not be retained in the aldehyde intermediate under the basic conditions.
Indeed, oxidation of (S)ꢀ2ꢀmethylbutanꢀ1ꢀol gave fully racemic 2ꢀmethylbutanoic acid (entry 9)
while (ꢀ)ꢀcisꢀmyrtanol afforded the thermodynamically more stable (+)ꢀtransꢀdihydromyrtenic
acid with complete inversion of stereochemistry (entry 10). No competing aldol condensation
from the intermediate aldehyde was observed in any of the examples in Table 2. All the
carboxylic acids in Table 1 and 2 were isolated by precipitation of the potassium salts followed
by treatment with aqueous hydrochloric acid, extraction with ethyl acetate and removal of the
solvent. This yielded sufficiently pure products that did not require further purification by
chromatography, distillation or recrystallization.
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Table 2. Dehydrogenative Oxidation of Aliphatic Alcohols to Carboxylic Acidsa
entry
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substrate
product
isolated yield (%)
82
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a
Conditions: Alcohol (2.5 mmol), KOH (3 mmol), 1 (0.025 mmol), PCy3·HBF4 (0.025 mmol),
toluene, reflux, 18 h, then aq. HCl. b Yield determined by 1H NMR.
The evolution of dihydrogen was measured by reacting 1.5 mmol of benzyl alcohol in a
Schlenk tube connected to a burette filled with water. A total gas volume of 64 mL was
collected, corresponding to approximately 2.7 mmol, which confirms that two equivalents of
dihydrogen are released in the reaction (Figure 2).
Figure 2. Development of dihydrogen over time.
The intermediate aldehyde was detected when monitoring the oxidation of benzyl alcohol by
GC. Actually, in the beginning of the reaction up to 26% of benzaldehyde accumulated in the
mixture (Figure 3). The aldehyde is a substrate for the transformation which was shown by
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subjecting benzaldehyde to the standard oxidation conditions which produced benzoic acid in
72% yield (Scheme 2). Notably, GC measurements of this transformation revealed that
benzaldehyde was rapidly converted into a mixture of benzyl alcohol and benzoic acid followed
by slow conversion of the alcohol to the acid (Figure 4).
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Figure 3. Benzaldehyde formation in the oxidation of benzyl alcohol.
Scheme 2. Dehydrogenative Oxidation of Benzaldehyde
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Figure 4. Benzyl alcohol formation in the oxidation of benzaldehyde.
These observations raise the question whether a Cannizzaro reaction is involved in the
oxidation of benzyl alcohols.15 Therefore, benzaldehyde was also reacted with KOH in the
absence of complex 1 (Scheme 3). After 1 h the aldehyde was completely consumed and a
mixture of benzoic acid and benzyl alcohol was formed according to 1H NMR. This clearly
illustrates that the Cannizzaro reaction is possible under the oxidation conditions and it may
explain the shorter reaction time with benzyl alcohols as compared to aliphatic alcohols.16
Scheme 3. Cannizzaro Reaction with Benzaldehyde
In an attempt to gain more experimental information about the reaction mechanism a
Hammett study with paraꢀsubstituted benzyl alcohols was set up in line with our earlier
investigations.14 Unfortunately, it was never possible to obtain a linear correlation between the σ
values for the different para substituents and the rate constants. This indicates that several
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mechanistic pathways take part in the overall transformation which again suggests the
involvement of the Cannizzaro reaction.
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We have previously determined the KIE to 2.29 for the amide synthesis with complex 1 from
1ꢀbutanol and benzyl amine.14 In that case it was necessary to measure the initial rates separately
for the deuterated and the nonꢀdeuterated alcohols since scrambling of the a protons occurs
rapidly when a mixture of labelled and nonꢀlabelled alcohol is reacted with complex 1.14 The
same scrambling was observed when benzyl alcoholꢀd2 was allowed to compete with nonꢀ
deuterated benzyl alcohol in a reaction with KOH and complex 1 in refluxing toluene.
Therefore, the KIE was also in this case measured in a nonꢀcompetitive manner where 1ꢀbutanol
was used as the alcohol. In two separate experiments 1ꢀbutanolꢀd10 and 1ꢀbutanol were reacted
with KOD and KOH, respectively, which afforded a KIE of 0.67. This is an unexpectedly low
value for a KIE where the deuterated substrates react 1.5 times faster than the nonꢀdeuterated
counterparts. Since deuteroxide is more basic than hydroxide17 it may indicate that the basicity
or the nucleophilicity of the base is important in the rateꢀdetermining step.
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To obtain a more detailed knowledge about the reaction pathway a density functional theory
(DFT) study was also included in the investigation in line with our earlier work.14 Since the
catalytic system includes a bulky phosphine ligand (PCy3) it is important to use a functional
which takes into account the dispersion interactions. Two wellꢀknown functionals B3LYPꢀD318
and M0619 were investigated where the former in general performed faster while with the latter
some optimizations failed to converge. As a consequence, the B3LYPꢀD3 functional in
combination with the LACVP*+ basis set20 was chosen.
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For calculating the Gibbs free energy (ꢀGtot), a combination of the gas phase energy of the
optimized structure (Egas), single point solution phase energy (Esol) and the Gibbs free energy
obtained from the frequency calculations at 383 K (ꢀG383K) was used (Eq. 1).21
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ꢀGtot = ꢀG383K + (Esol – Egas)
(1)
Two phosphine ligands that have similar electronic properties were used in the theoretical
studies. For the faster screening of the possible ligand orientations a small PMe3 ligand was
used. To better take into account steric properties of the phosphine ligand, the phosphine used in
the experimental studies (PCy3) was employed for the calculations of the catalytic cycle. Since it
was demonstrated in the experimental studies that the Cannizzaro reaction is a possible pathway
for the benzylic alcohols, a simple aliphatic alcohol ethanol was chosen as a model substrate
with which the reaction is very likely to proceed exclusively through the rutheniumꢀcatalyzed
pathway. Finally, instead of a free hydroxide ion, a hydroxide ion solvated with water molecules
was used because it was shown that the addition of water molecules helps to obtain results
which are closer to the experimental data.22 Even though the experiments were conducted with
toluene as a solvent, there is still some water present in the system because KOH contains 0.35 –
0.55 equivalents of H2O per equivalent of the hydroxide depending on the quality of the base
(85–90% of KOH in the reactant used in the study). Additionally, the hydroxide ion can be
solvated by the alcohol molecules that for simplicity are replaced by the water molecules in the
calculations. All these facts allow us to assume that the hydroxide ion involved in the catalytic
cycle is always solvated throughout the reaction. It was found that with either two or three water
molecules solvating the hydroxide ion, the energy of the step involving the solvated hydroxide
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remains almost the same. Therefore, a hydroxide ion solvated with two water molecules was
used in the computational study.
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During the initiation step, the dichloride ruthenium precatalyst 1 loses a molecule of
pꢀcymene14 and based on the literature precedents23 the two chlorine atoms are believed to be
replaced by a hydride and an alkoxide to give a highly electronically unsaturated 12ꢀe– complex.
This complex may be stabilized by coordinating a molecule of the phosphine and a hydroxide
ion. The resulting 16ꢀe– species should have a vacant coordination site cis to the alkoxide in
order for the βꢀhydride elimination to proceed. Out of all possible isomers, complex 3 (Scheme
4) with the phosphine ligand in the apical position has the lowest energy. After the βꢀhydride
elimination, complex 4 should be formed which turns out to be also the most favorable
configuration out of all possible isomers of species 4. These results correlate nicely with our
previous studies on the rutheniumꢀcatalyzed dehydrogenative amidation reaction which
demonstrated that the apical position for the phosphine ligand is the most favorable in the
similar ruthenium complexes.14 Since complexes 3 and 4 are the most stable species, we decided
to continue the studies with the following ligand orientation: the NHC and the phosphine ligands
occupy the two apical positions, while an aldehyde (or an alkoxide), a hydroxide ion cis to the
aldehyde, a hydride cis to the hydroxide ion, and another hydride (or an empty spot) cis to the
hydride all lie in one plane.
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Scheme 4. Most Stable Orientation of Ligands in Complexes 3 and 4
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After having determined the orientation of the ligands, the energy profile of the plausible
catalytic cycle with PCy3 instead of PMe3 was calculated (Scheme 5). After the initiation step
the alkoxideꢀdihydride complex 3 is formed and enters the catalytic cycle. As a formally 16ꢀe–
species 3 is stabilized by the agostic interaction of the ruthenium center with the C–H bond of
the αꢀcarbon atom of the alkoxide. This interaction leads to the elongation of the C–H bond by
0.089 Å as compared to the second nonꢀagostic bond at the same carbon atom and consequently
facilitates the βꢀhydride elimination which has the activation barrier of 38.4 kJ·mol–1.
Scheme 5. Proposed Catalytic Cycle
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After the βꢀhydride elimination, complex 4 is formed which contains a molecule of aldehyde
bound to ruthenium through the π system of the C=O double bond. Since the hydroxide ligand is
coordinated cis to the aldehyde, it can act as an internal nucleophile and attack the aldehyde to
give a hemiacetal. However, in order for this addition to occur, the aldehyde complex should
isomerize first for the proper alignment of the aldehyde and hydroxide ligands (Scheme 6). This
isomerization is exergonic by –11.4 kJ·mol–1 and it proceeds through complex 4b (with the
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aldehyde bound to ruthenium through the oxygen atom) which is 29.8 kJ·mol–1 higher in energy
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than the starting species 4a.
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Scheme 6. Isomerization of the Aldehyde Complex
We were unable to locate the transition state for the addition of hydroxide to the aldehyde due
to the sharp energy change that accompanied the shift in the coordination mode of the aldehyde
during the addition. While in species 4c the distances between the ruthenium center and the
atoms of the carbonyl group is comparable (rRu–O = 2.280 Å, rRu–C = 2.213 Å), the Ru–C bond
considerably elongates when the hydroxide comes closer to the carbonyl carbon. In order to
estimate the energy barrier of the addition, we performed a relaxed coordinate scan with the
simultaneous constrains on the distance between the hydroxide oxygen and carbonyl carbon
atom as well as the angle between the hydroxide oxygen atom and the C=O double bond (See
Supporting Information).
From the coordinate scan, the activation barrier for the addition of the hydroxide can be
estimated to be approx. 40 kJ·mol–1. The hemiacetal in species 5 is deprotonated by the cisꢀ
hydride to give an H2 complex 6 which exists in equilibrium with a trihydride species (Figure 5).
Once this species loses a molecule of H2, a spontaneous βꢀhydride elimination occurs to give a
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carboxylate and complex 7. All our attempts to locate the transition state for the βꢀhydride
elimination failed, since all geometry optimizations of species 6 without a molecule of H2
always led to the formation of a carboxylate which implies that the second βꢀhydride elimination
occurs with a high rate and thus cannot be the rateꢀlimiting step.
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Figure 5. Graphical representation of complex 6.
After the second βꢀhydride elimination, the carboxylate dissociates off from the ruthenium
center to give a dihydride complex which is stabilized by coordinating one hydroxide ion. Even
though the formed complex 7 is coordinatively unsaturated, all five ligands on ruthenium are
good electron donors which make species 7 the most stable intermediate of the proposed
catalytic cycle (Figure 6). Moreover, the optimization of complex 7 with a molecule of alcohol
attached to ruthenium yielded a very long O–Ru distance of 4.180 Å which indicated that the
alcohol, being a weak electron donor, does not coordinate to ruthenium. However, after the
alcohol has been deprotonated by the hydride, the formed alkoxide is bound to ruthenium to give
intermediate 2.
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TS4-5
4b
TS3-4
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Figure 6. Energy profile for proposed catalytic cycle with fully nonꢀdeuterated substrates in red
and partially deuterated species at key positions in black.
For the calculation of the kinetic isotope effect the following deuterated species were used:
OH– was replaced with OD– and CH3CH2OH with CH3CD2OD. In addition, the hydrogen atoms
originating from these two substrates were replaced with deuterium throughout the catalytic
cycle. As expected, the first part of the cycle has a higher barrier for the deuterated substrates
due to the cleavage of the C–H/D bond (TS3-4, 42.8 kJ·mol–1 for C–D bond vs. 38.4 kJ·mol–1
for C–H bond) which would be expected to result in a significant KIE. Interestingly, later in the
catalytic cycle the TS for the addition of the hydroxide (TS4-5) has virtually identical barriers
(53.0 kJ·mol–1 for C–D vs. 52.7 kJ·mol–1 for C–H) which could be part of the explanation for
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the observed inverse KIE of 0.67. However, since the computed value for this step alone (TS4-
5) is 1.08 there must be additional contributions to the difference observed with the
experimental value such as the difference in basicity and nucleophilicity between hydroxide and
deuteroxide.
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In summary, we have developed a new protocol for the dehydrogenative synthesis of
carboxylic acids which allows for an easy isolation of the products without the use of
chromatography, distillation or recrystallization. The reaction is performed in toluene with 1%
of complex 1 and a slight excess of KOH. The mechanism was studied computationally and a
plausible catalytic cycle identified. The reaction presents an additional application of NHC
complex 1 and highlights the value of this species for the development of new dehydrogenative
transformations with alcohols.
EXPERIMENTAL SECTION
General Information. All solvents were of HPLC grade and were not further purified. NMR
chemical shifts were measured relative to the signals of residual CHCl3 (
δH 7.26 ppm) and
CDCl3 ( C 77.16 ppm). HRMS measurements were made using ESI with TOF detection.
δ
General Procedure. A Schlenk tube was charged with complex 111a (11.5 mg, 0.025 mmol),
PCy3·HBF4 (9.2 mg, 0.025 mmol), KOH (168 mg, 3 mmol) and a stir bar. A cold finger was
attached and the tube was evacuated and refilled three times with argon. The primary alcohol
(2.5 mmol) (and sometimes 1.3 mmol of dodecane as internal standard) in toluene (5 mL) was
added and the Schlenk tube was placed in a preheated oil bath (T = 120 °C). The reaction was
monitored by GC until completion and the Schlenk tube was then removed from the oil bath and
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cooled to room temperature. Ethyl acetate (5 mL) was added and the white precipitate filtered
off and washed with pentane (15 mL) and ethyl acetate (15 mL). The precipitate was dissolved
in water (5 mL) and acidified to pH 1 with saturated aqueous HCl. The aqueous layer was
extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo to give the corresponding acid as a pure compound by 1H NMR.
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1
Phenylacetic acid (Scheme 1).24 Isolated as a white solid in 75% yield (255 mg). H NMR (400
13
MHz, DMSOꢀd6): δ 3.56 (s, 2H), 7.22‒7.33 (m, 5H). C NMR (100 MHz, DMSOꢀd6): δ 40.7,
126.6, 128.3, 129.4, 135.1, 172.7.
Benzoic acid (Scheme 1).25 Isolated as a white solid in 79% yield (241 mg). 1H NMR (400 MHz,
13
CDCl3): δ 7.47‒7.51 (m, 2H), 7.63 (tt, 2H, J = 1.3, 6.9 Hz), 8.13‒8.15 (m, 2H). C NMR (100
MHz, CDCl3): δ 128.7, 129.5, 130.4, 134.0, 172.5.
pꢀMethylbenzoic acid (Table 1, Entry 1).25 Isolated as a light purple solid in 88% yield (300 mg).
1H NMR (400 MHz, DMSOꢀd6): δ 2.36 (s, 3H), 7.29 (d, 2H, J = 8.5 Hz), 7.83 (d, 2H, J = 8.5
Hz), 12.77 (brs, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ 21.1, 128.0, 129.1, 129.3, 143.0,
167.3.
1
pꢀChlorobenzoic acid (Table 1, Entry 2).25 Isolated as a white solid in 82% yield (321 mg). H
NMR (400 MHz, DMSOꢀd6): δ 7.57 (m, 2H), 7.94 (m, 2H), 13.18 (brs, 1H). 13C NMR (100
MHz, DMSOꢀd6): δ 128.8, 129.7, 131.2, 137.8, 166.5.
1
pꢀBromobenzoic acid (Table 1, Entry 3).25 Isolated as a white solid in 70% yield (352 mg). H
NMR (400 MHz, DMSOꢀd6): δ 7.70‒7.72 (m, 2H), 7.85‒7.87 (m, 2H), 13.18 (brs, 1H). 13C
NMR (100 MHz, DMSOꢀd6): δ 126.9, 130.0, 131.3, 131.7, 166.6.
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pꢀIodobenzoic acid (Table 1, Entry 4).25 Isolated as a yellowish solid in 67% yield (415 mg). 1H
NMR (400 MHz, DMSOꢀd6): δ 7.68‒7.70 (m, 2H), 7.88‒7.90 (m, 2H), 13.13 (brs, 1H). 13C
NMR (100 MHz, DMSOꢀd6): δ 101.2, 130.3, 131.1, 137.6, 164.2, 167.0.
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pꢀMethoxybenzoic acid (Table 1, Entry 5).25 Isolated as a white solid in 60% yield (228 mg). H
NMR (400 MHz, CDCl3): δ 3.88 (s, 3H), 6.93‒6.97 (m, 2H), 8.05‒8.08 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 55.6, 113.9, 121.8, 132.5, 164.2, 171.2.
pꢀ(Methylthio)benzoic acid (Table 1, Entry 6).3d Isolated as a yellow pale solid in 67% yield
(282 mg). 1H NMR (400 MHz, DMSOꢀd6): δ 2.52 (s, 3H), 7.33 (d, 2H, J = 8.5 Hz), 7.85 (d, 2H,
J = 8.5 Hz), 12.83 (brs, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ 14.0, 124.9, 126.7, 129.7,
144.8, 167.1.
Biphenylꢀ4ꢀcarboxylic acid (Table 1, Entry 7).26 Isolated as a white solid in 49% yield (243 mg).
1H NMR (400 MHz, DMSOꢀd6): δ 7.43 (m, 1H), 7.50 (m, 2H), 7.73 (m, 2H), 7.80 (m, 2H), 8.02
(m, 2H), 12.98 (brs, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ 126.8, 126.9, 128.3, 129.1, 129.6,
130.0, 139.0, 144.3, 167.2.
pꢀ(Trifluoromethyl)benzoic acid (Table 1, Entry 8).27 Isolated as a white solid in 67% yield (317
mg). 1H NMR (400 MHz, DMSOꢀd6): δ 7.87 (d, 2H, J = 8.2 Hz), 8.13 (d, 2H, J = 8.2 Hz), 13.47
13
(brs, 1H). C NMR (100 MHz, DMSOꢀd6): δ 123.8 (q, J = 271.6 Hz), 125.6 (q, J = 3.7 Hz),
130.1, 132.5 (q, J = 32.0 Hz), 134.6, 166.2.
Nonanoic acid (Table 2, Entry 1).28 Isolated as a colorless oil in 82% yield (324 mg). H NMR
1
(400 MHz, CDCl3): δ 0.88 (t, 3H J = 6.7 Hz), 1.27‒1.35 (m, 10H), 1.63 (quint, 2H, J = 7.6 Hz),
2.34 (t, 2H, J = 7.6 Hz). 13C NMR (100 MHz, CDCl3): δ 14.2, 22.8, 24.8, 29.2, 29.3, 31.9, 34.2,
180.5.
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Decanoic acid (Table 2, Entry 2).29 Isolated as a colorless oil in 71% yield (306 mg). H NMR
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(400 MHz, CDCl3): δ 0.88 (t, 3H J = 6.9 Hz), 1.21‒1.35 (m, 12H), 1.60‒1.67 (m, 2H), 2.35 (t,
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2H, J = 7.4 Hz). C NMR (100 MHz, CDCl3): δ 14.3, 22.8, 24.8, 29.2, 29.4, 29.5, 32.0, 33.9,
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178.9.
3ꢀPhenylpropanoic acid (Table 2, Entry 3).29 Isolated as a white solid in 72% yield (270 mg). 1H
NMR (400 MHz, CDCl3): δ 2.65 (m, 2H), 2.92 (t, 2H, J = 7.6 Hz), 7.16‒7.28 (m, 5H), 11.55
(brs, 1H). 13C NMR (100 MHz, CDCl3): δ 30.7, 35.8, 126.5, 128.4, 128.7, 140.3, 179.6.
3ꢀMethylpentanoic acid (Table 2, Entry 4).30 Isolated as a transparent brownish oil in 84% yield
1
(244 mg). H NMR (400 MHz, CDCl3): δ 0.90 (t, 3H, J = 7.4 Hz), 0.96 (d, 3H, J = 6.7 Hz),
1.19‒1.30 (m, 1H), 1.34‒1.45 (m, 1H), 1.83‒1.95 (m, 1H), 2.14 (dd, 1H, J = 8.0, 15.0 Hz), 2.35
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(dd, 1H, J = 6.0, 15.0 Hz), 11.64 (brs, 1H). C NMR (100 MHz, CDCl3): δ 11.4, 19.4, 29.4,
31.9, 41.4, 180.4.
2ꢀEthylbutyric acid (Table 2, Entry 5).31 Isolated as a colorless oil in 60% yield (174 mg). H
1
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NMR (400 MHz, CDCl3): δ 0.94 (t, 6H J = 7.4 Hz), 1.50‒1.71 (m, 4H), 2.20‒2.27 (m, 1H). C
NMR (100 MHz, CDCl3): δ 11.9, 24.9, 48.8, 182.8.
Cyclopentanecarboxylic acid (Table 2, Entry 6).32 Isolated as a colorless oil in 60% yield (171
mg). 1H NMR (400 MHz, CDCl3): δ 1.53‒1.96 (m, 8H), 2.72‒2.80 (m, 1H), 11.22 (brs, 1H). 13C
NMR (100 MHz, CDCl3): δ 25.9, 30.1, 43.8, 183.5.
Methoxyacetic acid (Table 2, Entry 7).33 Isolated as a colorless oil in 51% yield (115 mg). H
1
NMR (400 MHz, CDCl3): δ 3.45 (s, 3H), 4.07 (s, 2H), 9.66 (brs, 1H). 13C NMR (100 MHz,
CDCl3): δ 59.5, 69.3, 175.4.
Hexanoic acid (Table 2, Entry 8).29 Isolated as a colorless oil in 66% yield (192 mg) (includes
1
4% of 5ꢀhexenoic acid according to NMR). H NMR (400 MHz, CDCl3): δ 0.88‒0.92 (m, 3H),
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1.28‒1.36 (m, 4H), 1.60‒1.68 (m, 2H), 2.35 (t, 2H, J = 7.6 Hz). 13C NMR (100 MHz, CDCl3): δ
14.0, 22.4, 24.5, 31.3, 34.2, 180.4.
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2ꢀMethylbutanoic acid (Table 2, Entry 9).34 Isolated as a colorless oil in 88% yield (225 mg). 1H
NMR (400 MHz, CDCl3): δ 0.95 (t, 3H, J = 7.0 Hz), 1.18 (d, 3H, J = 7.5 Hz), 1.45‒1.55 (m,
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1H), 1.66‒1.77 (m, 1H), 2.36‒2.44 (m, 1H). C NMR (100 MHz, CDCl3): δ 11.7, 16.5, 26.7,
41.0, 183.6.
(1S,2S,5S)ꢀ6,6ꢀDimethylbicyclo[3.1.1]heptaneꢀ2ꢀcarboxylic acid (Table 2, Entry 10). Isolated as
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a brownish sheer oil in 76% yield (321 mg). [α]D +1.9 (c 1.0, EtOAc). H NMR (400 MHz,
CDCl3): δ 0.87 (s, 3H), 1.23 (s, 3H), 1.53 (d, 1H, J = 10.0 Hz), 1.70‒1.80 (m, 1H), 1.83‒1.92
(m, 3H), 2.03‒2.21 (m, 3H), 2.93 (t, 1H, J = 9.0 Hz). 13C NMR (100 MHz, CDCl3): δ 16.7, 20.4,
23.9, 24.3, 26.5, 39.3, 40.2, 41.3, 43.8, 183.3. HRMS: m/z calcd for C10H17O2 169.1223 [M +
H]+, found 169.1217.
Computational Details. All calculations were performed in Jaguar35 by using the Maestro
graphical interface.36 All of the structures were optimized in the gas phase and the singleꢀpoint
solvation energy was calculated for the optimized structures by using a standard Poisson–
Boltzmann solver with suitable parameters for toluene as the solvent (dielectric constant: ε =
2.379, probe radius: r = 2.707 Å). Gibbs free energies were obtained from the vibrationalꢀ
frequency calculations for the gasꢀphase geometries at 298 K and 383 K. All of the transition
states were characterized by the presence of one negative vibrational frequency. Graphical
representation of the calculated structures was made in CYLview.37
ACKNOWLEDGMENT
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We thank the Danish Council for Independent Research – Technology and Production Sciences
for financial support (grant 09ꢀ066621).
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Supporting Information. Determination of the KIE, copies of 1H and 13C NMR spectra as well
as Cartesian coordinates and energies for the calculated structures. This material is available free
of charge via the Internet at http://pubs.acs.org.
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