5
Huang et al. Sci China Chem
Scheme 5 Capture and transformation of 64 (color online).
for the esterification. Although this hydrogen-bonding for-
mation may increase the solubility, computational study on
the esterification of amide 1a indicated the anion pair (spe-
cies I, Figure 2) formed by 3-nitrobenzyl alcohol had a
higher stability than pure 3-nitrobenzyloxide anion under the
basic conditions (–16.9 kcal/mol), with a hydrogen bond to
disperse the negative charge on oxygen atom, especially in
non-polar solvent like toluene. This is further confirmed by
the similar computational outcome found for phenol
(–12.3 kcal/mol).
Excess base will deprotonate all the phenols so that there is
no H-bond acceptor left. Consequently, species I will not be
generated and thus the catalytic process was hampered. After
generation, the species I can undergo nucleophilic attack at
the amide to form a very unstable intermediate II
(14.6 kcal/mol), leading to the formation of a relatively
stable tetrahedral intermediate anion III (6.1 kcal/mol), sta-
bilized by additional alcohol molecule via hydrogen-bond-
ing. The anion III could be converted to intermediate IV
(12.6 kcal/mol) through the electron transfer from oxygen
atom to nitrogen atom. The C–N bond between the carbonyl
group and nitrogen atom in intermediate IV could be cleaved
into an ester, along with the release of amine alkyloxide pair
V (–2.4 kcal/mol). Finally, protonolysis of the pair V with
another molecular alcohol could produce amine product VI
(–9.1 kcal/mol) and regenerate species I to complete the
catalytic cycle. When benzamide was applied instead of 1a
in the DFT calculations, the ∆G for all intermediates
are relatively high, especially for amine formation VI
(9.0 kcal/mol, Figure S3). This is also consistent with our
experiment results—benzamide is more challenging to be
transformed to esters, with only 38% yield obtained even
with extended reaction times (72 h, 3 in Scheme 4).
Scheme 4 The scope of N–H/alkyl/aryl substituted amides. Reaction
conditions: 0.5 mmol scale with 6.0 equiv. phenol/alcohol and 20 mol%
NaOtBu in 5.0 mL toluene at 150 °C for 72 h. Superscript a) isolated yields;
b) with2.0 equiv. alcohol and 20 mol% NaOtBu in 5.0 mL toluene at 150 °C
for 36 h (color online).
by the serine protease-catalyzed esterification [40], the ad-
duct of phenol and phenoxide anion may be responsible for
the esterification. When the ratio of phenol and sodium
phenoxide was 1:1, a 75% yield was achieved, which further
increased to 91% when the ratio was 9:1 (entries 2 and 3,
Table S2). Thirdly, the competition experiments were carried
out. The electron-deficient amide was found to be more re-
active (Scheme S3), which in accord with the relative elec-
trophilicity of the amide bond. At last, an intramolecular and
intermolecular competition reaction with 4-hydroxy-
phenethyl alcohol or the mixture containing equal amount of
phenol and benzyl alcohol were selected to react with amide
1a under the otherwise identical reaction conditions (Scheme
S4). The hydroxyl groups of phenols are inherently more
reactive than that of alkyl hydroxyl analogues, and 3:1 ratio
for phenol esters to alcohol esters were found in both cases,
which further supported the nucleophilic substitution path-
way.
To gain further insight of the reaction mechanism, attempts
of capturing and isolating the possible reaction intermediates
were made. As shown in Scheme 1, no esterification pro-
ducts 7a and 7b were detected when phenols with strong
electron-withdrawing groups (–NO2 or –CN) were applied as
substrates. Similar situation was observed with 3-nitrobenzyl
alcohol 63 as the substrate. It is worth noting that, only in this
case, a tetrahedral compound 64 was isolated (Scheme 5),
which was the possible intermediate for the esterification. No
tetrahedral intermediate was isolated when 4-nitrobenzyl
alcohol was applied, instead, ester product 23 was isolated in
10% yield (Scheme 2). Pleasingly, compound 64 was readily
converted into ester 65 after heating at 150 °C for several
hours or at ambient condition for several days. The isolation
and conversion of 64 demonstrates that a catalytic amount of
base can lead to the formation of a tetrahedral intermediate,
which is crucial for the esterification.
The calculation of apparent activation energy was carried
out (Figures S1 and S2). In light of the nucleophilic sub-
stitution reaction pathway, we assumed a quasi-second order
reaction mechanism. To simplify the calculation process, all
possible sub-reaction and concentration effects were omitted
and the reaction of amide and phenol to give the ester was
assumed to be quantitative. According to Arrhenius formula,
the apparent activation energy of benzamide to phenyl
benzoate 3 is to be 9.27 kcal/mol, which is in good agree-
ment with the DFT calculation (9.1 kcal/mol).
Computational density functional theory (DFT) calcula-
tions revealed the conjugated acid-base pair formation