Amide/Iminium Zwitterionic Catalysts for (Trans)esterification: Application in Biodiesel Synthesis

Article abstract of DOI:10.1021/acscatal.9b01959

A class of zwitterionic organocatalysts based on an amide anion/iminium cation charge pair has been developed. The zwitterions are easily prepared by reacting aziridines with aminopyridines. They are catalytically applicable to transesterifications and dehydrative esterifications. Mechanistic studies reveal that the amide anion and iminium cation work synergistically in activating the reaction partners, with the iminium cationic moiety interacting with the carbonyl substrates through nonclassical hydrogen bonding. The reaction can be applied to large-scale synthesis of biodiesel under mild conditions.

Full text of DOI:10.1021/acscatal.9b01959

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Article
Amide/Iminium Zwitterionic Catalysts for
(Trans)esterification: Application in Biodiesel Synthesis
Ying-Pong Lam, Xinyan Wang, Fei Tan, Wing-Hin Ng, Ying-Lung Steve Tse, and Ying-Yeung Yeung
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01959 • Publication Date (Web): 22 Jul 2019
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Amide/Iminium Zwitterionic Catalysts for
(Trans)esterification: Application in Biodiesel
Synthesis
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Ying-Pong Lam, Xinyan Wang, Fei Tan, Wing-Hin Ng, Ying-Lung Steve Tse,*
Ying-Yeung Yeung*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
(China)
ABSTRACT: A class of zwitterionic organocatalysts based on an amide anion/iminium cation
charge pair has been developed. The zwitterions are easily prepared by reacting aziridines with
aminopyridines. They are catalytically applicable to transesterifications and dehydrative
esterifications. Mechanistic studies reveal that the amide anion and iminium cation work
synergistically in activating the reaction partners, with the iminium cationic moiety interacting
with the carbonyl substrates through non-classical hydrogen bonding. The reaction can be
applied to large-scale synthesis of biodiesel under mild conditions.
KEYWORDS: biodiesel, esterification, orgnaocatalysis, mechanism, transesterification,
zwitterion
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1. INTRODUCTION
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Bifunctional organocatalysts have emerged in recent decades and play an increasingly
important role in organic synthesis. Thanks to the cooperative effect between the functional
groups in the bifunctional systems, the substrate reaction partners can be brought into close
proximity for efficient chemical transformations. Constitutional components such as Brønsted
bases/acids, Lewis bases, dihydrogen bonds and cooperative ion pairing are frequently included
in the design of bifunctional organocatalysts.1-9 An emerging class of bifunctional
organocatalysts is zwitterions (also referred to as inner salts),10 in which an anion and a cation
are site-isolated within a single molecule and the ion pair works synergistically to activate the
reaction partners. However, catalysis using zwitterions is underexploited, partly because of the
difficulties in identifying suitable catalyst architectures and preparation of zwitterionic catalysts.
Among the sporadic reports on zwitterion catalytic systems,1,11-12 oxide-containing zwitterions
are relatively the most studied. For instance, betaines (with oxide and ammonium) derived from
a number of skeletons have been utilized in a range of catalytic processes such as CO2 fixation,13-
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polymerization,17 photoredox reactions,18-19 and Aldol/Mannich-type reactions20-25 and
aziridine opening.26 Recently, seminal works on asymmetric catalytic reactions using chiral
quaternary ammonium betaines were independently reported by Ooi,27-33 Deng,34 Gong,35 and
Levacher.36 In one very recent report, a betaine Co(III) complex was applied in
copolymerization.37 In situ generated oxide/phosphonium zwitterionic catalysts are also
applicable in selected reactions. Gong reported in situ generated oxide/phosphonium zwitterions
for Mannich-type and Strecker-type reactions.38-39 Ranocchiari reported that in situ generated
oxide/phosphonium zwitterions with the influence of metal-organic frameworks could catalyze
the Aldol-Tishchenko reactions.40 Tado and Suga also reported the use of in situ generated
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aromatic oxide/phosphonium zwitterions for primary hydroxyl group selective acylation of
diols.41
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In contrast, zwitterionic catalysts containing other ion pairs are very rare. A pioneering work
by Brown documented the use of a zwitterionic imidazolium thiolate catalyst to promote the
hydrolysis of amides.42 Structurally unique zwitterionic carbon acids were established by Yanai
and Taguchi and have been applied in some acid-catalyzed transformations.43-46 In 2007, Ishihara
reported a seminal work using the sulfide/iminium zwitterion 3 with an anionic sulfide and a
cationic imine for transesterification.47,48 Later, our research team applied the same catalyst in
the medium-ring lactonization of olefinic acids and electrophilic halogention of arenes.49-50
Zwitterion 3 is an attractive catalyst platform because it can be easily prepared through the
nucleophilic attack of isothiocyanate 1 by an equal molar amount of 4-aminopyridine 2 (Figure
1A). In addition, the structurally well-defined charge pair system allows effective interaction
with the reaction partners. However, sulfide zwitterion 3 was found to exist in equilibrium with
its constitutional components 1 and 2 in solution phase, and isothiocyanate 1 would be hydrated
gradually in the presence of moisture,49 which limited its application. Herein, we are pleased to
disclose our recent success in the design and preparation of a new class of zwitterionic
organocatalysts 5 based on an amide anion/iminium cation pair. Zwitterions 5 could easily be
prepared and were found to be structurally stable. In addition, the catalytic protocol has been
successfully applied in transesterification and dehydrative esterification. A computational study
revealed that the cationic ammonium moiety in zwitterion 5 could interact with the intermediate
through non-classical hydrogen bonding. This newly developed methodology was found to be
applicable to the scalable synthesis of biodiesel.
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2. RESULTS AND DISCUSSION
2.1 Catalyst design and preparation
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Our study began with the design and preparation of zwitterion 5. We rationalized that instead
of using isothiocyanate 1, nucleophilic attack of the bicyclic aziridine system 4 by 4-
aminopyridine 2 would release the ring-strain and result in the energetically more favorable
zwitterion 5, which would inhibit the backward reaction (Figure 1B). The N-sulfonated aziridines
4 can readily be prepared through literature procedures.51 To our delight, tosyl aziridine 4a could
be opened by 4-(N,N-dimethylamino)pyridine (DMAP, 2a) in refluxing acetonitrile to give
zwitterion 5a in 72% yield (Figure 1B). Changing the N-sulfonamide at aziridine 4 (e.g. 4b)
and/or the aminopyridine partner [e.g. 4-pyrrolidylpyridine (PPY), 2b] yielded the structural
analogues 5b–5d. An X-ray crystallographic study on a single crystal sample of zwitterion 5a
was performed (Figure 1C). It was found that the N(3)-C(9) bond length (1.34 Å, the labeling is
based on the X-ray data) was significantly shorter than a typical C-N single bond, suggesting that
the bonding had considerable C=N character and the N(3) nitrogen was positively charged. We
believe that the electropositivity of the iminium cation was considerably enhanced because the
counteranion sulfonamide is effectively dissociated to a large extent as a result of its site
isolation in the carbon skeleton. Computational study on the electrostatic potential of 5a also
revealed that the iminium moiety possesses considerable positive charge (Figure 1C). Notably,
zwitterions 5 were found to be structurally stable and no decomposition was observed upon
heating, which could be attributed to the fact that the pyridinium moiety in 5 sat at the equational
position so that they could withstand decomposition through substitution or Hoffmann
elimination. In addition, zwitterions 5 were not hygroscopic so that they were easy to handle for
catalytic reactions.
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A
F3C
R
N
C
R
S
F3C
N
N
7
+
C
S
8
9
N
CF3
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1
CF3
2a
2b
3a
, R = NMe2
3b
, R = pyrrolidine
, R = NMe2
, R = pyrrolidine
unstable zwitterion
moisture sensitive
Me
B
Me
N
N
Me
Me
N
N
2a
1
5a
5b
, R = Ts (72%)
1
, R = Ms (75%)
MeCN, reflux
NR1
stable zwitterions
NR1
N
N
1
4a
4b
4c
4d
, R = Ts
, R = Ms
, R = Ns
, R = Tf
1
5c
, R = Ts (65%)
1
N
N
1
2b
5d
5e
5f
, R = Ms (68%)
1
1
, R = Ns (38%)
1
MeCN, reflux
NR1
1
, R = Tf (76%)
C
1.34 Å
Me
1.35 Å
N3
C9
Me
N
Ts
N
1.46 Å
1.49 Å
5a
XRD structure of 5a
Electrostatic potential of 5a
Figure 1. Design and Preparation of Aminopyridinium Zwitterionic Organocatalysts
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2.2 Synthesis of biodiesel through transesterification
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A
OCO(CH2)10CH3
OCO(CH2)10CH3
catalyst (5 mol%)
MeOH, 23 oC, 24 h
CH3(CH2)10CO2Me
9
7a
OCO(CH2)10CH3
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6a
7a
7a
7a
yield of
catalyst yield of
catalyst yield of
catalyst
Et3N
DMAP
PPY
PPh3
TBAI
[(n-dodec)3MeN]+Cl-
[Me4N]+[OCO2Me]-
tracec
tracec
tracec
trace
trace
0%
3b
5a
5b
5c
5d
5d
5d
5e
5f
0%
0%
5g
70%
72%
79%
>99%
99%a
99%b
0%
0%
5h
0%
5i
0%
5j
5k
60%
74%
NaOMe 32%c
trace
50 g scale
tBuOK
52%c
a
o
b
5d
5d
for 96 h.
Reaction was done using 2 mol% of
cReaction was done at 70 oC.
at 70 C for 2 h. Reaction was done using 2.5 mol% of
Me
Me
N
Me
Me
Me
N
Me
Me
N
N
N
R
N
NTs
NTs
NTs
Ph
NTs
5g
5h
, R = Ph
, R = H
5i
5j
5k
B
R
substrate
product yield
CH3
6b
6c
6d
7b
7c
7d
7e
99%
99%
99%
99%
5d
zwitterion
OCOR
OCOR
CH3(CH2)3
CH3(CH2)6
CH3(CH2)12
(5 mol%)
MeOH
23 oC, 24 h
MeOCOR
7
6e
6f
OCOR
6
7f
99%
CH3(CH2)7 (CH2)7
Figure 2. Transesterification of triglycerides 6 to FAMEs 7
The catalytic performances of zwitterions 5a-d in the transesterification of triglycerides 6 to
fatty acid methyl esters 7 (FAMEs, commonly known as biodiesel) were evaulated.52-55 Fatty
acid ester 6a was suspended in a solution of MeOH containing 5 mol% of zwitterionic catalyst 5
at 23 °C (Figure 2A). The transesterification proceeded smoothly and the FAME 7a was
obtained in 70-79% isolated yield when using zwitterions 5a-c. The efficiency was significantly
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enhanced when using zwitterion 5d bearing both a mesyl and a PPY substituents. The reaction
could be run with a lower catalyst loading (2 mol% of 5d) at 70 oC for 2 h, giving FAME 7a in
99% yield. In addition, the reaction was readily scalable (50 gram scale) and 7a was obtained
quantitatively. In sharp contrast, no reaction was observed when using zwitterion 3b as the
catalyst, attributed to the decomposition of the catalyst through methanolysis of isothiocyanate 1
(exist in equilibrium with 3b). Zwitterions 5e-f (with more electron-deficient sulfonamide), 5g-h
(different skeleton rigidity) and 5i-k (different distance between the cation and anion), which
were prepared using a similar method as that in 5a-d, were also examined and their performances
were inferior to 5d. These results suggest that the Brønsted basicity, structurally rigidity and
cation/anion distance in 5d might be the determining factors of catalytic performance. It was also
found that other catalysts including Brønsted bases (NaOMe, tBuOK), Lewis bases (Et3N,
DMAP, PPY, PPh3), and ammonium salts [tetra-n-butylammonium iodide (TBAI), tri-n-
dodecylmethylammonium chloride,56 and tetramethylammonium methyl carbonate57] were much
less effective in promoting the reaction under the same conditions.
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The reaction was also found to be applicable to other fatty acid esters 6b-f. For the case of 6f,
the corresponding FAME 7f was obtained in quantitative yield with the unsaturated system
remaining intact (Figure 2B).
FAME 6a could be separated simply by aqueous washing to remove the glycerol and
zwitterionic catalyst 5d. In addition, the by-product mixture containing glycerol (a glut by-
product from the production of biodiesel) and catalyst 5d could undergo transesterification with
ethyl acetate to give triacetin (99%) (Figure 3), which has various applications such as biodiesel
additive, antiknock agent, food additive, and plasticizer.58 The zwitterionic catalyst 5d could then
be recycled and reused in the next round of FAME 7 synthesis with similar performance.59 It is
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noteworthy that unlike some common methods such as base-catalyzed transesterification (which
requires anhydrous conditions to avoid hydrolysis of the ester to form carboxylic acid) and
catalyst-free transesterification in supercritical MeOH (which requires high temperature/pressure
and special equipment),52-55 this virtually neutral zwitterionic catalyst system could be operated
in an open-flask environment without the need of exclusion of moisture or the use of anhydrous
alcoholic solvents. In addition, clean conversion was achieved using conventional apparatus at
ambient conditions (1 atm and 23 °C). These features provide a solid foundation for the scalable
synthesis of biodiesel under mild organocatalytic conditions.
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Ac
O
O
OCO(CH2)10CH3
OCO(CH2)10CH3
Ac
(99%)
zwitterionic
5d
catalyst
(5 mol%)
Ac
triacetin
O
OCO(CH2)10CH3
MeOH
23 oC
24 h
6a
reflux
OH
OH
0.64 g (99%)
(1st round)
Ac
EtO
5d
CH3(CH2)10CO2Me
+
0.64 g (99%)
(5 mol%)
7a
(using recycled 5d)
OH
glycerol
by-product mixture
Figure 3. Catalyst recycle and triacetin synthesis
2.3 Transesterification of simple substrates
Next, the catalytic performance of zwitterions 5 in transesterification of other substrates was
studied. Benzyl alcohol (8a) was used as the model substrate and the reaction was conducted in
refluxing ethyl acetate (with 5Å molecular sieves in an additional funnel to remove the ethanol
by-product). Similar to the case of biodiesel synthesis, the catalytic performance of zwitterion 5d
remains superior to other structural analogues. (Figure 4A). Further experiments revealed that the
reaction could still proceed smoothly with 3 mol% of zwitterion 5d at a higher concentration.59
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A
B
9a
zwitterion yield of
-
0%
OH
5
zwitterion (5 mol%)
Ac
O
5a
5b
5c
5d
5g
4%
25%
19%
89%
8%
Ac
EtO
(0.2 M), 5Å MS
reflux, 24 h
8a
9a
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5d
zwitterion
(3 mol%)
Ac
R OH
R O
Ac
EtO
(0.5 M), 5Å MS
reflux
9
8
(time, isolated yield)
Ac
(2 mmol)
MeO
O
Ac
Ac
O
O
Ac
O
MeO
MeO
Cl
OMe
9a
9b
(32 h, 95%)
9c
9d
(20 h, 98%)
(20 h, 93%)
(24 h, 99%)
Ac
O
Ac
O
Ac
Ac
CH3(CH2)7O
CH3(CH2)9O
9e
9f
(36 h, 92%)
9g
(36 h, 87%)
9h
(24 h, 94%)
(32 h, 68%)
Ac
O
Ac
O
Ac
O
9i
(24 h, 96%)
9j
(20 h, 97%)
9k
(32 h, 95%)
Ac
O
Ac
O
Ac
O
O
Ac
O
Ac
O
9l
9m
9n
(24 h, 81%)
9o
(36 h, 87%)
(24 h, 80%)
(48 h, 91%)
OTBS
O
Ac
O
O
Ac
O
O
Ac
Ac
O
O
O
Ac
O
OMe
9q
9p
(36 h, 97%)
(36 h, 72%)
Figure 4. Transesterification with EtOAc
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The optimized catalytic protocol was then applied to other alcohols (Figure 4B). In general, the
reaction worked well with various aliphatic alcohols 8a-i with electron-donating or withdrawing
substituents. Functionalities including alkene (8j-l), alkyne (8m), and furan (8n), which are
sensitive to conventional acid-mediated transesterification conditions,60 were compatible with the
zwitterion-catalyzed system to give the corresponding acetate products 9j-n in good-to-excellent
isolated yields. Acetylation of diols 8o and 8p could also be achieved to yield diacetates 9o
(91%) and 9p (97%) smoothly. Interestingly, triacetylated sugar derivative 9q was funished in
good isolated yield. It is worth mentioning that acetylation of alcohols, which is one of the most
common protection methods, typically requires the use of acetyl chloride or acetic anhydride.61
In contrast, our approach can easily introduce the protecting group acetate into alcohols without
acidic conditions.
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Next, transesterification of methyl esters with different alcohol partners was studied. Equal
molar amounts of alcohols 8 and methyl esters 10 were used and the reactions were conducted in
refluxing n-heptane to azeotropically remove the methanol by-product (Table 1). Again, the
catalytic protocol was found to be compatible with various functionalities. For instance, methyl
salicylate (10b) readily underwent transesterification with benzyl alcohol (8a) to give 11b in
98% yield with the phenol moiety remaining intact (entry 2). A 2:1 mixture of methyl ester 10d
and diol 8q gave the transesterified diester product 11f in 91% yield (entry 6). The catalytic
protocol was also found to be compatible with ,-unsaturated ester 10e, the bulkier ester 10f,
and ethyl ester 10g (entries 7-9). Interestingly, lactone 11j was obtained quantitatively through
the intramolecular transesterification of hydroxyl ester 10h (entry 10). However, the
transesterification of methyl benzoate and glycidol,56 which is a useful but challenging reaction,
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Table 1. Transesterification with Other Alcoholsa
5
6
7
8
9
O
O
5d
zwitterion
(3 mol%)
R1OH
8
+
R2 OR3
n-heptane, reflux (5Å MS)
OR1
R2
10
48 h
1
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Entry
Alcohol
Ester
Product
Yieldb
O
O
1
2
98%
98%
BnOH
8a
OMe
OBn
I
I
10a
11a
OH
O
OH
O
BnOH
8a
OMe
OMe
OBn
OBn
10b
11b
Ph
Ph
BnOH
8a
3
4
99%
90%
99%
91%
O
10c
O
11c
OMe
OMe
OMe
HO
Ph
Ph
Ph
O
Ph
O
10d
O
8k
11d
O
Ph
7
CH3(CH2)7OH
5
O
10d
O
11e
8g
Bn
O
O
Bn
6c
HO(CH2)6OH
6
O
10d
O
O
8q
11f
O
O
BnOH
8a
Ph
OMe
Ph
OBn
7
8
90%
86%
11g
10e
O
O
BnOH
OMe
OBn
11h
8a
10f
O
O
BnOH
9
92%
99%
Ph
OEt
10g
Ph
OBn
11i
8a
O
O
10d
O
HO
OMe
10h
11j
aReactions were carried out with 10 (2 mmol), 8 (2.2 mmol) and zwitterion catalyst 5d (0.06
mmol) in n-heptane (4 mL) at reflux under nitrogen atmosphere. bIsolated yield. c2 equivalents of
10d were used. dThe reaction time was 3 h.
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was sluggish when using catalyst 5d. It appears that the reaction scope of 5d is complementary
to that of tri-n-dodecylmethylammonium chloride.
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2.4 Dehydrative esterification
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During our substrate scope evaluation, it was surprising to realize that zwitterion 5d was able
to promote the reaction between succinic anhydride (12) and benzyl alcohol (8a) to give diester
13a. The reaction was found to go through a one-pot two-step sequence: (1) ring-opening of 12
by 8a to yield mono-ester 12’; (2) dehydrative esterification of 12’ to give diester 13a (Figure
5A). This result suggests that the catalytic protocol could catalyze the dehydrative esterification
between a carboxylic acid and an alcohol, which is known to be challenging due to the high
reaction barrier and strongly acidic catalysts are typically required to activate the carboxylic acid
substrates.62 The sulfide zwitterion 3b was found to be ineffective in catalyzing the reaction,
attributed to alcoholysis of isothiocyanate 1 by benzyl alcohol (similar to the case of
transesterification of 6a, Figure 1A).
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O
O
O
O
O
O
BnOH
5d
5
6
7
8
OBn
OBn
OH
OBn
zwitterion
(3 mol%)
BnOH
n-heptane, reflux
3Å MS, 48 h
O
12'
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12
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13a
(80%)
dehydrative
esterification
3b
no reaction with
B
R
O
O
O
O
OR
OR
5d
zwitterion
(3 mol%), n-heptane
+
ROH
reflux, 3Å MS, 48 h
O
13
12
(1 mmol)
8
(2 mmol)
=
n
1
13b
, R = 4-Me (84%)
2
1
1
3
4
13c
13d
13e
, R = 4-OMe (80%)
13g
13h
(86%)
1
R1
, R = 3,4,5-(OMe)3 (70%)
13i
13j
13k
, n = 2 (86%)
, n = 3 (80%)
, n = 4 (91%)
, n = 5 (82%)
1
, R = 4-NO2 (70%)
5
8
1
13f
, R = 4-CF3 (63%)
13l
(76%)
BnOH
O
O
O
BnO
OBn
5d
zwitterion
(3 mol%)
n-heptane, reflux
O
O
3Å MS, 48 h
14
15
(78%)
Figure 5. One-step Synthesis of Diesters from Succinic Anhydride
The generality of this reaction system was examined. The reactions were performed in
refluxing n-heptane with Dean-Stark apparatus to remove the water by-product in the
dehydrative esterification process. To our delight, a wide range of alcohols 8 bearing electron-
rich or electron-deficient substituents were found to be compatible and the corresponding diester
products 13b-13l could be obtained in good isolated yields under mild conditions (Figure 5B).
When replacing succinic anhydride (12) with glutaric anhydride (14), the corresponding diester
15 could still be obtained in 78% yield. It is noteworthy that diesters are useful starting materials
for block co-polymer production but harsh synthetic conditions are often required to synthesize
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diesters.66-64 We also examined the dehydrative esterification of other carboxylic acids 16 and
alcohols 8, and the desired ester products 17a-i were obtained smoothly (Figure 6). Starting from
diacids 16j-m, the corresponding diesters 17j and 17m could be obtained in 75%-83% yields.
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O
O
5d
zwitterion
(3 mol%), n-heptane
+
ROH
R1
OH
R1
OR
reflux, 3Å MS, 48 h
16
(2 mmol)
8
17
(2 mmol)
17b
17c
17d
17e
, R = Bn (84%)
, R = 4-Me-C6H4CH2 (72%)
, R = 4-O2N-C6H4CH2 (68%)
, R = n-nonyl (85%)
OBn
O
O
OR
17f
, R =
(72%)
Ph
17a
(83%)
(84% @ 40 mmol scale)
17g
, R =
(65%)
O
O
O
OBn
BnO
17j
OBn
OBn
O
O
(83% with 2 equiv of )
17h
17i
8
(81%)
(64%)
17k
17l
17m
8
, R = Bn (82% with 2 equiv of )
RO
OR
8
, R = 4-Me-C6H4CH2 (78% with 2 equiv of )
, R = 4-O2N-C6H4CH2 (75% with 2 equiv of )
O
O
8
Figure 6. Dehydrative Esterification of Alcohols and Carboxylic Acids
2.5 Mechanistic studies
The mechanism for the dehydrative esterification is particularly remarkable in that the reaction
could be promoted with a non-acidic catalyst.62 1H NMR experiments on two mixtures, benzyl
alcohol (8a)/5d and acetic acid/5d, were conducted and it appears that both the alcohol and the
carboxylic acid could interact with the zwitterion 5d.59 Density functional theory (DFT)
calculations at the level of M06-2X (with Grimme D3)65-68/6-311G(d,p) for the reaction between
butyric acid (16i) and benzyl alcohol (8a) were carried out to get a better understanding on the
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reaction (Figure 7A). On the basis of the NMR studies, two reaction pathways were considered:
(1) the sulfonamide deprotonates the carboxylic acid or (2) the sulfonamide deprotonates the
alcohol. The calculation results indicated that zwitterion 5d interacts with carboxylic acid 16i to
form intermediate Acid-R, which is more stable than the adduct 5d-R (formed by the
deprotonation of 8a by zwitterion 5d) by 3.2 kcal/mol. However, the subsequent step of
nucleophilic attack of the carbonyl carbon by the alcohol (Acid-TS1) is highly disfavored
because of the high free energy barrier (ΔG‡ = 42.2 kcal/mol). From studying the optimized
geometry, the zwitterion/alcohol adduct 5d-R undergoes the nucleophilic substitution at the
carbonyl carbon to give the ortho-ester intermediate 5d-IM through 5d-TS1, with a significantly
smaller free energy barrier (ΔG‡ = 28.7 kcal/mol). As predicted by the Eyring equation, the rate
constant associated with this small barrier is about 108 times larger than that of the barrier of 42.2
kcal/mol in Acid-TS1. The interconversion barrier between Acid-R and 5d-R is likely to be
significantly smaller than the energy barriers of 42.2 kcal/mol and 28.7 kcal/mol. Therefore,
Acid-R appears to be a trap in the catalytic cycle, and the reaction likely proceeds to the final
product via the rate-determining step 5d-R→5d-TS1. Subsequent collapse of the orthoester 5d-
IM through 5d-TS2 gives the ester product 17i and water together with the regeneration of the
zwitterionic catalyst 5d. Continuous removal of the water by-product from the reaction system
favors the product formation.
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In the optimized geometry of 5d-TS1, the pyrrolidine protons adjacent to the iminium cation in
zwitterion 5d are positioned in close proximity to the oxygen of the carbonyl of 16i with
distances at 2.40 and 2.63 Å (average = 2.51 Å, Figure 7B). These values are within the range of
a typical hydrogen bond interaction. Thus, we believe that a non-classical hydrogen bond69-72
might stabilize the intermediate and reduce the energy barrier. This result is also consistent with
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our NMR study in which the pyrrolidine’s proton signals shifted up-field upon the addition of
alcohol,59 potentially due to the interaction of the alkoxide anion with the pyrrolidine’s protons
through the non-classical hydrogen bonds. The system with the DMAP-derived catalyst 5b was
also analyzed by DFT (the free energy profile is provided in SI). We found that the reaction
encounters a considerably higher barrier (ΔG‡ = 30.4 kcal/mol) at the rate-determining step 5b-
TS1 as compared with 5d-TS1. We hypothesize that the movement of the pyrrolidine’s protons
in 5d is restricted as a result of the rigid PPY moiety, which can provide a better stabilization
effect to the carboxylic acid. In contrast, the rotatable methyl groups in the DMAP moiety of
zwitterion 5b might be less effective in stabilizing the transition state TS1 through the non-
classical hydrogen bond. Indeed, the closest distances between the carbonyl oxygen and the
methyl protons in 5b-TS1 were calculated to be 3.72 Å and 2.38 Å (average = 3.05 Å), whose
average is considerably longer than that in 5d-TS1. These computational studies reveal the
cooperative nature of the charge pair in zwitterion 5d in the dehydrative esterification.
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A
nPr
4
5
6
O
Bn
H
H
nPr
H
O
OBn
nPr
O
O
S
Bn
N
nPr
O
O
H
O
Bn
H
H
N
H
S
O
H
H
N
H
O O
N
O
N
O
N
O O
O
H
O
S
N
H
O
H
H
7
8
9
H
N
H
O
O
S
N
H
N
39.0
Acid-TS1
N
40
20
0
Me
N
30.4
5b-TS1
28.7
5d-TS1
28.6
5d-TS2
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17.4
5d-IM
OBn
8.6
H
S
O
nPr
5d +
17i + H2O
0.0
N
O
O
-3.2
Acid-R
O
H
5d-R
5b-R
H
Bn
O
N
N
nPr
O
H
O
O
Bn
O
S
H
H
O
nPr
N
H
N
O
O
O
O
S
N
R
N
N
5b
5d
, R = NMe2
, R = pyrrolidine
BnO
H
B
5b-TS1
5d-TS1
5d-IM
5d-TS2
Figure 7. (A) Calculated free energy profile of the proposed dehydrative esterification
mechanism. The zero of each free energy profile is defined to be the energy of the R state. (B)
Snapshots of the transition states. The distances between atoms (angstrom) are shown in black
dashed lines. The red numbers next to the atoms are the nitrogen and oxygen NBO atomic
charges from the catalyst and the acid.
DFT calculations for the reaction between benzyl alcohol (8a) and ethyl acetate with
zwitterionic catalyst 5d were also carried out (Figure 8). A stable complex Ester-R originated
from the hydrogen bond interaction between 5d and 8a was identified, which is consistent with
the NMR study.59 Based on the optimized energy profile, 8a attacks the ester (Ester-TS1) to
give the tetrahedral intermediate Ester-IM1 (stabilized by 7.2 kcal/mol). Similar to the case of
dehydrative esterification, the carbonyl group of ethyl acetate is activated by the non-classical
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hydrogen bond originated from the pyrrolidine’s protons (Ester-TS1, average distance of the
O...H = 2.493 Å). The step Ester-R→Ester-TS1 is the rate-determining step (ΔG‡ = 21.2
kcal/mol). Re-organization of the complex (Ester-IM1→Ester-IM2) followed by collapse of the
tetrahedral intermediate through Ester-TS2 gives transesterification product benzyl acetate (9a).
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Bn
BnO
BnO
O
O
S
O
S
O
H
O
O
O
H
O
O
Et
N
O
S
O
Et
N
H
H
O
Et
H
30
20
10
0
O
N
H
N
N
H
N
N
N
N
22.3
Ester-TS2
22.2
Ester-IM2
21.2
Ester-TS1
Ester-TS2
Ester-TS1
14.0
Ester-IM1
4.5
OEt
BnO
H
O
S
5d +
9a + EtOH
O
Bn
O
N
0.0
H
O
Ester-R
O
N
N
O
S
O
H
Et
N
O
N
N
Ester-IM1
Figure 8. Calculated free energy profile of the proposed transesterification mechanism. The
zero of each free energy profile is defined to be the energy of the R state.
Although the zwitterion is not Brønsted acidic, the non-classical hydrogen bond in 5d appears
to play an important role in activating the carbonyl group of carboxylic acid and ester in the
dehydrative esterification and transesterification, respectively. In addition, a suitable catalyst
pocket size (which is defined by the distance between the anion and the cation in the zwitterionic
system) seems to be crucial in accommodating the reaction partners for high catalytic
performance.
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3. CONCLUSIONS
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6
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8
In summary, a new zwitterionic organocatalytic protocol has been developed and applied in
(trans)esterification reactions. Mechanistic studies revealed that the catalyst can activate the
carbonyl substrates through non-classical hydrogen bonds. Further applications of this novel
catalytic protocol in other reactions are underway.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail for Y.-Y. Yeung: yyyeung@cuhk.edu.hk; Y.-L. S. Tse: stevetse@cuhk.edu.hk
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge.
Experimental details, CIF files, spectroscopic and analytical data for new compounds. (PDF)
ACKNOWLEDGMENTS
We are thankful for the financial support from the Research Grant Council of the Hong Kong
Special Administration Region (Project CUHK14315716) and The Chinese University of Hong
Kong Direct Grant (Project 4053203, 4053275). Special thanks to Professor K. Ishihara (Nagoya
University) for a fruitful discussion.
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REFERENCES
5
6
7
8
(1) Waser, M.; Novacek, J.; Gratzer, K. Cooperative Catalysis Involving Chiral Ion Pair
Catalysts. In Cooperative catalysis: Designing efficient catalysts for synthesis; Peters,
R., Ed.; Wiley-VCH: Germany, 2015; pp 197–226.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) Tian, S.; Chen, Y.; Hang, J.; Tang, L.; Mcdaid, P.; Deng, L., Asymmetric Organic
Catalysis with Modified Cinchona Alkaloids. Acc. Chem. Res. 2004, 37, 621–631.
(3) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D., Bifunctional
Amine‐Squaramides: Powerful Hydrogen‐Bonding Organocatalysts for Asymmetric
Domino/Cascade Reactions. Adv. Synth. Catal. 2015, 357, 253–281.
(4) Liu, X.; Lin, L.; Feng, X., Amide-based bifunctional organocatalysts in asymmetric
reactions. Chem. Commun. 2009, 6145–6158.
(5) Siau, W.; Wang, J., Asymmetric organocatalytic reactions by bifunctional amine-
thioureas. Catal. Sci. Technol. 2011, 1, 1298–1310.
(6) Brière, J.; Oudeyer, S.; Dalla, V.; Levacher, V. Recent Advances in Cooperative Ion
Pairing in Asymmetric Organocatalysis. Chem. Soc. Rev. 2012, 41, 1696-1707.
(7) Brak, K.; Jacobsen, E. N. Asymmetric Ion-Pairing Catalysis. Angew. Chem. Int. Ed.
2012, 2, 534-561.
(8) Qian, D.; Sun, J. Recent Progress in Asymmetric Ion-pairing Catalysis with Ammonium
Salts. Chem. Eur. J. 2019, 15, 3740-3751.
(9) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. The Progression of Chiral Anions from
Concepts to Applications in Asymmetric Catalysis. Nat. Chem. 2012, 4, 603-614.
20
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Page 21 of 29
ACS Catalysis
1
2
3
4
5
6
(10) McNaught, A. D.; Wilkinson, A. IUPAC. Compendium of Chemical Terminology (2nd
ed.); Blackwell Scientific Publications: Oxford, 1997.
7
8
9
(11) Legros, F.; Oudeyer, S.; Levacher, V., New Developments in Chiral Cooperative Ion
Pairing Organocatalysis by Means of Ammonium Oxyanions and Fluorides: From
Protonation to Deprotonation Reactions. Chem. Rec. 2017, 17, 429–440.
(12) Godemert, J.; Oudeyer, S.; Levacher, V. Chiral Ammonium Aryloxides: Efficient
Multipurpose Basic Organocatalysts. ChemCat Chem. 2016, 8, 74–85.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13) Xie, C.; Song, J.; Wu, H.; Zhou, B.; Wu, C.; Han, B., Natural Product Glycine Betaine
as an Efficient Catalyst for Transformation of CO2 with Amines to Synthesize N-
Substituted Compounds ACS Sustainable Chem. Eng. 2017, 5, 7086–7092.
(14) Tsutsumi, Y.; Yamakawa, K.; Yoshida, M.; Ema, T.; Sakai, T., Bifunctional
Organocatalyst for Activation of Carbon Dioxide and Epoxide To Produce Cyclic
Carbonate: Betaine as a New Catalytic Motif. Org. Lett. 2010, 12, 5728–5731.
(15) Liu X.-F.; Li, X.-Y.; Qiao, C.; Fu, H.-C.; He, L.-N., Betaine Catalysis for Hierarchical
Reduction of CO2 with Amines and Hydrosilane To Form Formamides, Aminals, and
Methylamines. Angew. Chem. Int. Ed. 2017, 56, 7425–7429.
(16) Zhou, Y.; Hu, S.; Ma, X.; Liang, S.; Jiang, T.; Han, B., Synthesis of cyclic carbonates
from carbon dioxide and epoxides over betaine-based catalysts. J. Mol. Catal. A: Chem.
2008, 284, 52–57.
(17) Guillerm, B.; Lemaur, V.; Cornil, J.; Lazzaroni, R.; Dubois, P.; Coulembier, O.,
Ammonium betaines: efficient ionic nucleophilic catalysts for the ring-opening
polymerization of L-lactide and cyclic carbonates. Chem. Commun. 2014, 50, 10098–
10101.
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1
2
3
4
5
6
7
8
9
(18) Uraguchi, D.; Torii, M.; Ooi, T., Acridinium Betaine as a Single-Electron-Transfer
Catalyst: Design and Application to Dimerization of Oxindoles. ACS Catal. 2017, 7,
2765–2769.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) Hasegawa, E.; Izumiya, N.; Miura, T.; Ikoma, T.; Iwamoto, H.; Takizawa, S.; Murata,
S., Benzimidazolium Naphthoxide Betaine Is a Visible Light Promoted Organic
Photoredox Catalyst. J. Org. Chem. 2018, 83, 3921–3927.
(20) Kundu, D.; Debnath, R. K.; Majee, A.; Hajra, A., Zwitterionic-type molten salt-
catalyzed syn-selective aza-Henry reaction: solvent-free one-pot synthesis of β-
nitroamines. Tetrahedron Lett. 2009, 50, 6998–7000.
(21) Kundu, D.; Majee, A.; Hajra, A., Zwitterionic-type molten salt: An efficient mild
organocatalyst for synthesis of 2-amidoalkyl and 2-carbamatoalkyl naphthols. Catal.
Commun. 2010, 11, 1157–1159.
(22) Kundu, D.; Bagdi, A. K.; Majee, A.; Hajra, A., Zwitterionic-Type Molten Salt: A Mild
and Efficient Organocatalyst for the Synthesis of 3-Aminoalkylated Indoles via Three-
Component Coupling Reaction. Synlett 2011, 1165–1167.
(23) Rahman, M.; Bagdi, A. K.; Kundu, D.; Majee, A.; Hajra, A., Zwitterionic‐Type Molten
Salt‐Catalyzed Multicomponent Reactions: One‐Pot Synthesis of Substituted Imidazoles
Under Solvent‐Free Conditions. J. Heterocycl. Chem. 2012, 49, 1224–1228.
(24) Rahman, M.; Roy, A.; Ghosh, M.; Mitra, S.; Majee, A.; Hajra, A., Organocatalysis by an
aprotic imidazolium zwitterion: a dramatic anion–cation cooperative effect on azide–
nitrile cycloaddition. RSC Adv. 2014, 4, 6116–6119.
(25) Qiao, Y.; Zhang, L.; Luo, S.; Cheng, J.-P., Chiral Zwitterions from Vicinal Diamines:
Effective and Recoverable Asymmetric Enamine Catalysts. Synlett 2011, 4, 495–498.
22
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Page 23 of 29
ACS Catalysis
1
2
3
4
5
6
7
8
9
(26) Ghosal, N. C.; Santra, S.; Das, S.; Hajra, A.; Zyryanov, G. V.; Majee, A.,
Organocatalysis by an aprotic imidazolium zwitterion: regioselective ring-opening of
aziridines and applicable to gram scale synthesis. Green Chem. 2016, 18, 565–574.
(27) Uraguchi, D.; Koshimoto, K.; Ooi, T., Chiral Ammonium Betaines: A Bifunctional
Organic Base Catalyst for Asymmetric Mannich-Type Reaction of α-Nitrocarboxylates.
J. Am. Chem. Soc. 2008, 130, 10878–10879.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(28) Uraguchi, D.; Koshimoto, K.; Miyake, S.; Ooi, T., Chiral Ammonium Betaines as Ionic
Nucleophilic Catalysts. Angew. Chem. Int. Ed. 2010, 49, 5567–5569.
(29) Uraguchi, D.; Koshimoto, K.; Ooi, T., Flexible synthesis, structural determination, and
synthetic application of a new C1-symmetric chiral ammonium betaine. Chem. Commun.
2010, 46, 300–302.
(30) Uraguchi, D.; Koshimoto, K.; Sanada, C.; Ooi, T., Performance of C1-symmetric chiral
ammonium betaines as catalysts for the enantioselective Mannich-type reaction of α-
nitrocarboxylates. Tetrahedron: Asymmetry 2010, 21, 1189–1190.
(31) Uraguchi, D.; Koshimoto, K.; Ooi, T., Ionic Nucleophilic Catalysis of Chiral
Ammonium Betaines for Highly Stereoselective Aldol Reaction from Oxindole-Derived
Vinylic Carbonates. J. Am. Chem. Soc. 2012, 134, 6972–6975.
(32) Uraguchi, D.; Oyaizu, K.; Ooi, T., Nitroolefins as a Nucleophilic Component for Highly
Stereoselective Aza Henry Reaction under the Catalysis of Chiral Ammonium Betaines.
Chem. Eur. J. 2012, 18, 8306–8309.
(33) Uraguchi, D.; Oyaizu, K.; Noguchi, H.; Ooi, T., Chiral Ammonium Betaine‐Catalyzed
Highly Stereoselective Aza‐Henry Reaction of α‐Aryl Nitromethanes with Aromatic
N‐Boc Imines. Chem. Asian J. 2015, 10, 334–337.
23
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Page 24 of 29
1
2
3
4
5
6
7
8
9
(34) Zhou, X.; Wu, Y.; Deng, L., Cinchonium Betaines as Efficient Catalysts for Asymmetric
Proton Transfer Catalysis: The Development of a Practical Enantioselective
Isomerization of Trifluoromethyl Imines. J. Am. Chem. Soc. 2016, 138, 12297–12302.
(35) Zhang, W.-Q.; Cheng, L.-F.; Yu, J.; Gong, L.-Z., A Chiral Bis(betaine) Catalyst for the
Mannich Reaction of Azlactones and Aliphatic Imines. Angew. Chem. Int. Ed. 2012, 51,
4085–4088.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(36) Claraz, A.; Landelle, G.; Oudeyer, S.; Levacher, V., Asymmetric Organocatalytic
Protonation of Silyl Enolates Catalyzed by Simple and Original Betaines Derived from
Cinchona Alkaloids. Eur. J. Org. Chem. 2013, 7693–7696.
(37) Chen, K.; Shi, G.; Li, H.; Wang, C.; Darensbourg, D. J., Design of Betaine Functional
Catalyst for Efficient Copolymerization of Oxirane and CO2. Macromolecules 2018, 51,
6057–6062.
(38) Wang, H.-Y.; Zheng, C.-W.; Chai, Z.; Zhang, J.-X. Zhao, G., Asymmetric cyanation of
imines via dipeptide-derived organophosphine dual-reagent catalysis. Nat. Commun.
2016, 7, 12720.
(39) Wang, H.-Y.; Zhang, K.; Zheng, C.-W.; Chai, Z.; Cao, D.-D.; Zhang, J.-X.; Zhao, G.,
Asymmetric Dual‐Reagent Catalysis: Mannich‐type Reactions Catalyzed by Ion Pair.
Angew. Chem. Int. Ed. 2015, 54, 1775–1779.
(40) Bauer, G.; Ongari, D.; Xu, X.; Tiana, D.; Smit, B.; Ranocchiari, M., Metal–Organic
Frameworks Invert Molecular Reactivity: Lewis Acidic Phosphonium Zwitterions
Catalyze the Aldol-Tishchenko Reaction. J. Am. Chem. Soc. 2017, 139, 18166–18169.
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ACS Catalysis
1
2
3
4
5
6
7
8
9
(41) Toda, Y.; Sakamoto, T.; Komiyama, Y.; Kikuchi, A.; Suga, H. A Phosphonium Ylide as
an Ionic Nucleophilic Catalyst for Primary Hydroxyl Group Selective Acylation of
Diols. ACS Catal. 2017, 7, 6150-6154.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(42) Keillor, J. W.; Neverov, A. A.; Brown, R. S., Catalysis of Amide Hydrolysis and
Formation under Neutral Conditions by a Zwitterionic Imidazolium Thiolate. J. Am.
Chem. Soc. 1994, 116, 4669–4673.
(43) Yanai, H.; Kobayashi, O.; Takada, K.; Isono, T.; Satoh, T.; Matsumoto, T., Sequential
Mukaiyama–Michael reaction induced by carbon acids. Chem. Commun. 2016, 52,
3280–3283.
(44) Yanai, H.; Yoshino, T.; Fujita, M.; Fukaya, H.; Kotani, A.; Kusu, F.; Taguchi, T.,
Synthesis, Characterization, and Applications of Zwitterions Containing a Carbanion
Moiety. Angew. Chem. Int. Ed. 2013, 52, 1560–1563.
(45) Yanai, H.; Ishii, N.; Matsumoto, T.; Taguchi, T., Organic Acid Catalysts in Reactions of
Lactones with Silicon Enolates. Asian J. Org. Chem. 2013, 2, 989–996.
(46) Yanai, H.; Sasaki, Y.; Yamamoto, Y.; Matsumoto, T. Chemoselective Two-Directional
Reaction of Bifunctionalized Substrates: Formal Ketal-Selective Mukaiyama Aldol Type
Reaction Synlett 2015, 26, 2457–2461.
(47) Ishihara, K.; Niwa, M.; Kosugi, Y., Zwitterionic Salts as Mild Organocatalysts for
Transesterification. Org. Lett. 2008, 10, 2187–2190.
(48) Hatanoa, M.; Ishihara, K., Lanthanum(III) catalysts for highly efficient and
chemoselective transesterification. Chem. Commun. 2013, 49, 1983−1997.
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Page 26 of 29
1
2
3
4
5
6
7
8
9
(49) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y., Efficient Medium Ring
Size Bromolactonization Using a Sulfur-Based Zwitterionic Organocatalyst. J. Am.
Chem. Soc. 2012, 134, 16492–16495.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(50) Xiong, X.; Tan, F.; Yeung, Y.-Y., Zwitterionic-Salt-Catalyzed Site-Selective
Monobromination of Arenes. Org. Lett. 2017, 19, 4243–4246.
(51) Watson, I. D. G.; Afagh, N.; Yudin, A. K., Cyclohexene imine (7-aza-
bicyclo[4.1.0]heptane). Org. Synth. 2010, 87, 161–169.
(52) Crocker, M., Thermochemical conversion of biomass to liquid fuels and chemicals; RSC
Publishing: Cambridge, 2010.
(53) Talebian-Kiakalaieh, A.; Amin, N. A. S.; Mazaheri, H., A review on novel processes of
biodiesel production from waste cooking oil. Appl. Energy 2013, 104, 683–710.
(54) Leung, D. Y. C.; Wu, X.; Leung, M. K. H., A review on biodiesel production using
catalyzed transesterification. Appl. Energy 2010, 87, 1083–1095.
(55) Lin, L.; Zhou, C.; Vittayapadung, S.; Shen, X.; Dong, M., Opportunities and challenges
for biodiesel fuel. Appl. Energy 2011, 88, 1020–1031.
(56) Tanaka, S.; Nakashima, T.; Maeda, T.; Ratanasak, M.; Hasegawa, J.; Kon, Y.; Tamura,
M.; Sato, K., Quaternary Alkyl Ammonium Salt-Catalyzed Transformation of Glycidol
to Glycidyl Esters by Transesterification of Methyl Esters. ACS Catal. 2018, 8,
1097−1103.
(57) Hatano, M.; Tabata, Y.; Yoshida, Y.; Toh, K.; Yamashita, K.; Ogura, K.; Ishihara, K.,
Metal-Free Transesterification Catalyzed by Tetramethylammonium Methyl Carbonate.
Green Chem. 2018, 20, 1193−1198.
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ACS Catalysis
1
2
3
4
5
6
(58) Gupta, M.; Kumar, N., Scope and opportunities of using glycerol as an energy source.
Renewable Sustainable Energy Rev. 2012, 16, 4551–4556.
7
8
9
(59) The details appear in SI.
10
11
12
13
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(60) Otera, J., Transesterification. Chem. Rev. 1993, 93, 1449–1470.
(61) Wuts, P. G. M.; Greene, T. W. Greene's Protective Groups in Organic Synthesis (4th
ed.); Wiley, New Jersey, 2007.
(62) Matsumoto, K.; Yanagi, R.; Oe, Y. in Carboxylic Acid-Key Role in Life Sciences (Badea,
G.-I.; Radu, G. L. eds.), InTechOpen; Ch 2, pp 7-34, 2018.
(63) Otera, J.; Nishikido, J. Esterification: Methods, Reactions, and Applications; Wiley-
VCH, Weinheim, 2010.
(64) Feng, H.; Lu, X.; Wang, W.; Kang, N.-G.; Mays, J. W. Block Copolymers: Synthesis,
Self-Assembly, and Applications. Polymers 2017, 9, 494.
(65) The level of the calculations was M06-2X (with Grimme D3)/6-311G(d,p) using
Gaussian 09 (ver. D.01). The transition states were verified by frequency calculations.
All the thermodynamic properties were evaluated at 373K. The atomic charges shown
were NBO charges.
(66) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.;
Marenich, A.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.;
Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.;
Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe,
D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
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7
8
9
Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J.
W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 09
Revision D. 01. Gaussian Inc. Wallingford CT 2009.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(67) Zhao, Y.; Truhlar, D. G., The M06 suite of density functionals for main group
thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and
transition elements: two new functionals and systematic testing of four M06-class
functionals and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215–241.
(68) Grimme, S.; Ehrlich, S.; Goerigk, L., Effect of the damping function in dispersion
corrected density functional theory. J. Comput. Chem. 2011, 32, 1456–1465.
(69) Johnston, R. C.; Cheong, P. H.-Y., C–H⋯O non-classical hydrogen bonding in the
stereomechanics of organic transformations: theory and recognition. Org. Biomol. Chem.
2013, 11, 5057–5064.
(70) Berg, L.; Mishra, B. K.; Andersson, C. D.; Ekström, F.; Linusson, A., The Nature of
Activated Non‐classical Hydrogen Bonds: A Case Study on Acetylcholinesterase–
Ligand Complexes. Chem. Eur. J. 2016, 22, 2672–2681.
(71) Molina, P.; Zapata, F.; Caballero, A., Anion Recognition Strategies Based on Combined
Noncovalent Interactions. Chem. Rev. 2017, 117, 9907–9972.
(72) Desiraju, G.; Steiner, T. The Weak Hydrogen Bond: In Structural Chemistry and
Biology; Oxford University Press, 2001.
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H
5
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N
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H
N
O
+
O
+
N
Ms
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OR1
OR2
R
R
stable zwitterionic catalyst
R2O
R1O
H
H
R2
O
R1
R2
= H, alkyl
= alkyl
O
R
R1
H
Ms
organocatalysis
catalyst recyclable
transesterification
dehydrative esterification
applicable to biodiesel synthesis
O
N
H
H
dual-activation
N
N
nitrogen
- Brønsted basic
hydrogen bond
- non-classical
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