Development and Applications of Transesterification Reactions Catalyzed by N-Heterocyclic Olefins

Article abstract of DOI:10.1021/acs.orglett.6b00835

A novel method to utilize N-heterocyclic olefins (NHOs), the alkylidene derivatives of N-heterocycic carbenes, as organocatalysts to promote transesterification reactions has been developed. Because of their strong Br?nsted/Lewis basicity, NHOs can enhance the nucleophilicity of alcohols for their acylation reactions with carboxylic esters. This transformation can be employed in industrially relevant processes such as the production of biodiesel, the depolymerization of polyethylene terephthalate (PET) from plastic bottles for recycling purposes, and the ring-opening polymerization of cyclic esters to form biodegradable polymers such as polylactide (PLA) and polycaprolactone (PCL).

Full text of DOI:10.1021/acs.orglett.6b00835

Letter
pubs.acs.org/OrgLett
Development and Applications of Transesterification Reactions
Catalyzed by N‑Heterocyclic Olefins
†
,‡
†
‡
†
,†
Marcus Blu
̈
mel, Janina-Miriam Noy, Dieter Enders, Martina H. Stenzel, and Thanh V. Nguyen*
†
School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
‡
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
*
S Supporting Information
ABSTRACT: A novel method to utilize N-heterocyclic olefins
NHOs), the alkylidene derivatives of N-heterocycic carbenes, as
(
organocatalysts to promote transesterification reactions has been
developed. Because of their strong Brønsted/Lewis basicity, NHOs
can enhance the nucleophilicity of alcohols for their acylation reactions
with carboxylic esters. This transformation can be employed in
industrially relevant processes such as the production of biodiesel, the
depolymerization of polyethylene terephthalate (PET) from plastic
bottles for recycling purposes, and the ring-opening polymerization of
cyclic esters to form biodegradable polymers such as polylactide (PLA) and polycaprolactone (PCL).
rganocatalytic chemistry has rapidly risen to prominence
biodiesel production, depolymerization of polyethylene tereph-
thalate (PET), and ROP of cyclic esters (Scheme 1). This study
demonstrates the bright future of NHOs as a new class of
versatile non-covalent organocatalysts in organic chemistry.
O
over the last 15 years because of its versatility in a broad
1
range of complicated organic transformations. Using specially
designed, small, nonmetallic organic compounds to promote
chemical reactions, organocatalysis offers selective and efficient
alternatives to traditional catalytic chemistry by organometallics
Scheme 1. NHOs Activate Alcohols for Nucleophilic
Reactions
2
or enzymes. Among major organocatalytic systems, N-
heterocyclic carbenes (NHCs) have been used extensively as
“umpolung” organocatalysts to promote fascinating chemical
reactions of carbonyl compounds via the formation of acyl anion
3
intermediates. This very well known role of NHCs overshadows
their ability to act as Brønsted/Lewis basic or nucleophilic
4
catalysts. Current NHC-base-catalyzed chemistry has been used
only in a few types of transformations such as transesterification,
enolate formation, Michael addition, and Morita−Baylis−
5
Hillman reactions.
We have recently highlighted the great potential of N-
heterocylic olefins (NHOs), the alkylidene derivatives of NHCs,
as a new class of organocatalysts with enhanced Brønsted/Lewis
6
basicity. These compounds have been used by Lu’s group for
The ester functional group is one of the most abundant
chemical moieties in organic chemistry. Since the direct
7
10
CO sequestration reactions and by Naumann, Thomas, and
2
Dove for ring-opening polymerization (ROP) of propylene
oxide. NHOs are highly ylidic olefins with an electron-rich
condensation reaction between carboxylic acids and alcohols
remains a nontrivial task, transesterification reactions from
8
11
exocyclic carbon center, which can act as a very strong Brønsted/
Lewis basic site. Similar to NHCs, they are known to
more readily available analogues have become one of the most
attractive options to access ester derivatives. Although there have
been numerous studies of this type of chemical transformation
4
,5
coordinate to alcohols to form Brønsted acid−base pairs of
1
2
4,5
13
8
,9
using organometallic, organocatalytic,
or bio-organic
NHO−alcohol complexes, which are synthetically equivalent
to the corresponding alkoxides. On the basis of this intrinsic
property of NHOs, we envisioned that NHOs could activate
alcohols for nucleophilic transformations such as transester-
ification reactions. We herein report the development of a new
method for NHO-promoted transesterification reactions, which
could then be applied to a range of synthetically important
chemical transformations such as selective acylation reactions,
promoters, a practically efficient method is still in high demand.
The highly basic NHOs, which are estimated to have basicities
comparable to that of the organic superbase phosphazene tBu-P
1
14
(
Scheme 1), appeared to be ideal catalytic systems for
Received: March 22, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00835
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the NHO-Catalyzed
Transesterification Reaction
Table 2. Effect of the Catalyst and Substrate Structures
a
1
2
3
b
entry
R , R , R OH
H, Me, EtOH
cat.
time (h)
yield (%)
c
1
A
2
2
80
83
90
88
85
84
88
85
90
88
91
92
81
29
−
d
B
2
H, vinyl, EtOH
A
B
A
B
A
B
A
B
A
B
A
A
A
1.5
2
c
n
3
H, Me, BuOH
3
3
n
4
H, vinyl, BuOH
1.5
2
c
5
H, Me, BnOH
H, vinyl, BnOH
1.5
4
b
c
6
1
entry equiv of EtOH
solvent
mol % A
additive
yield (%)
3
1
2
3
4
5
6
7
8
9
0
1
2
20
10
5
−
−
−
THF
5
5
5
5
5
5
5
5
2
1
0
−
−
−
−
−
−
58
54
49
61
62
41
80
80
69
62
trace
71
c
n
7
OMe, Me, BuOH
3
c
i
8
OMe, Me, PrOH
12
24
c
t
9
OMe, Me, BuOH
5
a
The reactions were carried out with 1.0 mmol of ester and 5.0 mmol
5
CH Cl
2
2
of alcohol in the presence of 5 mol % catalyst in 1 mL of THF at
ambient temperature until the TLC indicated no further change in the
reaction mixture. Yields of the isolated products. 0.5 g of 4 Å MS was
5
toluene
THF
d
d
d
d
d
d
5
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
b
c
5
CH Cl
d
i
2
2
also added. Dipp = 2,6-( Pr) C H .
2 6 3
5
THF
1
1
1
5
THF
THF
THF
5
mechanism is similar to what has been accepted to mos4t
accurately depict NHC-catalyzed transesterification reactions.
e
5
0
The use of 5 mol % sodium ethoxide in place of the catalyst
a
The reactions were carried out with 1.0 mmol of methyl benzoate
and ethanol in the presence of a catalytic amount of NHO A at rt until
the TLC indicated no further change in the reaction. 1 mL of solvent
was used. Yields of the isolated products. 0.5 g of 4 Å MS was used.
(
Table 1, entry 12) also led to comparable results, supporting our
hypothesis that the NHO−EtOH complex possibly acted as an
ethoxide equivalent.
Subsequently, we surveyed the effect of the catalyst and
alcohol substrate structures on the reaction outcome. NHO
b
c
d
e
5
mol % NaOEt was added as the catalyst.
15
catalyst B with bulky aryl substituents on both of the nitrogen
centers was used for comparison with the simple tetramethyl-
substituted NHO catalyst A. Interestingly, the reaction outcomes
with a range of primary alcohols were very similar for both
catalysts (Table 2, entries 1−6), which was in stark contrast to
transesterification reactions (Scheme 1). Thus, we started with
6
,8
testing a simple imidazolylidene-derived NHO (catalyst A,
Table 1) for its catalytic activity in the reaction between ethanol
and methyl benzoate. To our delight, catalyst A smoothly
promoted the formation of ethyl benzoate in moderate yield with
an excess amount of ethanol (Table 1, entries 1 and 2). When the
amount of ethanol was reduced to the standard 5 equiv, a solvent
was employed to facilitate the progress of the reaction (Table 1,
entries 3−10). THF and CH Cl were comparably good media
for this reaction. In order to increase the conversion rate,
molecular sieves were also added to the reaction mixture to
absorb the methanol byproduct, which led to improved yields.
We also attempted to optimize the catalyst loading (Table 1,
entries 8−10), but 5 mol % seemed to be the optimal amount of
catalyst for the reaction. Without the catalyst, we did not observe
any noticeable conversion (Table 1, entry 11).
We carried out NMR titration studies of the acid−base
exchange between NHO A and a range of organic superbases and
determined that the pK of the conjugate acid of NHO A falls
between those of DBU (24.3) and Bu-P phosphazene base
28.4) in acetonitrile-d . Studies by Dove’s group revealed that
NHOs can act as the Brønsted base to complex with the alcohol
for activation in a similar fashion to their parent NHCs. We also
observed a similar complexation between A and ethanol by NMR
4
,9,10
the NHC-catalyzed reactions.
Presumably, the enhanced
Brønsted basicity of NHOs overcomes any structural influence of
the cyclic backbone. Furthermore, it cannot be ruled out that the
cyclic structure is less influential over the catalytic activity in
NHOs than NHCs because the catalyst active site is now one
carbon farther from the heterocycle. Vinyl ester (Table 2, entries
2, 4, and 6) can be used to replace the methyl ester substrate to
avoid the need to use molecular sieves, as the former substrate led
to the formation of acetaldehyde as the byproduct in an
irreversible reaction. On the other hand, the structural
properties of the alcohols significantly altered the reaction
outcome (Table 2, entries 7−9). The reactivity decreased from
primary to secondary to tertiary alcohols, with the last one being
totally nonreactive toward this system. This observation
encouraged us to utilize tert-butoxide base to generate the
NHO catalysts in situ for the transesterification reactions
(Scheme 2), since the synthesis and isolation of NHO A is
2
2
10
a
t
1
14
(
3
t
complicated because of its air and light sensitivity. KO Bu has
previously been utilized to generate NHO B from its
corresponding imidazolium precursor. As the tert-butanol
byproduct of this process did not interfere with the trans-
esterification reaction, we postulated that the same results could
8
15
1
4
studies, which led us to propose that the transesterification
proceeds through the mechanism illustrated in Table 1. This
B
DOI: 10.1021/acs.orglett.6b00835
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of the NHO-Promoted
Transesterification Reaction
Scheme 3. Other NHO-Catalyzed Transesterification
Reactions
for this type of amidation reaction, as a similar process did not
work well on the primary amine analogues (Scheme 3b). This is
in good agreement with the corrected Brønsted base mode of
5a,8
action for NHC/NHO alcohol activation. The same catalytic
system can be used for the transesterification of stearic and capric
triglycerides to produce esters 3e and 3f (Scheme 3c), suggesting
the potential application of NHOs in biodiesel production.
To further investigate practical applications of this NHO-
catalyzed transesterification procedure, we carried out the
reaction between dimethyl terephthalate and an excess amount
of ethylene glycol (Scheme 4a). The reaction smoothly
proceeded to give BHET (3g) in excellent yield. BHET is a
synthetically valuable compound in plastic chemistry, as it can
undergo a direct-melt polycondensation reaction to afford PET.
Fascinatingly, the very NHO catalyst B could also efficiently
break down PET flakes from a recycled plastic bottle into the
same BHET monomer in a similar transesterification-type
be achieved with the in situ-generated NHO. Indeed, when we
explored the substrate scope of the transesterification reaction
t
(
Scheme 2) with a mixture of precatalyst pre-A and KO Bu,
NHO A was generated in situ. This mixture could conveniently
14
be used to mediate the reaction to afford a range of products in
yields (highlighted in red in Scheme 2) that were almost identical
to those of the reactions catalyzed by free NHO A. Thus, catalyst
t
A or the catalytic system pre-A/KO Bu efficiently promoted the
14
transesterification reactions to give numerous aromatic and
aliphatic esters (Scheme 2) in good to excellent yields. Many
types of functional groups were tolerated in these reactions. Acid-
sensitive functionalities such as silyl ether (2p, 2q) and
tetrahydropyranyl ether (2r) were also retained under these
reaction with ethylene glycol (Scheme 4b). This trans-
formation could be carried out under microwave irradiation or
conventional heating conditions with similar efficiencies. These
NHO-promoted reactions gave results comparable to those for
other reported depolymerization reactions using other strong
1
6
19
reaction conditions. The limitation of the method was again
with bulky secondary alcohols, which afforded low yields of the
corresponding ester products (2m, 2n).
organic bases such as TBD and DBU.
Encouraged by these interesting results and the elegant
polymerization of propylene oxide by Naumann, Thomas, and
8
We subsequently endeavored to turn this initial limitation into
an advantage, as selectivity for primary over secondary alcohols in
Dove, we decided to further investigate the role of NHOs as
organocatalysts for ring-opening polymerization of cyclic esters.
After screening a few sets of reaction conditions and monomer:-
initiator:NHO-catalyst ratios, we were delighted to observe that
17
acylation reactions is very important in organic synthesis. In a
18
reaction catalyzed by catalyst B using a 1:1 mixture of 2-(α-
naphthyl)ethanol and 1-(β-naphthyl)ethanol with methyl
benzoate as the limiting reagent, we obtained a mixture of the
corresponding products 3a and 3b in a ratio of 7:1 at ambient
18
catalyst B efficiently triggered the ROP reactions of ε-
caprolactone and lactide to afford the two biodegradable
polyesters PCL and PLA, respectively. These polyesters formed
14
−1
temperature (Scheme 3a). When the same reaction was carried
out at lower temperature, it provided better selectivity for the
with high molecular weights of 18.21 and 9.56 kg·mol and good
14
polydispersities of 1.71 and 1.56, respectively (Scheme 4c,d).
14
ester product of the primary alcohol 3a (9:1). This clearly
demonstrated the potential of the NHO-promoted trans-
formation in selective acylation reactions. Furthermore, NHO B
The steric bulk of the two N-Dipp groups in combination with
the decreased steric hindrance at the exocyclic methylene group
gave rise to higher molecular weights with similar polydispersities
in comparison with the ester ROP with a propylidene imidazole
NHO catalyst recently reported by Naumann, Thomas, and
9
can also be employed to catalyze amidation reactions between a
methyl ester and alcoholamines to give hydroxyl-substituted
amide products 3c and 3d in high yields (Scheme 3b). Since the
amidation reaction was nonreversible, no molecular sieve was
needed for these reactions. The alcohol functionality is requisite
20
1
Dove. Observation by H NMR spectroscopy confirmed that
these two polyesters have benzyl head groups and hydroxyl end
14
groups. In addition, the measured molecular weights are in
C
DOI: 10.1021/acs.orglett.6b00835
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. NHO-Promoted Depolymerization and
Polymerization Reactions of Biodegradable Polyesters
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00835.
Experimental details, analytical data, and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
t.v.nguyen@unsw.edu.au
■
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The project was supported by the Australian Research Council
Grant DE150100517). M.B. thanks the DAAD and the ERC for
■
(
funding the research exchange to UNSW.
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■
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(
(
6
(
̈
close proximity to the expected molecular weights considering
the initiator:monomer ratio and a monomer conversion of
almost 100%, which is suggestive of a living system. These two
polyesters marked the second new type of organopolymerization
reaction promoted by NHOs, thus once again emphasizing the
great potential of N-heterocyclic olefin organocatalysts in
polymer chemistry. Kinetic studies to further understand and
optimize these NHO-assisted polymerization transformations
are currently underway and will be reported in due course.
In conclusion, we have demonstrated that N-heterocyclic
olefins are a novel class of versatile organocatalysts for
transesterification reactions. Because of their strong Brønsted
basicity, NHOs can enhance the nucleophilicity of alcohols for
their reactions with carboxylic esters. This procedure can be
employed in various synthetically important applications such as
depolymerization of PET, production of biodiesel, and ring-
opening polymerization of cyclic esters to give biodegradable
polymers. This work once again demonstrates the bright future
of NHO organocatalysts in synthetic chemistry. We are currently
working on other types of NHO-organocatalyzed chemical
transformations and will endeavor to report these studies in due
course.
3
(
(
(15) Powers, K.; Hering-Junghans, C.; McDonald, R.; Ferguson, M. J.;
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(
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4
, NHO catalyst B was used in preference to catalyst A because of its
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(
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D
DOI: 10.1021/acs.orglett.6b00835
Org. Lett. XXXX, XXX, XXX−XXX