Electronic Activity Tuning of Acyclic Guanidines for Lactide Polymerization

Article abstract of DOI:10.1021/acs.macromol.5b02137

Novel aromatic guanidine-based organocatalysts for the ring-opening of l-lactide were synthesized and applied in comprehensive polymerization experiments and kinetic studies. The introduction of electronically active substituents led to a significant chan

Full text of DOI:10.1021/acs.macromol.5b02137

Article
pubs.acs.org/Macromolecules
Electronic Activity Tuning of Acyclic Guanidines for Lactide
Polymerization
Fabian Eisenreich, Philipp Viehmann, Fabian Muller, and Stefan Hecht*
̈
Department of Chemistry, Humboldt-Universitat zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
̈
S
* Supporting Information
ABSTRACT: Novel aromatic guanidine-based organocatalysts for the
ring-opening of L-lactide were synthesized and applied in compre-
hensive polymerization experiments and kinetic studies. The
introduction of electronically active substituents led to a significant
change in activity by 2 orders of magnitude. The formed polylactide is
featured with narrow polydispersity and high end-group fidelity, both
characteristics that are typical for living polymerizations. Besides that,
using linear free-energy relationships and DFT calculations revealed
new insights into the polymerization mechanism. The formation of an
adduct consisting of the catalyst and initiator/chain end turned out to
be the rate-limiting step.
active as compared to TBD originating from their lower
INTRODUCTION
■
basicity, which has been attributed to the out-of-plane rotation
of the pyrrolidine ring and thus to a weakened conjugation
between the three guanidine nitrogens.7c However, the activity
of such acyclic guanidines is still high and at least comparable to
other organocatalysts for the ROP of lactide, such as
thioureas7b,13 or 2-amidoindoles.14
A detailed knowledge of the interplay of electronic factors
and catalytic activity of guanidines would be worthwile in order
to develop creative approaches to achieve an elevated level of
control over polymerization processes, e.g., photoswitchable
polymerization catalysis.15 Hence, we synthesized various new
guanidine organocatalysts 1−3 bearing aromatic rings in order
to investigate the ability of electronically active substituents to
influence their catalytic activity (Figure 1). Note that
introduction of an aromatic moiety into the catalyst scaffold
The precise construction of customized materials associated
with desired physical properties represents one of the essential
challenges in materials science. Living polymerization techni-
ques, for instance, are important methods to achieve a high
degree of control over the polymerization process, which
enables the synthesis of complex polymer architectures.1
Organocatalysts have been attracting a significant attention2
in the field of ring-opening polymerizations (ROP) of cyclic
esters since the first approach3 was published in 2001. The
necessity to exclude metal contamination in the final polymers
for biomedical4 and microelectronic5 applications favors the use
of purely organic catalysts. Within the wide-ranging spectrum of
versatile polymerization catalysts6 the class of guanidines
features an outstanding activity toward the ROP of cyclic
esters.7 Guanidines are well-known for their high Brønsted
basicity as well as hydrogen bond donor and acceptor activity
and therefore successfully employed in a variety of organic
transformations,8 e.g., enantioselective reactions9 and trans-
esterifications.7a,10
Specifically, guanidines such as triazabicyclodecene (TBD)7a
or acyclic derivatives7c have been shown by Hedrick and
Waymouth to be efficient organocatalysts for the ROP of L-
lactide (LA). Polymerizations catalyzed by 0.1 mol % TBD
were completed after few seconds only, yielding polylactide
with a high degree of polymerization (DP = 100) combined
with a narrow polydispersity (PDI = 1.19).7a This remarkable
activity, rivaling the most active metal catalysts,11 is due to the
specific arrangement of the guanidine nitrogens, which provide
a dual activation of both the monomer and the initiating
alcohol via hydrogen bonds. Computational studies proved that
a mechanism involving only hydrogen bonds is energetically
preferred over an alternative nucleophilic pathway.12 On the
contrary, related acyclic guanidine catalysts are considerably less
Figure 1. Guanidine organocatalysts for polymerization of lactide.
Received: September 28, 2015
Revised: November 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.macromol.5b02137
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is key to achieve communication between a photoswitchable
unit (to be incorporated at a later stage) and the catalytically
active site.
the reaction mixture at different times, treated with excess of
benzoic acid, and analyzed by 1H NMR spectroscopy. All
polymerization experiments were conducted at least three
times. Clearly, the guanidine catalysts 1a−1d show a significant
difference in their activity (Figure 2). The polymerization times
RESULTS AND DISCUSSION
■
Since a modulation of the TBD scaffold is synthetically
challenging, we targeted the substitution of the aliphatic
residue(s) of the acyclic guanidine structure with aromatic
moieties. Synthesis of the new aromatic acyclic guanidine
derivatives 1−3 (Scheme 1) involved initial reaction of
Scheme 1. Synthesis of Aromatic Guanidines 1−3
Figure 2. Monomer conversion vs time for ROP of L-lactide catalyzed
by 1a−1d with M/I/C ratio = 50:1:1. Experiments performed in
triplicate (error bars represent standard deviation).
are ranging from 7 h for 1d with a dimethylamino group as a
strong electron donor to 48 h for 1b without any activating
group attached (Table 1). By adding a trifluoromethyl
pyrrolidine and morpholine with cyclohexyl or phenyl
isocyanate, respectively. Subsequently, the formed carboxa-
mides were transformed to their Vilsmeier salts, which were
reacted in situ with the different aniline derivatives to give the
guanidine hydrochlorides. In the final step, the hydrochlorides
were exposed to a potassium hydroxide solution to obtain the
free guanidines 1−3 quantitatively.
Table 1. Polymerization of L-Lactide Using Guanidine
a
Catalysts 1
The catalytic activity for the ROP of lactide of the
synthesized guanidines 1b, 2, and 3 was studied in a preliminary
polymerization experiment under conditions, which are
identical to the ones established by Hedrick for the case of
the acyclic guanidine. Polymerizations of L-lactide in dry
CH2Cl2 ([LA]0 = 2 M) with a monomer/initiator/catalyst (M/
I/C) ratio of 100:1:1 and with 1-pyrenebutanol acting as the
initiator were conducted. After a reaction time of 24 h the
b
b
time
[h]
conv
Mn
kapp [10−3
d
c
entry catalyst DP
[%]
[g mol−1
]
PDI
n.d.
h−1
]
1
2
3
4
5
6
7
1a
1b
1c
1d
1d
1d
1d
50
50
48
48
20
7
19
96
97
99
96
92
85
n.d.
4
0.3
4
7500
7900
7500
12800
19100
26100
1.06
1.07
1.06
1.04
1.08
1.18
73
50
167 11
602 23
n.d.
50
100
150
200
34
72
96
1
conversion of the monomer was determined via H NMR
n.d.
spectroscopy by integrating the characteristic methine proton
signals of both the polymer and residual monomer. Guanidines
1b and 2 led to a conversion of 36% and 17%, respectively,
whereas compound 3 was found to be entirely inactive, even at
higher catalyst loadings of 10 mol %. These results indicate a
significantly lower activity as a result of replacing the cyclohexyl
rings with aromatic phenyl moieties. The electron density of
the guanidine nitrogens is therefore delocalized over the π
system of the adjacent aromatic moieties, which has apparently
a detrimental impact on the associated basicity16 and thus on
the catalytic activity. Furthermore, by exchanging the
pyrrolidine structure with morpholine, which is in general
less basic17 (pKa(H2O) = 11.3 vs. 8.5), the catalytic activity is
entirely lost.
After these initial experiments the lead structure 1b was
further modified in order to fine-tune the respective catalytic
activity by introducing electronically active substituents, which
are compatible with the reaction conditions and do not engage
in side reactions such as transesterification. To investigate the
influence of the electronic properties of guanidines 1a−1d the
M/I/C ratio was decreased to 50:1:1 with the aim to achieve
reasonable reaction times for complete monomer conversion.
During the polymerization process aliquots were taken from
n.d.
a
Reaction conditions: [LA]0 = 2 M in CH2Cl2 with 1-pyrenebutanol as
b
c
initiator. Determined by 1H NMR spectroscopy. Determined by
d
GPC in THF (calibrated with polystyrene standards). Derived from
first-order kinetic relationship. n.d. = not determined.
substituent as electron-withdrawing group, the activity of 1a
is drastically reduced, which is displayed by a monomer
conversion of only 19% after 2 days.
Furthermore, polylactide with higher molecular weights (DP
= 100−200) could be obtained with 1d as catalyst in prolonged
reaction times. The yielded polylactide is characterized by
narrow polydispersity (PDI = 1.04−1.18), which is typically
associated with living polymerization processes. The living
character of the ROP is furthermore affirmed by the linear
relationship of the molecular weight Mn vs monomer
conversion, even until late stages of the polymerization (see
Supporting Information). Moreover, the overlap of the RI and
the UV traces of the GPC measurements shows a complete
integration of the pyrene-based initiator into the polymer
backbone (see Supporting Information). The molecular
weights determined by end-group analysis via 1H NMR
B
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spectroscopy are close to the theoretical target Mn values
corresponding to quantitative monomer conversion (see
Supporting Information). Concerning the stereochemistry of
the polymer no epimerization of the methyl group is observed
in the 13C NMR spectra. In addition, differential scanning
calorimetry (DSC) of PLA with DP = 100 revealed a melting
point Tm = 158 °C, which exactly matches previously reported
melting temperatures of isotactic PLA13c (see Supporting
Information).
In order to compare the performance of the catalysts more
precisely, the rate constants were determined by (pseudo) first-
order kinetic plots of ln([M]0/[M]t) vs time revealing a linear
relationship (Figure 3). As apparent from the different
suggests that below a certain basicity the mechanism is altered,
which is consistent with the strongly reduced activity.
To gain further insight, the obtained results were additionally
supported by comparing the adducts of 1 and methanol (as a
model alcohol), using density functional calculations (B3LYP/
TZVP/PCM)19 and implicit CH2Cl2 solvation (for a detailed
description see Supporting Information). The guanidine−
methanol interaction can be quantified by the extent of proton
transfer within the formed hydrogen bridge. The distance
between the basic guanidine nitrogen and the alcohol proton
decreases, whereas the bond dissociation energy (BDE) rises
with increasing electron density of the guanidines (Table 2). In
Table 2. Computationally Calculated Distances and Bond
Dissociation Energy (BDE) for Adducts of 1 and Methanol
as well as Gas-Phase Basicities
entry
catalyst
dN−H(OMe) [Å]
BDE [kcal/mol]
GB [kcal/mol]
1
2
3
4
5
1a
1.835
1.813
1.797
1.793
0.042
−4.5
−4.9
−4.9
−5.3
0.8
241
245
248
252
13
1b
1c
1d
Δmax
addition, the gas-phase basicities of 1a−1d were calculated and
are in good agreement with empirical determined basicities of
related acyclic guanidines.20 The basicities show the same trend
as compared with the adduct formation, which is consistent
with the observed activity differences and further verify the
impact of the substituents on the basic properties.
Figure 3. Kinetic analysis of the polymerization reaction according to a
(pseudo) first-order rate law (lines show the linear fits).
polymerization outcome the derived rate constants are highly
dependent on the nature of the substituent ranging from kapp
=
4 × 10−3 h−1 for 1a to kapp = 6 × 10−1 h−1 for 1d, thereby giving
raise to a difference in activity by a factor of 150 (Table 1).
With these rate constants in hand it is now possible to obtain
a better mechanistic understanding of the rate-determining step
during the polymerization process by using linear free-energy
relationships. When correlating the rate constants to the
Hammett constants18 of the respective substituents by applying
the classical Hammett equation a linear relationship with a
negative slope is obtained (Figure 4). The associated reaction
CONCLUSION
■
In summary, we synthesized new aromatic guanidine-based
organocatalysts for the ROP of L-lactide and investigated the
influence of electronic effects on their activity. It turned out that
the catalytic activity of acyclic guanidines could be retained
upon replacing one aliphatic cyclohexyl group with an aromatic
phenyl moiety. Importantly, this structural modulation allows
for tuning of the catalysts’ activity by incorporating electroni-
cally active substituents. By introducing strongly electron-
donating dimethylamino groups (1d), the catalytic activity was
enhanced by 2 orders of magnitude as compared to electron-
withdrawing trifluoromethyl groups (1a). This significant
reactivity difference is an important prerequisite to dynamically
alter the catalytic activity of guanidines with the aid of
photoswitchable systems, which is the subject of current efforts
in our research group.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.macro-
mol.5b02137.
■
S
Figure 4. Application of the Hammett equation to the rate constants
kapp and the respective Hammett constants σp of the substituents.18
Experimental procedures, characterization data, GPC
experiments, and details on DFT calculations (PDF)
constant ρ = −1.1 implies a slightly positively charged
transition state. This is in accordance with the basic character
of the guanidines, leading to a strong interaction and thus
activation of the initiating alcohol/propagating chain end by
formation of an alcohol adduct during the rate-limiting step.
The deviation of 1a from the linear correlation furthermore
AUTHOR INFORMATION
Corresponding Author
*E-mail: sh@chemie.hu-berlin.de (S.H.).
Notes
■
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Generous support by the European Research Council (ERC via
ERC-2012-STG_308117 “Light4Function”) is gratefully ac-
knowledged. F.E. is indebted to the Fonds der chemischen
Industrie for providing a doctoral fellowship. BASF AG, Bayer
Industry Services, and Sasol Germany are thanked for
donations of chemicals.
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