Regioselective ring-emitting esterification on azacyclohexane quaternary salts: A DFT and synthetic study for covalent fixation of electrostatic polymer self-assemblies

Article abstract of DOI:10.1021/jo400058f

A regioselective nucleophilic esterification upon six-membered, thus considered unstrained, azacyclohexane quaternary salts has been disclosed by DFT calculations using a model compound and subsequent experimental studies of nucleophilic substitution on N-phenyl-3,3-dimethylpiperidinium salt groups at the polymer chain ends by carboxylate anions. An exclusive ring-emitting esterification was proposed theoretically and confirmed experimentally to produce a simple ester group, in contrast to less robust amino-ester linkages through an alternative ring-opening process with strained five-membered ammonium salts. This reaction was subsequently applied to a prototypical process of an electrostatic self-assembly and covalent fixation (ESA-CF) technique to produce a ring polymer having simple ester linking units.

Full text of DOI:10.1021/jo400058f

Article
pubs.acs.org/joc
Regioselective Ring-Emitting Esterification on Azacyclohexane
Quaternary Salts: A DFT and Synthetic Study for Covalent Fixation of
Electrostatic Polymer Self-Assemblies
Akihiro Kimura, Shinnosuke Takahashi, Susumu Kawauchi,* Takuya Yamamoto, and Yasuyuki Tezuka*
Department of Organic and Polymeric Materials, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: A regioselective nucleophilic esterification upon
six-membered, thus considered unstrained, azacyclohexane
quaternary salts has been disclosed by DFT calculations
using a model compound and subsequent experimental studies
of nucleophilic substitution on N-phenyl-3,3-dimethylpiper-
idinium salt groups at the polymer chain ends by carboxylate
anions. An exclusive ring-emitting esterification was proposed
theoretically and confirmed experimentally to produce a
simple ester group, in contrast to less robust amino-ester
linkages through an alternative ring-opening process with
strained five-membered ammonium salts. This reaction was subsequently applied to a prototypical process of an electrostatic self-
assembly and covalent fixation (ESA-CF) technique to produce a ring polymer having simple ester linking units.
poly(tetrahydrofuran), poly(THF), proceeded predominantly
(80−90%) at the exo position: i.e., the N-adjacent methylene
unit of the polymer chain. Also, the elimination of N-
phenylpiperidine (ring-emitting) produces a simple ester
linkage (Scheme 1).9
INTRODUCTION
■
The ring strain conception has served over a century after
Baeyer’s report1 as a basis for understanding the chemical
reactivity of cyclic compounds.2 Ring strain has frequently or
intuitively been assumed to be a principal driving force of
controlling the reaction of ring systems in organic chemistry, in
biochemistry, and in polymer chemistry.2−4 Ring strain has also
been elucidated through theoretical and computational means,5
which have recently been contributing to rational interpreta-
tions of experimental results and furthermore to prediction of
the unknown experimental outcome.6 Typically, nucleophilic
ring-opening reactions by strained three-, four-, and five-
membered cyclic oxonium, sulfonium, and ammonium salts by
various nucleophiles have been exploited in a wide range of
practical chemical processes, including cationic ring-opening
polymerization.4 Carboxylates, in particular, have been
employed in routine esterification processes to form ether
esters, thioether esters, and amino esters.7
In the present study, we first conducted density functional
theory (DFT) calculations in order to obtain insights into this
counterintuitive observation. The DFT results showed that the
observed regioselection is likely explained by the higher energy
and frustrated transition state toward the ring-opening path in
comparison with that toward the ring-emitting path, despite the
absence of ring strain in the ground state six-membered cyclic
ammonium salts. By the DFT analyses, moreover, the 1,3-
diaxial steric interaction could exert a crucial influence on the
energy profile of the transition states of these nucleophilic
substitution reactions. Prompted by these DFT results, we
conducted experimental studies to realize an exclusive ring-
emitting esterification process by N-phenyl-3,3-dimethylpiper-
idinium salt groups at the polymer chain ends.
In contrast, six-membered cyclic onium salts are considered
strain-free and consequently incapable of inducing any selection
between ring-emitting and ring-opening paths. In addition, the
nonselective reaction should produce twice the amount of ring-
opening product formed by attack at two endo-methylene units
vs the ring-emitting counterpart produced by the reaction at one
exo-methylene unit. Indeed, regioselective nucleophilic sub-
stitution reactions of six-membered ammonium (piperidinium)
salts have scarcely been documented, except for N-methyl cyclic
ammonium derivatives, which in turn undergo exclusive attack
on the methyl group rather than ethyl or other alkyl
counterparts due to steric preferences.8 It was surprising,
therefore, to observe that nucleophilic substitution by a
carboxylate anion on N-phenylpiperidinium end groups of
We have subsequently applied this covalent fixation process
to produce a ring polymer having a simple ester linkage, which
is hard to obtain through an alternative common alcohol/acid
condensation or other nucleophile/electrophile esterification.
The controlled conversion of ion pairs into covalent forms has
so far been achieved by the ring-opening reactions of
moderately strained cyclic ammonium salts with carboxylate
counteranions. In addition, an electrostatic self-assembly and
covalent fixation (ESA-CF) process thereby has successfully
been employed to construct a wide variety of complex polymer
Received: January 11, 2013
Published: March 7, 2013
© 2013 American Chemical Society
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Scheme 1. Ring-Emitting and Ring-Opening Reactions of Six-Membered Cyclic Ammonium Salt End Groups with a Series of
Carboxylate Anions
architectures (topological polymer chemistry; see Scheme S1 in
the Supporting Information).10,11 The ESA-CF process has
recently been applied also as a versatile means of surface
modification of solids and fabrics.12 In these covalent fixation
processes, such moderately strained five-membered pyrrolidi-
nium13 and six-membered bicyclic quinuclidinium salts as well
as a five-membered thiolanium salt14 have currently been
applied. The regioselective ring-opening reaction took place, at
the prescribed elevated temperatures, through nucleophilic
substitution at the endo position of the N- and S-adjacent
methylene units of the cyclic onium salt unit.
An alternative covalent fixation protocol through a ring-
emitting process with polymer precursors having N-phenyl-
piperidinium end groups could produce simple and robust ester
linkages, in contrast to amino ester groups formed through the
relevant ring-opening process in the conventional ESA-CF
technique.15 Notably, moreover, a cyclic polymer including a
fluorescent perylene unit, which is specifically employed for
single-molecule spectroscopic studies, was prepared using a
polymer precursor having N-phenylpiperidinium end groups;
even the ring-emitting esterification of the unsubstituted N-
phenylpiperidinium group failed to proceed selectively.16 In this
particular case, the elimination of fluorescence-quenching N-
phenylamine groups from the polymer product was a
prerequisite for performing the single-molecule spectroscopic
measurements.
having N-phenylpiperidinium salt end groups carrying triflate
counteranions (1/triflate), were mixed with a THF solution
containing an excess amount (10 equiv) of tetra-n-butylammo-
nium benzoate or tetra-n-butylammonium p-methoxybenzoate.
The reaction mixture solution was refluxed to cause
esterification via a nucleophilic substitution reaction. For the
reaction with p-nitrobenzoate, on the other hand, the initial
triflate counterion of 1/triflate was replaced by p-nitrobenzoate
to avoid side reactions.20 The esterification products,
1a(em,op), 1b(em,op), and 1c(em,op) (Scheme 1), obtained
with the respective benzoate anions, were collected by
reprecipitation, and the regioselectivity of the reactions was
1
determined by means of H NMR analysis (Figure 1). Thus,
the ring-emitting/ring-opening reaction ratio (em/op) was
readily estimated by comparing the signals arising from the
benzoate groups at 6.9−8.3 ppm (unsubstituted benzoate at
7.4−8.1 ppm, p-methoxybenzoate at 6.9−8.0 ppm, or p-
nitrobenzoate at 8.2−8.3 ppm) and methylene groups adjacent
to the ester oxygen atoms at 4.3−4.4 ppm with those from the
N-phenyl groups at 6.6−7.2 ppm. It has been confirmed that, as
summarized in Table 1, concurrent ring-emitting and ring-
opening reactions were observed to take place, while the
regioselectivity in the nucleophilic substitution was scarcely
affected by the type of benzoates having different nucleophi-
licities. It is notable, in particular, that the ring-emitting
substitution (85−87%) prevailed despite the fact that the six-
membered azacyclohexane unit is intuitively considered free of
ring strain, as in the case of cyclohexane.
2. DFT Studies on the Transition States in the
Esterification of Azacyclohexane Quaternary Salts. The
serendipitous observation of the predominant ring-emitting
esterification with azacyclohexane quaternary salts was
subsequently studied by a DFT technique using a series of
model compounds, where an ethyl group was introduced in
place of the polymer chain for the sake of the calculations
(Scheme 2). It is notable that combined experimental/
theoretical studies on noncovalent self-assembly processes are
of increasing current interest.21 A restricted hybrid nonlocal
density functional, R-B3LYP,22 with the 6-31+G(d) basis set23
has been used for the calculations. The continuum conductor-
like polarizable continuum model (CPCM, COSMO)24 was
employed to include a solvent effect of THF to fit the terms
with the experimental conditions. The optimized transition
state structures were verified to have only one imaginary
frequency indicating the reaction coordinate by harmonic
vibrational frequency calculations (see the Supporting
Information for details). All of the calculations were carried
out by using the Gaussian 09 program.25
RESULTS AND DISCUSSION
■
1. Experimental Studies on the Regioselectivity in the
Esterification of Azacyclohexane Quaternary Salts. We
first examined the regioselectivity in the nucleophilic
substitution on the N-phenylpiperidinium units by carboxylate
anions of various nucleophilicity, including benzoate (pKa =
4.20), p-methoxybenzoate (pKa = 4.47), and p-nitrobenzoate
(pKa = 3.42) using poly(THF) having N-phenylpiperidinium
salt end groups.13 The phenyl substituent on the nitrogen atom
was purposely introduced in order to circumvent the
substitution reaction on this specific position (Scheme 1). An
alternative methyl substituent on the nitrogen atom promotes
the nucleophilic attack at this sterically favored position, even in
the case with that on the strained five-membered ammonium
salt.17 It is also notable that the pyridinium end group failed to
cause selective substitution at the exo position, instead resulting
in uncontrolled reactions on the pyridinium ring unit.18
As the employed poly(THF)s possessing ionic end groups,
having molecular weights of more than several thousands, were
readily soluble in the appropriate organic media, nucleophilic
substitution by various carboxylates was carried out in dry THF,
where the anion is free of hydration to form a “naked”
nucleophile to promote the reaction.19 Thus, poly(THF)
The differences in the transition state free energies
(ΔΔG⧧em−op) calculated at 339.15 K and 1 atm by using
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Table 1. Experimental and Calculated Ring-Emitting/Ring-
Opening Product Ratios (em/op) and Transition State Free
Energy Differences (ΔΔG≠em−op) in the Esterification on Six-
Membered Azacycloalkane Quaternary Salts by a Series of
Benzoate Anions
type of benzoate
a
anion
ring-emitting/ring-opening
calculated
para
experimental product ratio
ΔΔG⧧
em−op
b
c
substituent pKa
(em/op)
(kJ/mol)
H
4.20
4.47
3.42
85/15 (−4.9)
85/15 (−4.9)
−7.9 (94/6)
−8.7 (96/4)
−7.5 (94/6)
OCH3
NO2
87/13 (−5.4)
a
b
See Scheme 1 for the structures. The calculated ΔΔG⧧
values
em−op
in parentheses were obtained by using the equation ΔΔG⧧em−op = RT
ln (op/em) with R = 8.3145 × 10−3 kJ/(mol K) and T = 339.15 K,
which is the reflux temperature of THF as in the experimental
c
conditions. The calculated em/op values in parentheses were
obtained by using the equation ΔΔG⧧
= RT ln (op/em) with
em−op
R = 8.3145 × 10−3 kJ/(mol K) and T = 339.15 K, which is the reflux
temperature of THF as in the experimental conditions.
model compound I were subsequently compared in Figure 2A
(I(gs), I(em) and I(op), respectively). Throughout the
reaction, the azacyclohexane unit of I adopts a chair
conformation with the phenyl substituent at the axial position
and the ethyl counterpart (thus, corresponding to the polymer
chain in 1) at the equatorial position, respectively.27 This
specific structure was calculated to be favored also at the
transition state rather than an alternative form with the phenyl
group at an equatorial position, by 3.1 kJ/mol for the ring-
opening and 7.1 kJ/mol for the ring-emitting products,
respectively.28 Importantly, at the transition state in the ring-
opening path (I(op) in Figure 2A, top view), the azacyclohex-
ane ring is distorted through the elongation of the distance
between N1 and C6 to 2.125 Å from 1.539 Å at the ground
state (I(gs) in Figure 2A, top view). In contrast, the
corresponding bond distance at the transition state in the
ring-emitting path remains unchanged at 1.498 Å (I(em) in
Figure 2A, top view). In addition, the N1−C6−C5 angle at the
transition state in the ring-opening path (I(op) in Figure 2A,
top view) decreases significantly to 98.8° from 112.4° at the
ground state (I(gs) in Figure 2A, top view). On the other hand,
the corresponding angle in the ring-emitting path remains
unchanged at 112.5° (I(em) in Figure 2A, top view). These
results indicate the greater structural frustration at the
transition state in the ring-opening path than that in the ring-
emitting path, in which elongation of the distance between N1
and C7 (2.101 Å) does not affect the conformation of the
azacyclohexane unit (I(op) and I(gs) in Figure 2A, top view).
Thus, it is conceivable that the ring-emitting, rather than the
ring-opening, esterification is favored on the N-phenylpiper-
idinium end group.
1
Figure 1. H NMR spectra of (top) 1a(em,op), (middle) 1b(em,op),
and (bottom) 1c(em,op) (CDCl3, 25 °C).
statistical thermodynamics26 and the ring-emitting/ring-open-
ing product ratios (em/op) estimated thereby, together with
experimentally obtained values, are collected in Table 1. Thus,
the calculation results for N-phenylpiperidinium model
compound I with X = H of ΔΔG⧧
= −7.9 kJ/mol
em−op
(corresponding to em/op = 94/6), as well as I with X = OCH3
of −8.7 kJ/mol (em/op = 96/4) and I with X = NO2 of −7.5
kJ/mol (em/op of 94/6) comparatively agreed with the
experimental em/op ratios (and ΔΔG⧧
values estimated
em−op
therefrom) for a series of telechelics 1 with X = H for 85/15
(−4.9 kJ/mol), with X = OCH3 for 85/15 (−4.9 kJ/mol), and
with X = NO2 for 87/13 (−5.4 kJ/mol), respectively. It is
notable, moreover, that the DFT results coincide with the
experimental observations by the constant regioselectivity with
a series of benzoates having varied nucleophilic reactivities.
These results strongly suggest that the regioselectivity in the
present esterification process is driven by kinetic (transition
state energy) factors.
In order to realize an exclusive ring-emitting process by using
a modified N-phenylpiperidinium salt derivative, we have
subsequently conducted DFT calculations for a series of
model compounds having a variety of substituent patterns on
either the phenyl or azacyclohexane unit, to determine steric
and electronic effects on the transition state (Scheme 2, II−IV).
The results are collected in Table 2. The introduction of either
an electron-donating or electron-withdrawing substituent at the
4-position of the phenyl substituent has little influence on the
The DFT-optimized ground state and transition state
structures in the ring-emitting and the ring-opening routes of
ΔΔG⧧
value (for III −7.9 kJ/mol, and for −9.1 kJ/mol).
em−op
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Scheme 2. Series of Model Compounds Employed for the DFT Calculations on the Transition States of Their Ring-Emitting
and Ring-Opening Reactions with Carboxylate Counteranions
Figure 2. DFT-optimized ground state (gs) and the ring-opening (op) and the ring-emitting (em) transition state structures of the esterification by
benzoate upon (A) N-phenylpiperidine (I) and (B) N-phenyl-3,3-dimethylpiperidine salt groups (II). The benzoate anion is omitted for the sake of
clarity.
In contrast, the introduction of two methyl groups at the 3-
tion of dimethyl groups at the 3-position of the azacyclohexane
unit caused a significant increase of the dihedral angle for
II(op) to 30.6°, against the slight decrease for II(em) to 6.4° as
noticed in Newman projections (N1−C9) in Figure 2B. This
coincides with the substantial difference in the spatial
arrangement of substituent groups in II(op), where the group
containing C8 and the 3,3-dimethyl group are placed on the
same side in order to accommodate the carboxylate anion
coming toward C2 from the opposite side (II(op) in Figure 2B,
top view), whereas the spatial arrangement of substituent
groups both in II(em) and in the ground state commonly both
the group containing C8 and the 3,3-dimethyl group are placed
on opposite sides (II(gs) and II(em) in Figure 2B, top view).
The substantial structural rearrangement at the transition state
in the ring-opening path, II(op), is in parallel with the
enhanced steric frustration in comparison with the alternative
ring-emitting process, II(em). Consequently, it is conceived
that the exclusive ring-emitting esterification proceeds with N-
phenyl-3,3-dimethylpiperidinium salt groups at the polymer
chain ends.
position of the azacyclohexane unit (II) resulted in a
remarkable increase of the ΔΔG⧧
value (−22.0 kJ/mol)
em−op
to accelerate the ring-emitting process over the ring-opening
counterpart.
The DFT-optimized ground state and transition state
structures in the ring-emitting and ring-opening processes for
a N-phenyl-3,3-dimethylpiperidinium salt group were subse-
quently compared in Figure 2B (II(gs), II(em), and II(op),
respectively). First, the distorted azacyclohexane ring structure
is observed at the transition state in the ring-opening path, as in
the case of the unsubstituted model compound I (parts A and B
of Figure 2, top view). In addition, the 1,3-diaxial interaction
between a phenyl and a methyl group at the 3-position of the
azacyclohexane unit causes a remarkable rearrangement of the
spatial positions of the phenyl group around the N−Ph bond.
Thus, in contrast to the nearly constant dihedral angle of C2−
N1−C9−C10, namely 14.5° for I(op) and 13.4° for I(em), for
the unsubstituted model compounds shown in Newman
projections (N1−C9) in Figure 2A, the subsequent introduc-
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1
esterification protocol (Scheme 3). The H NMR spectra of
2 accompanying benzoate and biphenyldicarboxylate counter-
anions, 2/benzoate and 2/biphenyldicarboxylate, are shown in
Figure 3 (top) for the latter and in Figure S1 (top) in the
Supporting Information for the former. The introduction of the
respective counteranions was confirmed by the presence of
signals attributed to benzoate at 7.29−8.19 ppm and
biphenyldicarboxylate at 8.20 and 7.59 ppm, in addition to
those due to the N-phenyl-3,3-dimethylpiperidinium group at
7.47−7.66, 3.70−4.22, and 4.37−4.49 ppm. The subsequent
heat treatment of the ionic complexes 2/benzoate and 2/
biphenyldicarboxylate was performed in THF at concentrations
of 2.0 and 0.2 g/L, respectively, at reflux for 5 h, as the dilution
was requisite for effective intramolecular cyclization.11 The
covalently converted products, 3(linear) and 3(cyclic), were
recovered after column chromatographic purification in 77%
Table 2. Calculated Transition State Energy Differences
(ΔΔG≠em−op) and Product Ratios (em/op) for the Ring-
Emitting and Ring-Opening Reactions of N-
Phenylpiperidinium Derivatives (I−IV), Thianium (V), and
3,3-Dimethylthianium (VI) with a Benzoate Anion
model
substrate
calcd ΔΔG⧧
ring-emitting/ring-opening product
em−op
a
b
(kJ/mol)
ratio (em/op)
c
I
−7.9
−22.0
−7.9
−9.1
−9.1
94/6 (85/15)
d
II
100/0 (100/0)
III
IV
V
94/6
96/4
96/4
97/3
VI
−10.1
b
a
See Scheme 2. The em/op and ΔΔG⧧
values were
em−op
interconverted with each other by using the equation ΔΔG⧧
=
em−op
RT ln (op/em) with R = 8.3145 × 10−3 kJ/(mol K) and T = 339.15 K,
which is the reflux temperature of THF as in the experimental
1
yield for the former and in 56% yield for the latter. The H
c
NMR spectra showed a triplet signal arising from the
methylene protons adjacent to the ester oxygen atoms at
around 4.4 ppm, while no signals assignable to the N-phenyl
group were detectable between 6.0 and 7.2 ppm, indicating the
quantitative elimination of N-phenyl-3,3-dimethylpiperidine
(Figure 3 (bottom) and Figure S1 (bottom) in the Supporting
Information).
MALDI-TOF MS analysis further confirmed the production
of the covalently converted linear and ring poly(THF)s,
3(linear) and 3(cyclic), respectively (Figure 4A). Thus, a series
of peaks with an interval of 72 mass units corresponded to
poly(THF) having the specific end groups or the linking group
structure. The peak at m/z 3927.1 (Figure 4, top) matched a
Na+ adduct of 3(linear) with a DPn of 50 having benzoate ester
end groups, in agreement with the calculated molar mass of
3926.692 Da for (C4H8O) × 50 + C18H18O4 plus Na+.
Moreover, the peak at m/z 3924.9 (Figure 4A, bottom)
corresponded to 3(cyclic) with a DPn of 50 incorporating the
biphenyldicarboxylate linking group (the calculated molar mass
of 3924.676 Da for (C4H8O) × 50 + C18H16O4 plus Na+).
These molecular weights deviate by 2 mass units arising from
the difference between the chemical structures of two benzoate
and one biphenyldicarboxylate anion.
SEC traces of the covalently converted linear and ring
products, i.e., 3(linear) and 3(cyclic), respectively, were then
compared (Figure 5). Both products showed narrow size
distribution (PDI) of 1.17 for the linear and 1.22 for the ring
polymer products, and the linear product showed an apparent
peak molecular weight Mp of 7800 as a measure of the
hydrodynamic volume; this value was notably higher than that
of the ring polymer product (Mp) of 5900, despite both
products being derived from the common poly(THF)
precursor 2/triflate. The hydrodynamic volume ratio of the
linear and ring polymer products was thus estimated to be 0.76
and was in good agreement with previous studies.11,31 These
results demonstrate effective polymer cyclization through ring-
emitting covalent fixation by the selective elimination of N-
phenyl-3,3-dimethylpiperidine units at both chain ends.
conditions. The numbers in parentheses indicate the experimental
em/op for 1 reacted with benzoate (see Scheme 1). The numbers in
d
parentheses indicate the experimental em/op for 2 reacted with
benzoate (see Scheme 3).
The postulated 1,3-diaxial interaction upon the regioselec-
tivity in the esterification on the azacyclohexane quaternized
salts was further supported by DFT calculations of the
transition states of the relevant model compounds, namely
six-membered cyclic thianium (V) and its 3,3-dimethyl
derivative (VI); both are free of axial substituent groups on
the sulfur atom (Figure 2B).29 In contrast with the quaternary
ammonium salts of I and II (Table 2), the transition state
energy is hardly affected by the introduction of two methyl
groups at the 3-position of thiacyclohexane unit (−9.1 kJ/mol
for V and −10.1 kJ/mol for VI in Table 2). The DFT-estimated
ring-emitting/ring-opening product ratio of 96/4 with V and
97/3 with VI should indicate concurrent ring-emitting/ring-
opening esterification rather than an exclusive ring-emitting
process, as the relevant DFT-estimated product ratio of 94/6
for I (−7.9 kJ/mol) corresponds to the experimental ratio of
85/15 for 1a(em,op).
3. Selective Ring-Emitting Esterification by Azacyclo-
hexane Quaternary Salts for Topological Polymer
Chemistry. Prompted by the computational studies described
so far, we synthesized N-phenyl-3,3-dimethylpiperidine by the
reduction of N-phenyl-3,3-dimethyl-2,6-piperidinedione,29,30
which was prepared by the reaction of 2,2-dimethylglutaric
acid with aniline as shown in eq 1 below.
Poly(THF) having N-phenyl-3,3-dimethylpiperidinium
groups (2/triflate) was subsequently prepared by the end-
capping reaction of a living poly(THF) with N-phenyl-3,3-
dimethylpiperidine. The nucleophilic substitution reaction of
2/triflate by benzoate anion was conducted first to test
experimentally the DFT-predicted regioselectivity. Thereafter,
poly(THF) having N-phenyl-3,3-dimethylpiperidinium groups
accompanying a biphenyldicarboxylate counteranion, 2/biphe-
nyldicarboxylate, was subjected to the ESA-CF cyclization
process as a prototypical reaction for topological polymer
chemistry to demonstrate the potential of the present
CONCLUSION
■
By a combination of DFT and experimental studies, we have
successfully developed an exclusive ring-emitting esterification
process, which provide a “click” type chemical process to form
simple ester linkages applicable to a wide variety of polymer
reactions, replacing the relevant ring-opening process resulting
in less stable amino-ester linkages. This new covalent fixation
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Scheme 3. Ring-Emitting Reaction of N-Phenyl-3,3-dimethylpiperidinium Salt Groups at Polymer Chain Ends
Figure 3. 1H NMR (300 MHz) spectra of telechelic poly(THF)
having N-phenyl-3,3-dimethylpiperidinium salt groups carrying a
biphenyldicarboxylate counteranion, 2/biphenyldicarboxylate (top),
and the covalently linked product, 3(cyclic) (bottom) (CDCl3, 25 °C).
See also Figure S1 in the Supporting Information.
Figure 4. MALDI-TOF mass spectra of the linear polymer product
obtained by the telechelic poly(THF) having N-phenyl-3,3-dimethyl-
piperidinium salt groups with benzoate counteranions, 3(linear) (top),
and the ring polymer product obtained with a biphenyldicarboxylate
counteranion, 3(cyclic) (bottom). (MALDI-TOF mass; linear mode,
matrix: dithranol with sodium trifluoroacetate. DPn denotes the
number of monomer units in the product.).
protocol is significant in practice, not only for topological
polymer chemistry but also for versatile polymer reactions and
surface modifications, since the esterification is one of the most
important chemical reactions, ubiquitous not only in
bioprocesses but also in polymer and other materials
productions.
prepared by neutralization of p-nitrobenzoic acid (>99.0%) and
biphenyldicarboxylic acid (>97.0), respectively, with sodium hydroxide
(NaOH, >95.0%). Sodium benzoate (>99.5%), 2,2-dimethylgulutaic
acid (>98.0%), p-toluenesulfonic acid hydrate (99%), and lithium
aluminum hydride (>98.0%) were used as received. Other reagents
were used as received otherwise noted. Wakosil C-300 was used as
received for flash chromatography.
Reaction of Poly(THF) having N-Phenylpiperidinium Salt
End Groups (1/triflate) with p-Methoxybenzoate. The reactions
of poly(THF) having N-phenylpiperidinium salt end groups (1/
triflate) with a series of benzoate anions were performed by the
EXPERIMENTAL SECTION
■
Materials. Poly(THF) having six-membered cyclic N-phenyl-
piperidinium salt groups (1/triflate) was prepared according to the
method reported previously.32 Tetra-n-butylammonium p-methoxy-
benzoate was synthesized by neutralization of p-methoxybenzoic acid
(>99.0%) with tetra-n-butylammonium hydroxide (40% in water).
Sodium p-nitrobenzoate and disodium biphenyldicarboxylate were
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and the concentrated solution was passed through a plug of silica gel
with n-hexane/acetone (2/1 v/v). Reprecipitation from acetone into
ice-cooled water and subsequently from acetone into dry ice/acetone
cooled n-hexane afforded an esterification product, 1c (18.5 mg,
Mn(NMR) = 6100, Mp(SEC) = 5900, PDI = 1.21).
Synthesis of N-Phenyl-3,3-dimethyl-2,6-piperidinedione. To
a refluxing o-xylene (125 mL) solution of 2,2-dimethylglutaric acid
(16.7 g, 0.10 mol) and p-toluenesulfonic acid (0.40 g, 2.1 mmol) was
slowly added an o-xylene (10 mL) solution of aniline (11.1 g) over 2 h.
The mixture was further refluxed for 24 h, and the resulting water was
azeotropically removed. The reaction mixture was cooled to 0 °C and
washed three times with water. The organic phase was evaporated to
dryness under reduced pressure, and the residue was suspended in
acetone with sonication. The suspension was filtered through a filter
paper, and the filtrate was evaporated to dryness under reduced
pressure. A CH2Cl2 solution of the residue was filtered through a plug
of silica gel with CH2Cl2 to afford a solid substance, which was
recrystallized from an acetone solution by vapor diffusion of n-hexane
to allow isolation of N-phenyl-3,3-dimethyl-2,6-piperidinedione (7.50
g) in 33% yield.
Preparation of N-Phenyl-3,3-dimethylpiperidine. A THF
solution (15 mL) of N-phenyl-3,3-dimethyl-2,6-piperidinedione
(2.73 g, 12.6 mmol) was added to a THF (135 mL) solution of
lithium aluminum hydride (0.96 g, 25 mmol) at 25 °C, and the
mixture was refluxed for 1 h. Water (200 mL) and ethyl acetate (200
mL) were added to the reaction mixture at 0 °C, and the organic phase
that separated was filtered, washed with brine, dried with Na2SO4, and
concentrated under reduced pressure. The residue was filtered through
a plug of silica gel with chloroform to allow isolation of N-phenyl-3,3-
dimethylpiperidine (0.91 g) in 38% yield.
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ 1.00 (s, 6H; −CH3),
1.35 (t, J = 6.1 Hz, 2H; −CH2CH2C(CH3)2−), 1.67−1.76 (m, 2H;
−NArCH2CH2−), 2.82 (s, 2H; −NArCH2C(CH3)2−), 3.07 (t, J = 5,6
Hz, 2H; −NArCH2CH2−), 6.78 (t, J = 7.3 Hz, 1H; Ar-H para to N),
6.90 (d, J = 7.8 Hz, 2H; Ar-H ortho to N), 7.23 (t, J = 8.2 Hz, 2H; Ar-
H meta to N). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 22.4, 26.9,
31.0, 37.4, 49.7, 62.6, 116.5, 118.7, 128.9, 152.6. H−H and C−H
COSY spectra are given in the Supporting Information (Figures S2
and S3, respectively).
Synthesis of Poly(THF) Having N-Phenyl-3,3-dimethylpiper-
idinium Salt End Groups (2/triflate). 2/triflate was prepared
according to the previous report for the preparation of 1/triflate31 with
slight modification. Thus, triflic anhydride (17 μL, 0.10 mmol) was
added to THF (15 mL), and polymerization was allowed to proceed
for 11 min at 25 °C with stirring. Thereupon, a THF solution (0.20
mL) of distilled N-phenyl-3,3-dimethylpiperidine (0.20 mg, 1.1 mmol)
was added, and the solution was stirred for another 30 min. Unreacted
THF was then removed under reduced pressure, and the residue was
reprecipitated from acetone into dry ice/acetone cooled n-hexane to
afford 2/triflate (556 mg, Mn(NMR) = 5600, PDI = 1.17).
Synthesis of a Linear Poly(THF) with Simple Ester Linkages
(3(linear)). The counteranion exchange reaction of 2/triflate was first
performed to give 2/benzoate by the following procedure. An acetone
solution (1.5 mL) of 2/triflate (100 mg, 18 μmol) was added dropwise
into an ice-cooled aqueous solution (50 mL) containing sodium
benzoate (129 mg, 50 equiv) with vigorous stirring. The precipitate
that formed was collected by filtration and dried under reduced
pressure. The reprecipitation procedure was repeated, and 64 mg of a
crude product (2/benzoate with 81% ion-exchange rate) was collected,
with a trace amount of water retained to avoid uncontrolled reactions.
The esterification reaction with 2/benzoate was performed as
follows. A weighed amount of 2/benzoate (50 mg) was dissolved in
THF (50 mL), and the resulting solution was refluxed for 3 h.
Thereafter, most of the solvent was removed under reduced pressure,
and the concentrated solution was passed through a plug of silica gel
with n-hexane/acetone (2/1 v/v). Reprecipitation from acetone into
ice-cooled water and subsequently from acetone into dry ice/acetone
cooled n-hexane afforded linear poly(THF) with simple ester linkages,
3(linear) (39 mg, Mn(NMR) = 8300, Mp(SEC) = 7800, PDI = 1.17).
Figure 5. SEC traces of the linear polymer product obtained by
telechelic poly(THF) having N-phenyl-3,3-dimethylpiperidinium salt
groups with benzoate counteranions, 3(linear) (top), and the ring
polymer product obtained with a biphenyldicarboxylate counteranion,
3(cyclic) (bottom) (THF as eluent at late flow 1.0 mL/min, with a
TSK G3000HXL column).
procedure reported previously with unsubstituted benzoate.9 Thus, a
weighed amount of 1/triflate (50 mg) and tetra-n-butylammonium p-
methoxybenzoate (39.4 mg) was dissolved in THF (50 mL), and the
resulting solution was refluxed for 3 h. Thereafter, most of the solvent
was removed under reduced pressure, and the concentrated solution
was passed through a plug of silica gel with n-hexane/acetone (2/1 v/
v). Reprecipitation from acetone into ice-cooled water and
subsequently from acetone into dry ice/acetone cooled n-hexane
afforded an esterification product, 1b (34.6 mg, Mn(NMR) = 4900,
Mp(SEC) = 6300, PDI = 1.11), in 69% yield.
Reaction of Poly(THF) having N-Phenylpiperidinium Salt
End Groups (1/triflate) with p-Nitrobenzoate. The counteranion
exchange reaction of 1/triflate was first performed to give 1/p-
nitrobenzoate by the following procedure. An acetone solution (2.0
mL) of 1/triflate (200 mg, 44 μmol) was added dropwise into an ice-
cooled aqueous solution (100 mL) containing sodium 4-nitrobenzoate
(420 mg, 50 equiv) with vigorous stirring. The precipitate that formed
was collected by filtration and dried under reduced pressure. The
reprecipitation procedure was repeated, and 156 mg of a crude product
(1/p-nitrobenzoate, with 91% ion-exchange rate) was collected, with a
trace amount of water retained to avoid uncontrolled reactions.
The esterification reaction with 1/p-nitrobenzoate was performed as
follows. A weighed amount of 1/p-nitrobenzoate (50 mg) was
dissolved in THF (250 mL), and the resulting solution (0.2 g/L) was
refluxed for 3 h. A large amount of THF was used to prevent the side
reaction between the nitro group and azacycloalkane quaternary salt.
Thereafter, most of the solvent was removed under reduced pressure,
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Synthesis of a Ring Poly(THF) with Simple Ester Linkages
(3(cyclic)). The counteranion exchange reaction of 2/triflate was
performed to give 2/biphenyldicarboxylate by the following procedure.
An acetone solution (2.0 mL) of 2/triflate (200 mg, 36 μmol) was
added dropwise into an ice-cooled aqueous solution (100 mL)
containing disodium biphenyldicarboxylate (511 mg, 50 equiv) with
vigorous stirring. The precipitate that formed was collected by
filtration and dried under reduced pressure. The reprecipitation
procedure was repeated, and 162 mg of a crude product (2/
biphenyldicarboxylate with 84% ion-exchange rate) was collected, with
a trace amount of water retained to avoid uncontrolled reactions.
The covalent fixation of 2/biphenyldicarboxylate was performed as
follows. A weighed amount of 2/biphenyldicarboxylate (50 mg) was
dissolved in THF (250 mL), and the resulting solution (0.2 g/L) was
refluxed for 3 h. Thereafter, most of the solvent was removed under
reduced pressure, and the concentrated solution was passed through a
plug of silica gel with n-hexane/acetone (2/1 v/v). Reprecipitation
from acetone into ice-cooled water and subsequently from acetone
into dry ice/acetone cooled n-hexane afforded a ring poly(THF) with
simple ester linkages, 3(cyclic) (28 mg, Mn(NMR) = 7200, Mp(SEC)
= 5900, PDI = 1.22).
DEDICATION
■
Dedicated to Professor Eric J. Goethals in honor of his 75th
birthday.
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ASSOCIATED CONTENT
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* Supporting Information
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A scheme showing polymer topologies by the ESA-CF
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: skawauch@polymer.titech.ac.jp (S.K.); ytezuka@o.cc.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We are grateful to Prof. M. Kakimoto for access to NMR
facilities. We thank the Academy for Global Leadership (A.K.)
and Challenging Research President’s Honorary Award (T.Y.)
of the Tokyo Institute of Technology, Mizuho Foundation for
the Promotion of Sciences (T.Y.), The Kurata Memorial
Hitachi Science and Technology Foundation (T.Y.), and
KAKENHI (23106709, T.Y.; 23685022, T.Y.; 23350050,
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