Exploiting aggregation to achieve phase separation in macrocyclization

Article abstract of DOI:10.1002/chem.201203433

The aggregation properties of poly(ethylene glycol) (PEG) can be exploited in organic synthesis to control dilution effects. Through the use of solvent mixtures containing PEG₄₀₀/MeOH, macrocyclization by Glaser-Hay coupling can be conducted at high concentrations. The origin of the selectivity has been studied by using surface tension measurements, UV spectroscopy, and chemical tagging and demonstrates the dependence of the yield and selectivity on the aggregation of PEG₄₀₀ and its ability to preferentially solubilize organic substrates, resulting in a phase separation from the catalyst system. Copyright

Full text of DOI:10.1002/chem.201203433

DOI: 10.1002/chem.201203433
Exploiting Aggregation To Achieve Phase Separation in Macrocyclization
Anne-Catherine Bꢀdard and Shawn K. Collins*[a]
Abstract: The aggregation properties of poly(ethylene glycol) (PEG) can be ex-
ploited in organic synthesis to control dilution effects. Through the use of solvent
mixtures containing PEG400/MeOH, macrocyclization by Glaser–Hay coupling can
be conducted at high concentrations. The origin of the selectivity has been studied
by using surface tension measurements, UV spectroscopy, and chemical tagging
and demonstrates the dependence of the yield and selectivity on the aggregation
of PEG400 and its ability to preferentially solubilize organic substrates, resulting in
a phase separation from the catalyst system.
Keywords: aggregates · alkynes ·
Glaser–Hay coupling · macrocycles ·
poly(ethylene glycol) · surface ten-
sion
Introduction
The study of macrocycles and their unique properties,[1] in
both industrial and academic settings, are plagued by the
difficulties associated with their synthesis. In the absence of
any conformational restraint, the key ring-closing reaction
to synthesize a macrocycle is typically slow, resulting in com-
peting oligomerization. High dilution is the most common
solution[2] for inhibiting intermolecular reactions between
substrates, but the large volumes of solvent that are required
can be problematic.[3] In addition, the associated environ-
mental impact of solvent disposal renders most macrocycli-
zation reactions unacceptable under the principles of green
chemistry.[4]
In a program aimed at developing new macrocyclization
Scheme 1. Comparing macrocyclization routes to diyne 2.
strategies, our group has recently devised an alternative
strategy for Glaser–Hay macrocyclization reactions that
allows them to be conducted at high concentrations
(Scheme 1).[5] The macrocyclization procedure employed
mixtures of poly(ethylene glycol) (PEG)400/MeOH as a sol-
vent combination and could be performed even at high tem-
peratures by using microwave heating.[5b] With the use of
the PEG400/MeOH solvent combination, the cyclization of
diynes could be conducted at concentrations up to 0.1m,
which is an increase in the concentration of the reaction by
a factor of 500 when compared to traditional conditions.
The discovery of the PEG400/MeOH solvent system was
spurred by the desire to develop a biphasic macrocyclization
protocol.
It was hoped that by sequestering the catalyst system and
macrocyclization substrate into different phases,[6] the key
bond-forming process would take place at the interface of
the two solvents, where the relative concentration of sub-
strate is low. Unfortunately, our initial investigations with
organic/aqueous systems (PhMe/H2O) that remained bipha-
sic throughout the reaction were unsuccessful at promoting
the cyclization (Scheme 2). Remarkably, when homogeneous
mixtures of PEG400/MeOH were employed, the macrocycli-
zations were promoted with high efficiency and selectivi-
ty.[7,8]
Although
anxious
to
investigate
whether
PEG400/MeOH mixtures could be used in other macrocycli-
zation reactions, we believed that the scope of the macrocyc-
lization protocol could not be extended before more insight
into the origin of the selectivity was obtained. Given the
well-documented tendency for PEG to form aggregates in
solution and consequently the numerous applications in me-
dicinal chemistry and materials science,[9,10] it is surprising
that exploitation of its aggregation effects in organic synthe-
sis had not previously been explored.
[a] A.-C. Bꢀdard, Prof. Dr. S. K. Collins
Dꢀpartement de Chimie, Centre for Green Chemistry and Catalysis
Universitꢀ de Montrꢀal
CP 6128 Station Downtown, Montrꢀal, Quꢀbec H3C 3J7 (Canada)
Fax : (+1)(514)-343-7586
E-mail: shawn.collins@umontreal.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203433.
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FULL PAPER
Scheme 2. Macrocyclization to form
2 by using biphasic conditions
(PhMe/H2O) or homogenous mixtures of PEG400/MeOH. Successful mac-
rocyclization reactions at high concentrations employ solvent mixtures of
PEG400/MeOH that appear homogeneous to the naked eye: what is the
origin of the efficiency?
Herein, we provide insight into a possible mechanism for
the high selectivity that is observed during macrocyclization
with the use of PEG400/MeOH mixtures and which invokes
the formation of aggregates by the PEG400. The importance
of PEG aggregates has been studied by using three different
techniques, including surface tension measurements, UV
spectroscopy, and chemical modification of the substrate
and catalyst.
Figure 1. Surface-tension measurements for homogenous mixtures of
PEG400 (top) or ethylene glycol (bottom) in MeOH (empty circles) at
608C and influence on macrocyclization (3!4) (filled circles, see
Table 1).
the formation of aggregates with increasing ratios of
PEG400/MeOH.[15] The surface tension was found to slowly
increase at low ratios of PEG400/MeOH, then rapidly in-
crease between 40–70% PEG400/MeOH, ending in a plateau
at approximately 70% PEG400/MeOH from which a critical
aggregate concentration could be calculated.[14] As a control,
surface tensions were measured in homogenous mixtures in
which the PEG solvent was replaced by ethylene glycol, as
this represents the smallest building block or monomer of
PEG but is sufficiently short in length that it should not
form aggregates in solution (Figure 1, bottom). As expected,
the surface tension measurements showed a linear trend
(R2 =0.9922) over a range of different mixtures of ethylene
glycol/MeOH, which is indicative of a non-aggregated solu-
tion.
After confirming the presence of aggregates in homoge-
nous mixtures of PEG400/MeOH, we sought to study their
influence on the yield of the cyclization of diyne 3 at various
ratios of PEG400/MeOH (Table 1, entries 1–6). When the
cyclization was performed in pure MeOH, a small quantity
of product 4 was observed (22%) and the remaining starting
material 3 was oligomerized.[16] However, when only a small
amount of PEG400 was added (10% PEG400/MeOH), the iso-
lated yield of the desired macrocyclic diyne 4 was increased
to 45% yield. As the ratio of PEG400/MeOH increased, so
Results and Discussion
Aggregate formation in poly(ethylene glycol) homogenous
mixtures: Poly(ethyleneglycol) (PEG) is known to form ag-
gregate structures in solution; their properties can often be
controlled through judicious choice of the length of the
PEG polymer chain.[9,10] The biocompatibility of PEG-de-
rived polymers has lead to applications as possible drug de-
livery agents in biological systems.[11] PEG is considered a
green solvent because, in addition to its relative non-toxicity,
it has a low volatility and its solubility properties are often
tunable.[12] In the Glaser–Hay macrocyclization systems pre-
viously reported (Scheme 1), the formation of aggregates by
PEG400 was proposed to account for the phase separation
between the catalyst systems and the organic substrates,
thus effectively controlling the molarity of the macrocycliza-
tion reaction. To confirm the existence of aggregates and
their impact on macrocyclization, surface tension measure-
ments[13,14] with PEG400 in MeOH mixtures at 608C were
performed to mimic the previously optimized reaction con-
ditions (Figure 1, top).
The surface tensions of homogenous mixtures of PEG400
in various ratios with MeOH were first studied (Figure 1,
top). Gratifyingly, the resulting S-shaped curve confirmed
did the isolated yield of diyne
4
(62% at 33%
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S. K. Collins and A.-C.; Bꢀdard, S. K. Collins, Chem. Commun. 2012, 48, 6420–6422 Bꢀdard
Table 1. Yields of macrocycle 4 at various ratios of PEG400 or ethylene
glycol in MeOH.[18]
spectively) and were identical to what had previously been
observed at other ratios of ethylene glycol/MeOH. In addi-
tion, when 90% or pure ethylene glycol was used, the start-
ing diyne 3 was not recovered at the end of the reaction and
extensive oligomerization was observed. The fact that the
yield of 4 does not vary significantly in ethylene glycol/
MeOH solutions that do not form aggregates further implies
the importance of aggregation for achieving efficient macro-
cyclization at high concentrations. These results as a whole
verify that aggregation has a direct influence on the yield of
the macrocyclization reaction and prove its importance for
achieving efficient macrocyclization at high concentrations.
Entry
Additive
% Additive/MeOH
Yield 4
[%][a]
1
2
3
4
5
PEG400
0
10
33
66
90
100
0
24
45
62
81
Determination of the phase preference of substrate and cat-
alyst: Poly(ethylene glycol) has good solubility in a variety
of organic solvents and can effectively dissolve organic mol-
ecules.[12] The preferential conformation of PEG in polar
media has been determined to be helical; this minimizes in-
teractions of the aliphatic chains with the solvent.[19,20] The
folding creates a lipophilic environment that is responsible
for the ability of PEG to solubilize organic molecules within
its aggregates.[16] Consequently, it was believed that the or-
ganic macrocyclization substrates were residing preferential-
ly in the PEG aggregate, as opposed to the MeOH solvent.
To probe the solvent environment around a typical organic
substrate, UV spectroscopy measurements were performed
with the acyclic diyne 3 in homogenous mixtures of PEG400
and MeOH (Figure 2).[21,22]
69[b,c]
<5[b,c]
24
6
7
ethylene glycol
8
9
10
11
12
10
33
66
90
100
24
34
26[b]
27[b]
16[b]
[a] All compounds were isolated by flash chromatography on silica gel.
Unless otherwise stated, all remaining starting material 3 was oligomer-
ized, see ref. [16]. [b] Some precipitation of the catalyst mixture was ob-
served after 2d. [c] Remaining mass balance comprised of recovered 3.
PEG400/MeOH and 81% at 66% PEG400/MeOH). However,
when the solvent ratio was further increased to 90%
PEG400/MeOH, the yield of the desired product 4 dropped
to 69%. At the highest ratio of 90% PEG400/MeOH, the re-
maining mass balance comprised of unreacted 3, suggesting
that the reactivity of the cata-
Evidence for the preferential solubilization of the organic
substrate 3 in PEG400 comes from the spectral changes ob-
lyst system was decreased at
high PEG400/MeOH ratios. Re-
actions performed in pure
PEG400 exhibited extremely
slow reaction rates and very
little desired product was ob-
served, even after 7 days.[17]
Once again as a control, the
macrocyclization of 3 was inves-
tigated in solvent mixtures of
ethylene glycol in MeOH,
which was confirmed to not
form aggregates in solution
(Figure 1, bottom and Table 1,
entries 7–12). When the cycliza-
tion of 3 to form 4 was conduct-
ed with low ratios of ethylene
glycol/MeOH (10 or 33%), the
product yields were low and
mirrored the yields that were
obtained when the cyclization
was conducted in pure MeOH
(Table 1, entry 7, 24%). At
higher ratios of ethylene glycol
(66 or 90%), the yields again
remained low (26 and 27% re- Figure 2. Absorbance measurements of diyne 3 in various solvent mixtures.
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Phase Separation In Macrocyclization
FULL PAPER
served from mixing 3 with various percentages of PEG400 in
MeOH. The absorption maxima of the diyne 3 in 100%
PEG400 was 288 nm and was essentially identical to the ab-
sorption maxima of the compound in 100% MeOH. Howev-
er, the absorbance intensities were different; the absorbance
maxima were smaller in 100% MeOH (0.64 in PEG400 vs.
0.57 in MeOH). When the spectrum for the diyne 3 in 75%
As expected, when the tagged acyclic diyne 7 was submitted
to identical reaction conditions, little change in the yield was
observed (64% yield of 8 by using microwave irradiation).
Because the cyclization behavior of the two esters 5 and 7
was identical, this suggests that the organic substrate 5 pref-
erentially resides within the PEG aggregate. Next, the solu-
bility preference of the copper catalyst was probed. Towards
PEG400/MeOH
(very
close
to
the
ratio
of
this goal, a derivative of tetramethylethlyene diamine
66% PEG400/MeOH, which gave the highest yields of 3 in
previous studies; see Table 1) was recorded, the measured
absorbance was very similar (0.63) and the spectrum closely
resembled that of 3 in 100% PEG400. As the amount of
MeOH was increased to 50%, the absorbance intensity
(0.62) and curve continued to almost overlap with the spec-
trum that was obtained for 3 in PEG400. Even the spectra
obtained for 3 in 25% PEG400/MeOH shows only a slightly
smaller absorbance intensity, and it is still similar to the
curve that was observed for the diyne 3 in 100% MeOH.
The similarity of all curves to the spectrum of 3 in 100%
PEG400 points to a preference for diyne 3 to reside within
the PEG400 aggregate. To provide further insight into where
the substrate and catalyst were preferentially solubilized,
chemical tagging of both the catalyst and substrate was per-
formed.
(TMEDA) was prepared and tagged with the same benzyl
group as ester 7 (see 9), and was studied in the macrocycli-
Scheme 4. Macrocyclization of diyne 5 with a tagged TMEDA derivative
9.
Chemical tagging of substrate and catalyst: To elucidate the
phase preference of the substrate and catalyst in the macro-
cyclization process, the ester diyne 7, in which the appended
benzyl ester was substituted with three poly(ethylene ether)
sidechains, was prepared.[23] The benzyl ester tag was includ-
ed at a remote ester position to be sufficiently far away
from the diynes as to not directly affect the macrocycliza-
tion. Most importantly, the appended tag can be used as a
means to assure the ester 7 prefers inclusion into a PEG ag-
gregate.[24] The macrocyclization studies could then be com-
pared to the isolated yields obtained for the ester substrate
5, which was previously investigated under the optimized
macrocyclization conditions (Scheme 3).
zation of 5 (Scheme 4). Once again, the macrocyclization
with ligand 9 would be compared to the cyclization using
TMEDA (5!6, 65% yield). It was assumed that the PEGy-
lated 9 would force the resulting Cu complex into the PEG
phase. The macrocyclization of 5 in homogenous PEG400 by
using TMEDA/Cu complexes displayed very slow reaction
rates (>90% 5 recovered) and low yields of desired prod-
ucts (<5% yield of 6 in 100% PEG400, Scheme 4). As such,
we expected the results of the macrocyclization of 5, using
the tagged ligand 9, to display a reactivity profile similar to
reactions that were performed in pure PEG400. When the
cyclization (5!6) using ligand 9 was performed, the yield of
the macrocyclization dropped dramatically (65!10%). In
addition, the reaction rate had slowed considerably and
even after microwave irradiation for 18 h, 32% of the start-
ing material 5 was recovered. The rest of 5 was assumed to
be converted to oligomers.[16] The results of the above ex-
periment point to the Cu/TMEDA catalyst system preferen-
tially residing in a MeOH phase, while the organic substrate
resides within a PEG400 aggregate or phase.
Macrocyclization of the diyne methyl ester 5 under the
PEG400/MeOH optimized conditions resulted in a 65% yield
of the desired product 6 when using microwave irradiation.
The surface tension measurements, UV spectroscopy, and
chemical tagging experiments clearly invoke the formation
of aggregates by the PEG400. The preferential solubility of
the organic substrates within the PEG aggregate suggest
that slow diffusion of the organic diyne towards the MeOH
phase, in which the relative concentration of the diyne
would be low, would be necessary for reaction with the cata-
lyst system. The slow diffusion of the organic diyne towards
Scheme 3. Macrocyclization behavior of tagged ester 7.
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Conclusion
[6] Micellar catalysis could achieve a similar phase separation but has
been mostly exploited as a route towards achieving catalysis in hy-
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In summary, surface tension measurements, UV spectrosco-
py, and chemical tagging have been used to elucidate the
origin of the efficiency in macrocyclic Glaser–Hay couplings
that can be performed at high concentrations. The present
study confirms that the aggregation abilities of PEG400 can
be harnessed for use in organic synthesis. In the Glaser–Hay
macrocyclization protocol previously developed, the cycliza-
tion of diynes could be conducted in high yields at concen-
trations up to 0.1m, which is an increase in the concentration
of the reaction by a factor of 500.
These selective and high-yielding macrocyclizations are
due to aggregates of PEG400 that can act to mimic phase
separation, which is normally achieved by using organic/
aqueous mixtures. Chemical tagging displayed the solubility
preferences of the catalyst system for MeOH and substrate
for inclusion within a PEG aggregate. Furthermore, the
degree of aggregation was shown to greatly influence the
yields of macrocyclization. Despite the variety of applica-
tions for PEG-derived aggregates in medicinal chemistry
and materials science, the application of its aggregation ef-
fects in organic synthesis have not been explored. The in-
sight gained by this study can now be exploited to expand
the scope to other important transformations, such as mac-
rocyclic olefin metathesis and macrolactonization. In addi-
tion, this study suggests that the aggregation properties of
PEG could be used to control concentration effects in other
chemical reactions[25] or as an alternative to traditional aque-
ous/organic biphasic reaction conditions.
[8] PEG400/MeOH (2:1) solvent mixtures remained homogeneous at
room temperature for over a year.
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Acknowledgements
The authors acknowledge the Natural Sciences and Engineering Re-
search Council of Canada (NSERC), Universitꢀ de Montreal and the
Centre for Green Chemistry and Catalysis (CGCC) for generous funding.
A.-C.B. thanks NSERC (Vanier Graduate Scholarship), the FQRNT, and
CGCC for graduate scholarships. The authors thank Mr. Pierre Mꢀnard-
Tremblay for help with the surface tension measurements, Mr. Claude-
Rosny Elie for help with the UV spectroscopy measurements, and Prof.
Andreea Schmitzer and Ms. Vanessa Kairouz for helpful discussions.
[14] Colour copies of Figure 1 can be found in the Supporting Informa-
tion.
[15] Critical aggregation concentration (CAC)=28% PEG400/MeOH.
[16] The formation of cyclic dimers and acyclic dimers or trimers can be
observed by TLC analysis. Mass spectrometric analysis of crude re-
action mixtures can be used to identify these oligomers.
[17] The addition of PEG400 to the reaction does increase the viscosity of
the reaction medium. Reactions performed at different stirring
speeds or in the absence of stirring afforded similar yields.
[18] For clarity, the effect of solvent mixture composition on the yield of
4 is shown in Table 1 for reactions using traditional (oil bath) heat-
ing. The same trends in yield were observed when microwave heat-
ing was used. This data can be found in the Supporting Information.
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[20] In an effort to probe the average size of the aggregates, light-scatter-
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[3] Dilution can render macrocyclization problematic on larger scales;
for an impressive example of industrial macrocyclization, see: V.
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Phase Separation In Macrocyclization
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periods of time, or treatment under ultrasonication, did not promote
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[22] Colour copies of the UV spectra can be found in the Supporting In-
formation.
[23] For a full description of the synthesis of the tagged compounds 7
and 9, see the Supporting Information and W. Yang, P. F. Xia, M. S.
Wong, Org. Lett. 2010, 12, 4018–4021.
Received: September 25, 2012
Revised: October 31, 2012
Published online: December 28, 2012
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