Four component Passerini polymerization of bulky monomers under high shear flow

Article abstract of DOI:10.1039/d1cc02984c

We introduce a four component Passerini polymerization utilizing sterically bulky isocyanide monomers. Under typical Passerini conditions, bulky isocyanides do not react within standard Passerini reaction timescales (hours). We overcome this challenge via the unique physiochemical conditions present in a vortex fluidic device, reducing the reaction time to 2 h on average. Under these high-shear thin-film conditions, bulky isocyanides are readily incorporated into the multicomponent polymerization without the need of high-pressure or temperature. Finally, we demonstrate that the four component approach using functional cyclic anhydrides allows for post-polymerization modification.

Full text of DOI:10.1039/d1cc02984c

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Four component Passerini polymerization of bulky
monomers under high shear flow†
Cite this: Chem. Commun., 2021,
57, 8328
Bryan T. Tuten, *a Aaron H. Bui,a Sandra Wiedbrauk,a Vinh X. Truong,a
b
a
Received 7th June 2021,
Accepted 21st July 2021
Colin L. Raston
and Christopher Barner-Kowollik
*
DOI: 10.1039/d1cc02984c
rsc.li/chemcomm
We introduce a four component Passerini polymerization utilizing traditional three component framework. The first major advance
sterically bulky isocyanide monomers. Under typical Passerini con- for higher component Passerini reactions in the realm of polymer
ditions, bulky isocyanides do not react within standard Passerini science was pioneered by Meir and coworkers, employing alcohols
reaction timescales (hours). We overcome this challenge via the in a pressurized CO2 atmosphere to generate carbonic acids as the
unique physiochemical conditions present in a vortex fluidic device, acid component, thereby directly incorporating CO2 into poly-
reducing the reaction time to 2 h on average. Under these high-shear meric materials.10 One major drawback of Passerini-based multi-
thin-film conditions, bulky isocyanides are readily incorporated into component polymerizations is that sterically bulky components
the multicomponent polymerization without the need of high- drastically decrease their reaction rate.11 Typically, these obstacles
pressure or temperature. Finally, we demonstrate that the four are only overcome with increased temperature and/or pressure.12
component approach using functional cyclic anhydrides allows for A rapidly emerging area of research which overcomes the typically
post-polymerization modification.
inconvenient methods of high temperatures and high pressures is
the use of thin films under high shear conditions, pioneered by
The Passerini reaction is one of the most versatile reactions in Raston and team with the development of the vortex fluidic device
modern macromolecular chemistry,1 finding utility in post- (VFD).13 The standard VFD instrument consists of a 20 mm
polymerization modification,2 multicomponent polymerization outside diameter quartz tube (ca. 17.5 mm internal diameter)
techniques,3 soft matter materials design,4 single-chain polymer with a hemispherical base, which is spun at high speeds (up to
nanoparticle formation,5 and biocompatible materials.6 With 9000 rpm) at a set tilt angle, typically at 451 as the optimal angle
simple reagents, fast reaction times, 100% atom economy and for a diverse range of applications. Operating under the unique
high yields, the Passerini reaction has become an invaluable conditions of the VFD offers many key advantages unavailable to
synthetic tool. Classically consisting of three components–isocya- standard reaction flasks, for example in controlling protein fold-
nides, aldehydes (and less commonly ketones), and carboxylic ing and photoredox reactions, or accelerating enzymatic
acids–the barrier to entry for polymer chemists is very low from a reactions.13 The VFD can also be used as a flow chemistry system,
synthetic point of view. However, there are more exotic iterations further enhancing its utility.14
of the Passerini reaction–emerged in recent years–involving either
At high RPMs and at a 451 degree tilt angle, the thin film in
alternative functional groups such as acidic phenols (the Passer- the VFD is generated down to a thickness of ca. 200 mm, leading
ini–Smiles reaction),7 thiocarboxylic acids,8 and recently from our to high mechanical shear forces arising from the Coriolis force
team, thioaldehydes.9 By changing the nature of the functional from the hemispherical base of the tube and twisted eddies
group, the resulting ester/amide linkage can be tuned to incorpo- from the Faraday waves. These are manifested as topological
rate other linking combinations such as thioester/amide, or ester/ fluid flows to submicron dimensions, as spinning top and
thioamides. In addition to modifying the functional group, there double helical flows, respectively15 Within this environment
has been focus on introducing additional components into the of high shear and intense micro mixing, the traditional kinetic
barrier of sterically bulky substituents can be overcome without
a Centre for Materials Science, School of Chemistry and Physics, Queensland
University of Technology (QUT), 2 George Street, Brisbane, QLD 4000, Australia.
E-mail: bryan.tuten@qut.edu.au, christopher.barnerkowollik@qut.edu.au
b Institute for Nanoscale Science and Technology, College of Science and
Engineering, Flinders University, Bedford Park, South Australia, 5042, Australia
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc02984c
the need for high temperatures and/or increased pressures.16
Indeed, the topological fluid flows in the VFD generate arrays of
high temperature (4200 1C) and likely high pressure a few mm
in diameter on the surface of the tube with molecules rapidly
streaming through them.15 This new phenomena has exciting
potential for controlling reactions which would otherwise
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Scheme 1 Overview of the hydroxybenzaldehydes (green), cyclic anhydrides (blue), and isocyanides (orange) explored in VFD-enabled four component
Passerini polymerizations in the current study as well as the proposed reaction mechanism.
require high temperature and pressues, with the VFD achieving which was subsequently sealed with a modified rubber septum
the equivalent conditions when operating under ambient tem- (refer to Scheme S1, ESI†). The volume in our MCPs did not exceed
perature and pressure. Another advantage to the synthesis of 0.3 mL in order to avoid the thin film touching the septum at the
macromolecules in the VFD is the absent risk of tube blockage, top, which would disturb the fluid mechanics of the set-up.15a The
observed in classical flow chemistry instruments.15b,17
tubes were all held at 451 tilt angle and rotated at 7000 rpm for 2 h,
Herein, we introduce a four component (alcohol, anhydride, followed by precipitation into diethyl ether. Both in the VFD and
aldehyde, and isocyanide) Passerini multicomponent polymer- under normal reaction conditions, the reactions proceeded at
ization (MCP), using various hydroxy benzaldehyde isomers, ambient temperature and without the need for a base as evidenced
cyclic anhydrides, and isocyanides. The combination functions by both NMR spectroscopy and size exclusion chromatography
due to the hydroxy moiety ring opening the anhydride, gener- (SEC, Fig. S1–S32, ESI†). The decrease in the aldehyde proton
ating the carboxylic acid in situ, which can subsequently resonance and the addition of the characteristic ester/amide a
proceed with the standard Passerini reaction mechanism. proton resonance of the Passerini product are characteristic NMR
Critically, this MCP can be carried out with a bulky isocyanide signals highlighting conversion. Additionally, the SEC traces for all
at ambient temperature in a VFD, whereas it is not feasible samples highlight the characteristic shape for a step-growth poly-
under standard reaction conditions.
merization (refer to Fig. S1–S16, ESI†). Subsequently, we switched
Scheme 1 displays a selection of the broad range of compo- the hydroxybenzaldehyde to the more acidic 4-hydroxybenzal-
nents that can be utilized in this four component Passerini dehyde. Again, the reaction both in the VFD and under regular
MCP. Starting with commercially available cyclohexyl isocyanide, conditions proceeded smoothly at ambient temperature and without
3-hydroxybenzaldehyde and cyclic anhydrides, we initially explored the need for a base, demonstrating that indeed the Passerini–Smiles
the electronic effects of the various hydroxybenzaldehydes to type reaction is not taking place. It should be noted that while the
1
determine if the phenol pKa effected the MCP. Wishing to avoid aldehyde H NMR resonance is drastically reduced in all samples,
the potential for parasitic Passerini–Smiles type reactions (where the nature of step-growth polymerization implies the presence of
phenols participate as the acid component), we commenced with a polymer chains with aldehyde end groups. These two polymeriza-
less acidic phenol by way of 3-hydroxybenzaldehyde and the less tion series with hydroxybenzaldehydes A and B, cyclic anhydrides
bulky cyclohexyl isocyanide. For the control reactions, all compo- 1 to 4, and cyclohexyl isocyanide (‘‘b’’) highlight the utility of our four
nents were added to a 1 mL vial, dissolved in 0.1 mL of acetonitrile component multicomponent polymerization strategy, particularly
and the mixture allowed to stand for 16 h before being precipitated with the addition of functional cyclic anhydrides, which are directly
into diethyl ether. All control polymers in this series (samples incorporated into the polymer backbone.
p(A-1-b), p(A-2-b), p(A-3-b), and p(A-4-b)) polymerized well (refer to
Repeating the above two experimental matrices, yet with tert-
Fig. S4–S7 and S21–S24, ESI†). For our VFD conditions, we operated butyl isocyanide (‘‘a’’), produced markedly different results (Table 1).
in ‘confined mode’, implying that all the reaction components were Upon switching to the bulkier isocyanide, no reactions with either
added to the quartz tube and dissolved in 0.1 mL of acetonitrile, the 3-hydroxybenzaldehyde or the 4-hydroxybenzaldehyde under
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Table 1 Four component Passerini polymerization results of tert-butyl
isocyanide via VFD and non-VFD methods
VFD. With the intense micro mixing and high mechanical shear
forces, we can address the challenges of overcoming the high kinetic
barrier posed by bulky monomers such as tert-butyl isocyanide. Our
approach utilizing the VFD proved successful. We attribute the
ability to successfully overcome this kinetic barrier in the VFD to
the high shear topological fluid flows in the film.15 These micro-
sized spinning top and double helical vortices generate localized
high temperature (and pressure) pockets on the surface of the tube,
producing an environment where the thermodynamic product is
strongly preferred over the kinetic product, leading to the successful
incorporation of the bulky tert-butyl isocyanide (Fig. 1).
To address the possibility of whether or not parasitic Passer-
ini–Smiles events were taking place during VFD polymeriza-
tions, we synthesized a simple non-phenolic benzaldehyde
monomer. By adding two methylene units as a spacer for the
hydroxy group, we bypass the ability for the hydroxy group to
function as the Passerini–Smiles acidic phenol. With this
control monomer, the bulky tert-butyl isocyanide, and under
VFD conditions, we were easily able to synthesize polymeric
material (refer to Fig. S33 and S34, ESI†).
Methoda
Sample
Mn (g molÀ1
)
Ð
Yieldc (%)
b
VFD
VFD
VFD
VFD
Control
Control
Control
Control
VFD
VFD
VFD
p(A-1-a)
p(A-2-a)
p(A-3-a)
p(A-4-a)
p(A-1-a)
p(A-2-a)
p(A-3-a)
p(A-4-a)
p(B-1-a)
p(B-2-a)
p(B-3-a)
p(B-4-a)
p(B-1-a)
p(B-2-a)
p(B-3-a)
p(B-4-a)
2510
2220
3900
1620
N/A
N/A
N/A
N/A
1030
915
1830
1020
N/A
1.7
1.8
3.6
1.5
N/A
N/A
N/A
N/A
1.5
1.5
1.9
54
71
91
27
0
0
0
0
34
69
82
80
0
0
0
VFD
1.6
Control
Control
Control
Control
N/A
N/A
N/A
N/A
N/A
N/A
N/A
0
a
VFD method was conducted at 7000 rpm for 2 h at 451 tilt angle in a
sealed quartz test tube. The control experiment was carried out in
b
1.2 mL SEC vial for 16 h at ambient conditions. Mn are determined via
c
SEC in THF based on PMMA standards. Yield determined by polymer
recovered after precipitation.
With the development of a new four component Passerini
based MCP as well as the conditions required to synthesize
standard conditions produced sufficient polymer to analyze after these materials with bulky side-groups, we have demonstrated
precipitation (o1 mg, 24 h reaction time). Bulky monomers and that they can be readily equipped with various functional
side groups have often been challenging entities in polymer handles depending on the cyclic anhydride utilized. In our
chemistry.18 With the exception of some highly reactive ring opening case, we selected the commercially available maleic anhydride
metathesis polymerizations (ROMP), which are able to polymerize at which, after VFD polymerization, was used in
a post-
mild temperatures, there are limited examples of defect-free poly- polymerization modification reaction utilizing a Michael Addi-
merizations with bulky constituents.19 Due to this issue, either a tion with thiol terminated poly(ethylene glycol) (PEG) to
grafting-to or grafting-from approach onto a pre-existing polymer generate a PEG-ylated brush polymer (Fig. 2 and Fig. S33, ESI†).
backbone is typically employed. Thus, we turned to the unique The multimodal peak shape of p(A-2-a)-thio, while non-
physiochemical conditions present in high shear thin-films in the intuitive, is to be expected when a low dispersity, low molecular
Fig. 1 Representative SEC chromatograms (THF as eluent solvent and PMMA standards) and 1H NMR spectra of VFD-enabled polymerization with
20 mm diameter hemispherical base tube, 7000 rpm for 2 h at a tilt angle of 451 at ambient temperature.
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photochemical research program. C. L. R. acknowledges the
ARC and the Government of South Australia for generous
funding.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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