Strain-Promoted Cycloaddition of Cyclopropenes with o-Quinones: A Rapid Click Reaction

Article abstract of DOI:10.1002/anie.201800937

Novel click reactions are of continued interest in fields as diverse as bio-conjugation, polymer science and surface chemistry. Qualification as a proper “click” reaction requires stringent criteria, including fast kinetics and high conversion, to be met. Herein, we report a novel strain-promoted cycloaddition between cyclopropenes and o-quinones in solution and on a surface. We demonstrate the “click character” of the reaction in solution and on surfaces for both monolayer and polymer brush functionalization.

Full text of DOI:10.1002/anie.201800937

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Accepted Article
Title: Strain-promoted cycloaddition of cyclopropenes with o-quinones:
a rapid click reaction.
Authors: Han Zuilhof, Digvijay Gahtory, rickdeb Sen, Andriy R Kuzmyn,
and Jorge Escorihuela
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800937
Angew. Chem. 10.1002/ange.201800937
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Strain-promoted cycloaddition of cyclopropenes with o–quinones:
a rapid click reaction
Digvijay Gahtory, Rickdeb Sen, Andriy R. Kuzmyn, Jorge Escorihuela, and Han Zuilhof*
Abstract: Novel click reactions are of continued interest in fields as
diverse as bio–conjugation, polymer science and surface chemistry.
Qualification as a proper ‘click’ reaction requires stringent criteria,
including fast kinetics and high conversion, to be met. Herein, we
report a novel strain-promoted cycloaddition between cyclopropenes
and o–quinones in solution and on a surface. We demonstrate the
‘click character’ of the reaction in solution and on surfaces for both
monolayer and polymer brush functionalization.
conversion[16] within 4 h with high surface-bound rates (k2 = 33 ±
2 M–1s–1).[17] A distinct feature of this reaction is, however, the use
of a relatively large, hydrophobic 8–membered ring, which in itself
is not necessary for bio–conjugations and typically
disadvantageous in sterically crowded environments such as
polymers and surfaces. Thus, a smaller, yet fast, stable and easily
synthesizable alternative is quite desirable. With this goal in mind,
we hypothesized that a smaller dienophile such as a strained
cyclopropene could meet these criteria.
The discovery and application of novel click reaction strategies is
a growing domain[1] that has garnered significant interest amongst
(bio-)organic[2] and material chemists.[3] Since the introduction of
the copper-catalyzed azide alkyne cycloaddition (CuAAC),[4]
major advances have been made in this regard. Specifically the
development of metal-free click reactions[5] that are either strain-
promoted or catalyzed by simple bases is noteworthy. Examples
include the strain-promoted azide–alkyne cycloaddition
(SPAAC)[5] – which uses a highly strained cyclooctyne motif – a
range of inverse electron-demand Diels-Alder (IEDDA) reactions
such as the tetrazine–trans–cyclooctene (TCO)/cyclopropene
click,[6] and most recently a series of sulfur-fluoride exchange
(SuFEx) reactions.[7] Most of these reactions involve strained
reactants (alkyne or alkene) that accelerate the reaction or a
highly facile bond exchange.[8] There also has been a growing
increase in the use of photochemical click reactions in this
regard.[9] The advantages of such reactions include metal-free
conditions,[10] faster kinetics[11] and good-to-excellent yields.[12]
The strain-promoted oxidation–controlled cyclooctyne–1,2–
quinone cycloaddition (SPOCQ)[11] shown in Scheme 1, is another
example of such a click strategy. The fast kinetics of this reaction
in solution (k2 = 496 ± 70 M–1s–1) makes it amenable for e.g.
accelerated site–specific protein conjugation,[11a,12] cell
labelling[13] and hydrogel preparation.[14] An additional feature of
this reaction is that quinone formation can be triggered by
enzymatic[12] or electrochemical[15] oxidation, thus providing an
inducible click handle. In addition, when used for surface
functionalization, SPOCQ achieves a rarely obtained quantitative
Scheme 1. Scheme showing the inspiration for strain-promoted click between
quinones and cyclopropenes.
1–Methyl–3–substituted cyclopropenes have been recently
reported for fast IEDDA cycloadditions with tetrazines.[18] This
click reaction has been widely used for glycoprotein
conjugation,[19] cell imaging,[20] etc.[21] Moreover, the higher
stability of substituted cyclopropenes[18a] as compared to TCO, an
alternative strained alkene, is an additional advantage. Based on
these findings, we envisaged that cyclopropenes could serve as
a potentially novel candidate for facile conjugation with o–
quinones both in solution and on surfaces.
Herein, we report a novel click reaction between strained
alkenes, namely 1–methyl–3–substituted cyclopropenes, and o–
quinones. We determine the rate constants for the reaction in
solution using UV spectroscopy and on a surface using DART–
HRMS.[17] Furthermore, we also demonstrate the quantitative
nature of the reaction on surfaces and demonstrate its versatility
using anti–fouling polymer brush functionalization. Finally, we use
density functional theory (DFT) to study the reaction mechanism
in more detail. We believe that the high solution-phase yields,
minute–scale completion times for monolayer modification
coupled with the ability for polymer functionalization demonstrate
the wide potential of this novel reaction.
D. Gahtory, Dr. R. Sen, A. R. Kuzmyn, and Prof. Dr. H. Zuilhof
Laboratory of Organic Chemistry, Wageningen University and Research
Stippeneng 4, 6708 WE, Wageningen, The Netherlands
Dr J. Escorihuela
Departamento de Química Orgánica, Facultad de Química, Universidad de
Valencia, Avda. Vicente Andrés Estellés s.n., 46100-Burjassot, Valencia,
Spain.
Prof. Dr H. Zuilhof
School of Pharmaceutical Sciences and Technology, Tianjin University, 92
Weijin Road, Tianjin, People’s Republic of China
Department of Chemical and Materials Engineering, King Abdulaziz
University, Jeddah, Saudi Arabia
The cyclopropene probes were designed based on the balance
between reactivity and stability found by Devaraj and co–
workers.[18b] To this end, we synthesized 1–methylcyclopropenes
2, 5 and 7 (Scheme 2; see ESI for details). Compound 5 and 7
were derived as fluorinated aromatic ester and carbamate,
E–mail: han.zuilhof@wur.nl
Supporting information for this article is given via a link at the end of the
document.
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k2 = 1.95 ± 0.02 M-1s-1
0.5
0.4
0.3
0.2
1.0
5 + 8
0.5
0.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
Time (min)
0
5
10
15
20
25
Time (min)
Figure 1. UV kinetics (at 385 nm) of the reaction between cyclopropenes 5 and
t–butyl quinone 8 at 30 °C in methanol; inset: Linear plots of ln [(I – It)/(I – I0)]
vs time (min), to obtain 2nd-order constants; [5] = 5 mM.
of this exothermic reaction (Hcalc = -31 to -35 kcal/mol) in more
detail. For that purpose, we used the dispersion-corrected B97D
density functional, which has been proved to give accurate
activation energies for SPOCQ cycloaddition reactions,[25] and the
Conductor–like Polarizable Continuum Model (CPCM) to mimic
methanol. These computations yield that the cycloaddition
reaction proceeds through a non-synchronous transition state
(TS), as shown by the distances for both new C-C bonds (see
Figure 2). In addition, the activation free energies for the endo–
cycloaddition of 5 and 8 are lower than that of the exo–approach
(7.5 vs. 9.0 kcal/mol, respectively). A subsequent distortion
analysis shows that this difference is largely caused by the
smaller distortion energy that is required to obtain the endo TS
compared to that for the exo–TS (22.1 vs. 22.6 kcal/mol). The TS
geometries also suggest that the cycloaddition is favored on the
face away from the 3–methyl substituent of the cyclopropene ring.
These activation energies are higher than those calculated for
bicyclo[6.1.0]non-4-yne and cyclooctyne, with barriers of 4.9 and
6.9 kcal/mol, respectively, and rate constants of 838 and 51
Scheme 2. Synthesis of methyl-substituted cyclopropenes (2, 5 and 7) and
reaction with t-butyl quinone, 8. See ESI for detailed synthetic procedures.
respectively, from cyclopropene alcohol 3. The aromatic
fluorinated head groups were chosen to ease visualization by
XPS and DART–HRMS characterization after surface
functionalization, based on previous experience.[22] Following the
synthesis of the cyclopropene probes, we performed a reaction
between 5 and t–butyl quinone (8), which proceeded with good
yield in solution (75 %) at room temperature within 4 h. The
resulting cycloadducts (mixture of isomers) were isolated and
thoroughly characterized by NMR (see ESI, section S2.5). Based
on NOESY and COSY correlations, we deduced an endo–
configuration of the resultant cycloadducts (three-membered ring
formed away from quinone oxygen atoms; see section S5 in ESI).
Next, we determined the reaction kinetics in solution for
compounds 2, 5 and 7 (see ESI for experimental conditions,
section S3.1) by following the decay of the characteristic UV
absorption signal for the quinone at 385 nm.[11a] In accordance
with literature data,[18] 2 showed a sluggish kinetics (k2 = 0.20 ±
0.04 M–1s–1; Figure S3.1) with reaction completion in about 1 h. In
contrast, the fluorinated ester 5 and carbamate 7 showed rapid
kinetics (k2 = 1.95 ± 0.02 M–1s–1 and 1.70 ± 0.01 M–1s–1;
respectively) and the reaction is completed within 5 min (Figure 1
and Figure S3.1). These rates bring this reaction into the realm of
potentially useful for in vivo application according to Houk’s
classification of metal-free click reactions.[23] As explained in their
study, the orthogonal reactivity of 1,3 di-substituted
cyclopropenes coupled with high reaction rates enables their
application in multicomponent imaging as well.
(
M−1s−1, but lower than that of dibenzoazacyclooctyne 12.1
kcal/mol, with k2 = 0.51 M−1s−1),[25] and those reported for the
Diels-Alder reaction of cyclopropenes and butadiene (21-27
kcal/mol).[22] The marginally slower reaction of 7 and 8, the
cycloaddition proceeds similarly via a non-synchronous endo–TS
with an activation barrier of 7.9 kcal/mol (vs 7.5 kcal/mol for 5;
vide supra). In this case, the distortion energies for the
cyclopropene and o-quinone were found to be higher (26.3
kcal/mol, respectively).
The potential of this novel click reaction should become
evident in crowed environments, where the small size of
cyclopropene is of relevance. Thus, we tested the applicability of
this click reaction for surface functionalization. Surface
functionalization provides difficult reaction conditions due to the
steric constraints and immobility of one of the reaction partners. A
100% reaction efficiency is specifically in high demand, as
purification after covalent on–surface reactions is simply not
possible. We envisaged that the highly efficient and fast nature of
our novel reaction would also translate on a surface. For this
purpose, activated aluminum (Al) surfaces (M0) were modified
with dodecyl (C12) Br–terminated phosphonic acids diluted with
octyl chains in a 3:1 ratio, to get M1 surfaces (ESI, section S1).
This was followed by coupling with 3,4-dihydroxybenzylamine
Density functional theory (DFT) calculations were performed
using Gaussian 16,[24] in order to study the reaction mechanism
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O1s
F1s
M2
M3
690
688
686
684
682
C1s
Br3p
P2s
Al2p
M1
exo-TS
endo-TS
M2
F1s
9.0, 22.6, -32.7
7.5, 22.1, -32.4
N1s
M3
Figure 2. B97D/6-311+G(d,p) transition state geometries for the exo– and
endo– attack of 5 + 8. Bond lengths reported in Å. Solution-based activation free
energies (red), distortion energies (green) and reaction free energies (blue) are
in kcal/mol.
800 700 600 500 400 300 200 100
Binding Energy (eV)
0
Figure 3. Stacked XPS wide scan spectra of M1–M3 surfaces; insert: F1s narrow
range spectra of M2 and M3 surfaces.
hydrobromide and oxidation to o–quinones with NaIO4 to yield M2
surfaces (Scheme 3).
XPS wide scan analysis (Br/P = 1:4 for M1 and N/P = 1:4 for M2
surfaces, Figure S4.2–4.4) coupled with the disappearance of the
Br3d signal (at 67.0 eV, Figure S4.5) in XPS narrow scan for M2
confirmed formation of surface-bound o–quinones. M2 surfaces
were then subject to a 5 mM solution of 5, to yield clicked M3
surfaces (Scheme 3). F/P ratios (3:4) in the XPS wide (Figure 3
and Figure S4.6) and narrow scan F1s and P2s analysis (Figure
4) confirmed a quantitative click reaction (100 ±3 % yield) within
20 min. The standard deviation of the reaction yield was
determined over a hexaplet of independent samples prepared on
different days to ensure rigorous reproducibility of the reaction.
For testing polymer brush functionalization, we utilized
poly(MeOEGMA) brushes that have been shown to possess good
anti–fouling properties.[26] Bromine–ended polymer brushes (M5)
were prepared by SI–ATRP (ESI, section 1) on silicon nitride (SiN)
surfaces and analyzed by XPS (Figure 5 and S4.8–S4.13) and
AFM (thickness = 11 ± 1 nm, roughness = 2.2 nm, Figure S4.14).
This was followed by coupling and subsequent oxidation steps to
yield o-quinone-terminated brushes M6 (Scheme 3), as shown by
the disappearance of the Br3d signal in the XPS wide and narrow
scan analysis (Figure 3c and S4.15–S4.17). To compare the
clickability of strained alkyne (BCN derivative) versus strained
alkene (cyclopropene) on polymer brushes, we performed both
the reactions on M6 surfaces and calculated the approximate
conversion via the ratio of F1s (686.0 eV)/N1s (~400.7 eV) signals
from narrow scan analysis (Figure S4.19 and S4.23). With a
BCN–C4F9 analogue,[17] the reaction yielded a ~30 % yield, while
the sterically advantageous cyclopropene provided ~60 %
conversion (each averaged over 6 samples). This further shows
the wide applicability of this approach for polymer modification.
% At. Conc. : 54.8
Area: 27.3
% At. Conc. : 45.2
Area: 22.5
F1s
P2s
194
192
190
188
186
184
692
688
684
680
Binding Energy (eV)
Binding Energy (eV)
Figure 4. XPS F1s and P2s narrow scan spectra of M3 surfaces showing the
atomic concentration of the two elements, respectively.
For interfacial kinetics determination, we followed over the
course of the reaction on M2 surfaces the growth of an MS–
ionizable tag (p–CF3 benzoate anion [m/z 189.016]) obtained by
aromatic ester fragmentation from M3 surfaces by DART–HRMS
(Figure 5).[22a] Given the relatively short reaction time of 20 min
(cf. 4 h for the previously reported SPOCQ reaction) we could
follow the kinetics over the entire kinetic regime. As also
confirmed by XPS results, the reaction tends to an asymptotic limit
within 20 min, signaling completion. The second–order rate
constant (k2) was found to be 0.50 ± 0.01 M–1s–1 at 30 °C. Despite
the slightly reduced rate, it is quite remarkable that the reaction
Scheme 3 Scheme for preparation of quinone-terminated surfaces (M3) and
reaction with 5. See ESI for more detail.
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still achieved complete conversion within 20 min. In contrast, the
SPOCQ reaction (k2 = 3.3 M-1s-1 for first 70% conversion;
afterwards more complex and slower kinetics) achieves
quantitative conversion only in 4 h. This further emphasizes the
positive role played by smaller sterics of the cyclopropene motif
as compared to a bulky cyclooctyne. We believe the “clean
kinetics” of this reaction to be a significant benefit over its
predecessor interfacial SPOCQ. These kinetics also reveal a
more general point on the difference between dilute solution data
and those relevant in crowded environments. The surface-bound
cyclopropene-o-quinone click is only 4 times lower than in solution.
In contrast, the SPOCQ reaction is ~150 times slower on the
surface than in solution. In other words: the solution-based
kinetics, but also quantum chemical data mimicking solutions,
provide an important first indication on the relative rate in crowded
environments – however, these data may still be up to two orders
of magnitude off when predicting relative rates and efficiencies of
different click or coupling reactions under the conditions whether
these reactions are actually most useful, namely in crowded
environments. One-on-one transposition of solution data to e.g.
surface modification, polymer modification or bio-conjugation
efficacy is therefore not generally allowed, and more detailed
considerations and/or calculations are in order. Surface-bound
rates might more closely mimic the rates relevant in those
situations.
show that the small size of the cyclopropene moiety is highly
advantageous in crowded environments, as present in e.g.
polymer and bio-conjugation reactions, and on surfaces.
Furthermore, we believe that the use of 1–methyl–3–substituted
cyclopropenes will therefore also be highly useful for bio–
conjugations that require small reagents.
Acknowledgements
The authors thank NanoNextNL (program 5A), and NWO (ECHO
project 712.012.006) for funding, Reamon Bouman and Dr.
Sidharam Pujari for practical assistance, and Prof. Floris van Delft
for insightful discussions.
Keywords: metal–free click; SPOCQ; polymer brushes; monolayers;
cyclopropene; kinetics; mass spectrometry.
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30
Time (min)
40
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Digvijay Gahtory, Rickdeb Sen, Andriy
R. Kuzmyn, Jorge Escorihuela and Han
Zuilhof*
Page No. – Page No.
Smaller
dienophile
Strain-promoted cycloaddition of
cyclopropenes with o–quinones: a
rapid click reaction
Click
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