Reversible control of nanoparticle functionalization and physicochemical properties by dynamic covalent exchange

Article abstract of DOI:10.1002/anie.201409602

Existing methods for the covalent functionalization of nanoparticles rely on kinetically controlled reactions, and largely lack the sophistication of the preeminent oligonucleotide-based noncovalent strategies. Here we report the application of dynamic covalent chemistry for the reversible modification of nanoparticle (NP) surface functionality, combining the benefits of non-biomolecular covalent chemistry with the favorable features of equilibrium processes. A homogeneous monolayer of nanoparticle-bound hydrazones can undergo quantitative dynamic covalent exchange. The pseudomolecular nature of the NP system allows for the in situ characterization of surface-bound species, and real-time tracking of the exchange reactions. Furthermore, dynamic covalent exchange offers a simple approach for reversibly switching - and subtly tuning - NP properties such as solvophilicity.

Full text of DOI:10.1002/anie.201409602

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DOI: 10.1002/anie.201409602
Supramolecular Chemistry
Reversible Control of Nanoparticle Functionalization and
Physicochemical Properties by Dynamic Covalent Exchange**
Flavio della Sala and Euan R. Kay*
Abstract: Existing methods for the covalent functionalization
of nanoparticles rely on kinetically controlled reactions, and
largely lack the sophistication of the preeminent oligonucleo-
tide-based noncovalent strategies. Here we report the applica-
tion of dynamic covalent chemistry for the reversible modifi-
cation of nanoparticle (NP) surface functionality, combining
the benefits of non-biomolecular covalent chemistry with the
favorable features of equilibrium processes. A homogeneous
monolayer of nanoparticle-bound hydrazones can undergo
quantitative dynamic covalent exchange. The pseudomolecular
nature of the NP system allows for the in situ characterization
of surface-bound species, and real-time tracking of the
exchange reactions. Furthermore, dynamic covalent exchange
offers a simple approach for reversibly switching—and subtly
tuning—NP properties such as solvophilicity.
methods only operate within tightly defined conditions and
offer limited scope for customization. On the other hand, non-
biomolecular strategies will allow the full gamut of synthetic
chemistry to be exploited in the optimization of nanomaterial
structure, function, and properties. Innovative designs
exploiting noncovalent interactions for NP functionaliza-
tion,[4] aggregation,[5] and surface immobilization[6] have
recently been explored, but these non-biomolecular systems
cannot yet match the stability, specificity, and selectivity of
oligonucleotide hybridization. Postsynthetic covalent modifi-
cation of NP-bound monolayers is an attractive alternative,
but traditionally this strategy has relied on kinetically
controlled reactions,[7] which at best produce statistical
mixtures of products and only offer one-shot opportunities
for functionalization. Thermodynamically controlled covalent
bond-forming reactions instead combine the error-correcting
and stimuli-responsive features of equilibrium processes with
the stability and structural diversity of covalent chemistry.[8]
The first examples of dynamic covalent exchange taking place
on 2D surface-confined molecular monolayers,[9a–c] or at the
surface of self-assembled phospholipid bilayers,[9d,e] have
recently been reported. We now show that such reactions
may also be successfully performed on 3D NP-bound mono-
layers. We present prototypical “dynamic covalent NP build-
ing blocks”: gold nanoparticles (AuNPs) bearing a homoge-
neous monolayer of N-aroylhydrazones (Figure 1), through
which reversible control of NP functionalization and proper-
ties can be achieved.
D
espite tremendous advances in the preparation of nano-
particles (NPs) from a range of materials,[1] manipulation and
characterization of NP surface functionality remains a crucial
challenge in the quest to exploit the often remarkable
properties observed within this newfound region of chemical
space. Direct incorporation of surface-bound functional
molecules during NP synthesis is intrinsically restrictive,
demanding compatibility with the synthesis conditions. Post-
synthetic substitution of temporary surface species in
a “ligand exchange” process can facilitate the introduction
of a wider range of surface-bound functionalities, independ-
ent of the NP synthesis methods.[2] Yet, such processes are
often irreversible, inefficient, and can lead to NP surface
reconstruction or etching.
A generalizable synthetic approach whereby a set of NP
“building blocks” may be predictably functionalized, manip-
ulated, and assembled is therefore highly desirable. The
potential of such a concept is well exemplified by oligonu-
cleotide-functionalized nanomaterials.[3] Yet, biomolecular
[*] F. della Sala, Dr. E. R. Kay
EaStCHEM School of Chemistry, University of St Andrews
North Haugh, St Andrews KY16 9ST (UK)
E-mail: ek28@st-andrews.ac.uk
[**] This work was supported by the EPSRC (EP/K016342/1 and DTG),
the University of St Andrews, and by a Royal Society of Edinburgh/
Scottish Government Fellowship (E.R.K.). We are grateful to Dr.
Catherine Botting and the University of St Andrews BSRC Mass
Spectrometry and Proteomics Facility (supported by the Wellcome
Trust) for on-NP LDI-MS measurements, Dr. Tomas Lebl and
Melanja Smith for assistance with NMR measurements, Ross
Blackley for assistance with TEM measurements, and the EPSRC UK
National Mass Spectrometry Facility (NMSF) at Swansea University.
Figure 1. Preparation and reversible surface modification of a dynamic
covalent NP building block exploiting N-aroylhydrazone surface mono-
layers.
Hydrazones display stability under a wide range of
conditions, yet undergo covalent exchange reactions in the
presence of acid or nucleophile catalysts,[10] making them
particularly useful for creating dynamic covalent systems with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409602.
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good differentiation between kinetically labile and locked
states.[11] This combination of behaviors likewise appeared
ideal for a robust but exchangeable linkage for the con-
struction of dynamic covalent AuNPs.[12] Ligand 1 bears an N-
aroyl hydrazone unit, connected through an aliphatic linker to
a thiolate functionality for binding to AuNP surfaces (Fig-
ure 2a).[13] The alkyl linker encourages the formation of
monolayers, while all unbound contaminants could be
removed by NP precipitation and washing. Verification of
both comprehensive purification, and the structural integrity
of NP-bound 1,[16] were essential for being able to unambig-
uously characterize the surface-confined dynamic covalent
1
processes. AuNP-1 displays characteristically broad H and
19F NMR spectra (Figure 2b and c) consisting only of the
resonances expected for a single-component monolayer of 1.
The absence of nonsolvent unbound contaminants was
confirmed by T2-filtered 1H NMR spectroscopy using the
recently developed CPMG-z pulse sequence (Figures 2b,
bottom, and S3).[17] Corroboration of the surface-bound
molecular structure was provided by LDI-MS, whereby all
major ions could be assigned as originating from desorbed
1 (Figures 2 f and S4).[18] Finally, only products consistent with
a homogeneous monolayer of 1 were detected after iodine-
induced oxidative ligand stripping from AuNP-1 (Figure S5).
Directly tracking reactions that occur on molecules
confined to non-uniform faceted surfaces, within a heteroge-
neous population of NPs, presents several challenges. Inher-
ently low concentrations, fast transverse relaxation, and
chemical shift heterogeneity combine to yield broad, weak
1H NMR spectra for NP-bound molecules (Figure 2b,
middle), making quantitative deconvolution of resonances
from structurally similar species extremely challenging.[19]
Incorporating fluorine labels allowed us to exploit the
significant chemical shift dispersion and excellent sensitivity
of 19F NMR spectroscopy to interrogate the composition of
hydrazone-bound monolayers before and after dynamic
covalent exchange reactions (Figure 3).
A stable colloidal suspension of AuNP-1 in 10% D2O/
[D7]DMF was treated with an excess of p-(trifluoromethyl)-
benzaldehyde (5) and CF3CO2H.[20] After 16 h at 508C,
19F NMR spectroscopy showed that the signal for NP-bound
p-fluorobenzylidene hydrazone 1 had decreased in intensity
and two new resonances had appeared: one corresponding to
free p-fluorobenzaldehyde (6), and another corresponding to
NP-bound p-(trifluoromethyl)benzylidene hydrazone 2 (see
Figure S10 for full sweep width crude and purified spectra).
Unbound molecular species (released 6, excess 5, and
CF3CO2H) were removed by NP precipitation and washing
with nonsolvents, yielding a NP sample with a mixed mono-
layer comprising 90% hydrazone 2 and 10% hydrazone
1 (AuNP-10.120.9, Figure 3b). By subjecting this sample again
to the same exchange conditions, followed by purification as
before, yielded a pure sample of AuNP-2 (Figure 3b). A
homogeneous monolayer of 2 was confirmed by 19F and
1H NMR spectroscopy (Figures 3b, middle, S9, and S11),
LDI-MS (Figures 3c, middle, and S12), and oxidative ligand
stripping (Figure S13).[21]
The dynamic covalent exchange process is entirely
reversible. Treatment of AuNP-2 with 6, under identical
exchange conditions to before, produced a sample displaying
a mixed monolayer of the two hydrazones in the ratio 1:1
(AuNP-10.520.5, Figure 3b). Subjecting this sample to a further
excess of 6 increased the ratio of hydrazones 1:2 in the
monolayer to approximately 3:1 (AuNP-10.7420.26, Figure 3b).
Peaks corresponding to mixed disulfide in the LDI-MS of
AuNP-10.7420.26 (Figure 3c, bottom) indicate the intimate
Figure 2. Synthesis and characterization of AuNP-1. a) Nanoparticle
synthesis. 1) AuPPh3Cl, borane tert-butylamine complex, DMF/THF
1:9, RT, 6 h. b) 1H NMR spectra ([D7]DMF, 500.1 MHz, 295 K): 12
(top); AuNP-1 (middle); AuNP-1 T2-filtered spectrum (bottom). Sig-
nals at 8.02, 3.50, 2.92, and 2.75 ppm correspond to residual non-
deuterated solvent and water. c) 19F NMR spectra ([D7]DMF,
470.5 MHz, 295 K): 12 (top); AuNP-1 (bottom). d) Size distribution of
a representative batch of AuNP-1 (mean diameter 3.39ꢀ0.61 nm).
e) UV/Vis spectrum of AuNP-1 in DMF (SPR lmax =509 nm). f) LDI-
MS of AuNP-1.
a well-ordered surface monolayer, maximizing van der Waals
interactions between neighboring chains,[2a] whereas the outer
tetraethylene glycol unit confers compatibility with polar
solvents and conformational flexibility at the dynamic cova-
lent reactive site.[14]
Gold nanoparticles bearing a homogeneous monolayer of
1 were prepared in a one-step, single-phase process,[15] which
consistently yielded NPs of mean diameters in the range of
2.8–3.4 nm, with dispersities < 20% (Figures 2d and S6), and
exhibiting a well-defined surface plasmon resonance (SPR,
Figures 2e and S6). The absence of surfactants or temporary
ligands facilitated the preparation of single-component
2
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5.[22] Comparing the resulting kinetic profile to that of a freely
dissolved model compound under the same conditions (Fig-
ure S20) indicates a clear kinetic inhibition for the NP-bound
reaction. Fitting to derive apparent rate constants
(Table S1),[22] counterintuitively revealed the inhibitory
effect to be stronger in one reaction direction (kNP/kMOL
-
(F!CF3) = 0.2) than the other (kNP/kMOL(CF3!F) = 0.5),
corresponding to an equilibrium endpoint that favors
AuNP-1 more strongly than predicted by the model reaction
in bulk solution. Slower kinetics for the NP-bound process
might be expected on the basis of simple steric arguments.
However, it is unclear whether the very small increase in size
on converting 1 to 2 can explain the differential effect on the
exchange rates, or whether other intra-monolayer interac-
tions or local concentration effects are also at play.
Mild and reversible methods for postsynthetic NP modi-
fication are highly desirable and would have significant
benefits for nanomaterial property control, handling, and
processability. For example, tuning solvent compatibility is
often required to match an optimized NP synthesis route with
a specific end application,[23] yet existing methods involve
either encasing a nanoconstruct in a polymeric modifier,
encapsulation in micelles, or completely replacing the surface
ligands. The latter strategy may be considered as a dynamic
exchange of the Au S bond.[2] However, completely replacing
ꢁ
the stabilizing monolayer is a relatively harsh and slow
process. Whereas hydrazone exchange at 508C (as described
in Figure 3) reaches 90% exchange within 24 h, the ligand
exchange of AuNP-1 with disulfide 22 takes several days to
reach an endpoint exhibiting far lower conversion (63%)
under analogous conditions (Figure S21), and does not
proceed at all at ambient temperatures.[24] By exchanging
only simple units on the periphery of the stabilizing mono-
layer, dynamic covalent exchange occurs rapidly under mild
conditions; it furthermore avoids the necessity for multistep
synthesis of several thiol-containing ligands, offers simple
purification of the modified NPs from the molecular exchange
species, and is entirely reversible.[24]
Figure 3. a) Hydrazone exchange between AuNP-1 and AuNP-2. Con-
ditions: aldehyde (20 equiv with respect to 1), CF3CO2H (5 equiv with
respect to 1), D2O/[D7]DMF 1:9, 508C. b) Partial 19F NMR spectra
([D7]DMF, 470.5 MHz, 295 K), from top to bottom: AuNP-1; AuNP-
10.120.9; AuNP-2; 10.520.5; AuNP-10.7420.26 . c) Partial LDI-MS spectra of
AuNP-1 (top), AuNP-2 (middle), and AuNP-10.7420.26 (bottom).
To demonstrate the potential of dynamic covalent
exchange for reversible property control, we sought to
introduce simple aldehyde exchange units, chosen to confer
different solvophilic characteristics on our dynamic covalent
AuNP building blocks (Figure 4). AuNP-1 functionalized
with p-fluorobenzylidene hydrazone showed good colloidal
stability only in polar aprotic solvents such as DMF and
DMSO (Figure 4, top). Treating AuNP-1 with an excess of
hydrophobic aldehyde 7 and CF3CO2H in 10% D2O/
[D7]DMF at 508C resulted in complete precipitation of the
NPs within 1.5 h. The solid was easily recovered by centrifu-
gation, and then purified from all molecular species by
redispersion in methanol followed by precipitation with
hexane. The resulting residue exhibited markedly different
solubility properties to AuNP-1 and could be readily re-
redispersed in organic solvents of intermediate polarity, such
as chloroform or tetrahydrofuran (AuNP-3, Figure 4, left).
Analysis of the reaction supernatant by 19F NMR spectros-
copy indicated > 95% conversion of the starting NP-bound p-
fluorobenzylidene hydrazones (Figure S23). On the other
mixing of hydrazones on the NP surface,[18] whereas the lower
extent of exchange in this reverse process is in line with the
greater stability expected for the p-(trifluoromethyl)benzyli-
dene hydrazone.[10c] Importantly, these mixed hydrazone
samples allowed us to confirm that quantification of the
monolayer composition by integrating the broad NP-bound
19F NMR signals was consistent with the results of iodine-
induced oxidative ligand stripping and subsequent analysis of
the released molecular species (Figure S17).
The ability to quantify both NP-bound and unbound
species using 19F NMR spectroscopy allowed us to track
hydrazone exchange in real time and explore the effects of
surface confinement on reactivity. The concentrations of all
four fluorinated species (AuNP-1, AuNP-2, 5, 6) were
monitored during the exchange of AuNP-1 with aldehyde
1
hand, H NMR and LDI-MS analysis of the new NP sample
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environments on reactivity, which have not been so readily
accessible from analogous 2D surface-bound systems.[8b]
Determining the complex influence of nanoscale features,
such as surface curvature and monolayer composition, on
reactivity is the next step that can now be addressed in the
development of dynamic covalent NP building blocks to
become flexible and versatile nanomaterial synthons.[25]
Received: October 1, 2014
Revised: November 28, 2014
Published online: && &&, &&&&
Keywords: dynamic covalent chemistry · gold nanoparticles ·
.
hydrazones · supramolecular chemistry
Figure 4. Reversible switching of AuNP solvophilicity properties by
hydrazone exchange. For full conditions, see the SI, Section 11.
Solvents in the inset pictures: A=hexane, B=chloroform, C=tetrahy-
drofuran, D=methanol, E=DMF, F=water.
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(Figures S22 and S24) were consistent with the expected m-
alkoxybenzylidene hydrazone. Clearly, dynamic covalent
exchange of NP-bound hydrazones occurred to give AuNP-
3 and the consequent marked change in solvent compatibility.
In a similar manner, AuNP-3 could be converted to
AuNP-4, which showed excellent colloidal stability in water
(Figure 4, right). o-Sulfonylbenzylidene hydrazone was con-
firmed as the major constituent of the NP-bound monolayer
by a combination of 1H NMR spectroscopy and LDI-MS
(Figures S28–S30). Each of these exchange reactions proved
to be entirely reversible, such that any of the three AuNP
systems, exhibiting markedly different solvophilicity proper-
ties, could be accessed from either one of the other two by
treatment with the appropriate aldehyde exchange unit
(Figure 4 and Scheme S2). Interestingly, during the conver-
sion of AuNP-3 to AuNP-1, a sample was obtained exhibiting
solubility properties that were intermediate between the two
extremes (Scheme S2). That this state arises from a mixed
monolayer of hydrazones 3 and 1 was confirmed by LDI-MS
analysis, which presented ion fragments originating from both
possible hydrazones in roughly equal intensities (Figure S27).
Subjecting this material to a further round of exchange with
aldehyde 6 then yielded a sample displaying indistinguishable
physical and chemical properties to AuNP-1 produced by all
other routes. Thus, it is possible to access a continuum of
AuNP solvophilicity characteristics across a remarkably wide
range by fine-tuning the monolayer composition through the
appropriate choice of exchange conditions.
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together with
a significantly larger mean NP diameter
(> 4.5 nm). This highlights one of the advantages of the dynamic
covalent NP approach: allowing controlled manipulation of
surface functionality within otherwise identical NP samples.
[22] Kinetic studies were performed in the presence of aldehyde 5
(1 equiv) and CF3CO2H (20 mm) at 258C. Subscripts “NP” and
“MOL” are used to indicate parameters for the NP-bound and
model bulk solution reactions, respectively. The kinetic param-
eters were determined by fitting using the COPASI software
package: S. Hoops, S. Sahle, R. Gauges, C. Lee, J. Pahle, N.
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[24] See SI for further discussion and quantitative comparison of
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Pedulli, C. Gentilini, S. Polizzi, P. Pengo, P. Scrimin, L. Pasquato,
J. Am. Chem. Soc. 2005, 127, 16384 – 16385; c) H. S. Mandal, H.-
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Hill, S. J. Hurst, C. A. Mirkin, Nano Lett. 2009, 9, 317 – 321; and
unimolecular and bimolecular photoreactions: e) A. J. Kell,
R. L. Donkers, M. S. Workentin, Langmuir 2005, 21, 735 – 742;
f) T. Zdobinsky, P. Sankar Maiti, R. Klajn, J. Am. Chem. Soc.
2014, 136, 2711 – 2714.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Supramolecular Chemistry
F. della Sala, E. R. Kay*
Ligand swap shop: Dynamic covalent
hydrazone exchange within a homoge-
neous monolayer bound to the surface of
gold nanoparticles is tracked in real time.
The introduction of appropriately func-
tionalized aldehyde exchange units allows
reversible tuning of nanoparticle solvo-
philicity and presents a generalizable
covalent approach to postsynthetic
modification of nanoparticle functionali-
zation and properties.
&&& — &&&
Reversible Control of Nanoparticle
Functionalization and Physicochemical
Properties by Dynamic Covalent
Exchange
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!