Construction of Linear Polymers, Dendrimers, Networks, …turroserver.chem.columbia.edu/PDF_db/publications... · Sharpless and coworkers introduced the click chemistry concept in

Review

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Construction of Linear Polymers, Dendrimers,Networks, and Other Polymeric Architecturesby Copper-Catalyzed Azide-AlkyneCycloaddition ‘‘Click’’ Chemistry

Jeremiah A. Johnson, M. G. Finn, Jeffrey T. Koberstein,Nicholas J. Turro*

The enrichment of materials synthesis with the diverse chemical building blocks and func-tional groups of small molecule organic chemistry has been greatly accelerated in recent yearsby the introduction of the copper-catalyzed azide-alkyne cycloaddition (CuAAC). The efficiencyand modular nature of this unique reaction enablesmaterials chemists to prepare novel functionalmaterials of unprecedented complexity. This reviewsummarizes the application of CuAAC to the field ofmaterials construction, defined here as the prep-aration of materials with architectural integritydependent upon the triazole linkage. Recent examples,including linear polymers, dendrimers, polymer net-works, polymeric nanoparticles, and other polymericarchitectures, are described.

J. A. Johnson,Department of Chemistry, Columbia University, 3000 Broadway,MC3157, New York, New York 10027, USAM. G. FinnDepartment of Chemistry and The Skaggs Institute for ChemicalBiology, The Scripps Research Institute, 10550 North Torrey PinesRoad, La Jolla, California 92037, USAJ. T. KobersteinDepartment of Chemical Engineering, Columbia University, 500W. 120th Street, New York, New York 10027, USAN. J. TurroDepartment of Chemistry and Chemical Engineering, ColumbiaUniversity, 3000 Broadway, MC3157, New York, New York 10027Department of Chemistry and The Skaggs Institute for ChemicalBiology, The Scripps Research Institute, 10550 North Torrey PinesRoad, La Jolla, California 92037, USAE-mail: [email protected]

Macromol. Rapid Commun. 2008, 29, 1052–1072

� 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Introduction

Every chemistry student learns the second law of

thermodynamics: the entropy of the universe is always

observed to increase. A glance at the recent explosion of

papers describing the use of click chemistry may leave one

with a similar sense of increasing disorder. However, as a

referee pointed out to us, the terms of thermodynamics

provide a more apt analogy: the field of click chemistry is

an open system in constant exchange with its environ-

ment (other disciplines). As in living systems, entropymay

also decrease locally when certain forces intersect, and

click chemistry certainly has helped to give life to the

realization of long-held goals in materials science, as

we discuss in several examples below. The timeline of the

development and evolution of this enabling philosophy

and technology is instructive.

DOI: 10.1002/marc.200800208

Construction of Linear Polymers, Dendrimers, Networks, and . . .

Jeremiah A. Johnson received a B.S. in biomedical engineering with a secondmajor in chemistry fromWashington University inSt. Louis in 2004 where he studied novel fluoropolymer-based antifouling coatings in the laboratory of Professor Karen L.Wooley. He is currently a fourth year graduate student at Columbia University working in the laboratories of Professor NicholasJ. Turro and Professor Jeffrey T. Koberstein. He has spent his graduate school summers working at The Scripps ResearchInstitute in the laboratory of Professor M. G. Finn. In his graduate work, Jeremiah has developed a general synthesis of ozone-and photo-degradable polymeric materials of well-defined structure, and has studied both the copper-catalyzed andstrain-promoted ‘‘click’’ crosslinking of these materials, the latter in collaboration with Professor Carolyn R. Bertozzi. He alsocontributed to the development of ‘‘universal ligands’’ for the synthesis of functionalized nanoparticles. Jeremiah was therecipient of an American Chemical Society Division of Organic Chemistry graduate fellowship in 2007 and recently received the2008 Hammett award from Columbia University’s Department of Chemistry.M.G. Finn received his bachelor’s degree in chemistry from the California Institute of Technology in 1980, and his Ph.D. from theMassachusetts Institute of Technology in 1986. His doctoral research with Professor K. Barry Sharpless focused on themechanism of the titanium-tartrate catalyzed asymmetric epoxidation reaction. After an NIH postdoctoral fellowship withProfessor James P. Collman at Stanford University, he joined the faculty of the University of Virginia in 1988. There he developedorganometallic reagents for organic synthesis, until a sabbatical at The Scripps Research Institute exposed him to opportunitiesat the intersections of chemistry and biology. He moved to Scripps in 1999, where he helped establish ‘‘click chemistry’’ as aconcept and implement it in the laboratory for purposes of bioconjugation, synthesis, and materials science. He has alsodeveloped virus-like capsid particles as practical scaffolds for the polyvalent display of functional molecules. With thesestructures, his laboratory now pursues targets in cancer biology, immunology, and enzyme evolution.Jeffrey T. Koberstein received a Bachelor’s degree in Chemical Engineering from the University of Wisconsin, and a Doctorate inChemical Engineering from the University of Massachusetts in 1979. After a year of postdoctoral research at the Centre deRecherches sur les Macromolecules in Strasbourg, France, he joined the Chemical Engineering faculty at Princeton University.From 1986 to 1999 he was a member of the Polymer Program within the Department of Chemical Engineering and Institute ofMaterials Science at the University of Connecticut, where he was Associate Professor (1986–89) and Professor (1989–1999) ofChemical Engineering. From2000 to 2005 hewas Professor and Chair of Chemical Engineering at ColumbiaUniversity. In 2003 hewas appointed as the Percy K. and Vida L. W. Hudson Professor of Chemical Engineering. Recently, Professor Koberstein chairedthe Materials Engineering and Science Division of the American Institute of Chemical Engineers and received the Stine awardfrom that division in 2006. In 2007, he was elected fellow of AIChE. He is currently co-director of the NSF-IGERT program inMultiscale Phenomena in Polymer Materials. Current research interests include: DNA and carbohydrate microarray technology;ultrathin ceramic and nanoparticle composite films for gas separation; reorganization,modification, and patterning of functionalpolymer surfaces; surface modification of nanoparticles; and smart polymer surfaces for biomaterial applications.Nicholas J. Turro has been teaching at Columbia University since 1964 and is currently the Wm. P. Schweitzer Professor ofChemistry and Professor of Chemical Engineering and Applied Chemistry, as well as Professor of Earth and EnvironmentalEngineering. He received his B.A. from Wesleyan University in Connecticut in 1960 and his Ph.D. in 1963 from the CaliforniaInstitute of Technology under George S. Hammond. Dr. Turro had a postdoctoral position at Harvard University from 1963 to1964. He has written over 800 scientific publications and 2 textbooks on molecular photochemistry. His recent awards includethe 2005 Theodor Forster Award from the German Chemical Society and the 2007 NicholsMedal by the New York Section of theAmerican Chemical Society. He is a member of the National Academy of Sciences and the American Academy of Arts andSciences.

Sharpless and coworkers introduced the click chemistry

concept in 2001, explicitly attempting to bring the

chemical sensibility of polymer chemistry to the world

of organic chemists.[1] Of course all chemists prize

reactions of high efficiency, and the click reactions

introduced in that original paper were mostly already

known. Sharpless and coworkers focused their attention,

however, on the enabling conviction that all branches of

chemical science could benefit from the same abiding

focus on function, and the same acceptance of a relatively

limited but extraordinarily powerful palette of bond-

forming reactions that has always characterized the field

of polymer and materials synthesis. The subsequent few

years brought a resounding affirmation of that expecta-

tion, with an explosion of papers worldwide applying the



tenets of click chemistry to a range of applications which

could arguably not be approached by any other means.

‘‘Click chemistry’’ focuses on the extraordinary power of

a very few reactions which form desired bonds under

diverse reaction conditions, with highly diverse building

blocks, in high yields and with no (or conveniently

separated) byproducts.[2] For materials chemists, an

appreciation of the value of such processes is decidedly

not new. The reactions that modern click chemistry

has created, and one process in particular, have thereby

brought new capabilities to a field better prepared

than any other to take advantage of them. That process

is the popular copper-catalyzed azide-alkyne cyclo-

addition (CuAAC), which is the subject of this review

(Scheme 1).

www.mrc-journal.de 1053

J. A. Johnson, M. G. Finn, J. T. Koberstein, N. J. Turro

Scheme 1. Copper-catalyzed azide-alkyne cycloaddition (CuAAC).Throughout this review, triazole units will be shown in blue.

Scheme 2. Materials construction versus functionalization. Func-

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The CuAAC reaction was first reported in 2002 by the

laboratories of Meldal and Sharpless, in the latter case as a

direct result of an appreciation of the potential for such a

reaction in the context of the click chemistry concept.[3,4]

The mechanistic and procedural details of this reaction are

largely beyond the scope of this review and we direct the

reader to several references from the primary[5–8] and

review[9] literature on these topics. Recent reports of new

classes of accelerating copper-binding ligands,[10] the

isolation of a copper(I)triazolide click intermediate,[11]

and a novel way to remove all traces of copper from click

reaction mixtures are particularly relevant.[12] We will

focus on the application of CuAAC to the construction of

interesting materials in the rest of this review. A number

of excellent review articles in the past year have

summarized the use of CuAAC in polymer and materials

synthesis,[13–23] but new reports appear quite frequently in

this fast-moving field. We therefore endeavor to bring the

reader the most recent advances available, but also to set

them in context with older examples when appropriate.
tionalization route a) involves decoration of a material by attach-ment of a modifying moiety. Route b) involves alteration of thematerial without the incorporation of new agents (for exampletert-butyl ester conversion to carboxylic acid by hydrolysis). Use ofCuAAC for the materials construction step is the focus of thisreview although it has also proven powerful for materials func-tionalization via route a.
Materials Modification versus Construction

There are two fundamentally different ways to use any

reaction inmaterials synthesis: to constructmaterials or to

modify them (Scheme 2). Modification (‘‘decoration’’ or

‘‘functionalization’’), pertains to the attachment or

removal of functionality to or from an already existing

material thereby imbuing it with new properties. Scheme

2 illustrates two potential means by which materials can

be modified - route a in which new modifier building

blocks are added to the material, and route b in which one

or more existing blocks are chemically altered. Perhaps the

most important requirements of route a modification

reactions are chemoselectivity (to ensure functionalization

at the desired site) and high yield (to ensure complete

functionalization), challenges that the CuAAC reaction is

well equipped tomeet. The vast majority of applications of

CuAAC reactions to materials synthesis therefore involve

the modification of polymers, surfaces, dendrimers,

nanoparticles, viruses, networks, and other structures

via route a. Furthermore, thanks to the orthogonal

reactivity of CuAAC, route b schemes can be used in

conjunction with CuAAC functionalization to yield che-

mically diverse macromolecular structures [for example,

constructing and modifying materials derived from

poly(tert-butyl acrylate) (PtBA) enables the orthogonal



route b conversion of hydrophobic PtBA to hydrophilic

poly(acrylic acid) (PAA) via acid hydrolysis].

Material construction pertains to building an architec-

ture and the reactions thus employed provide the mortar

with which the building blocks of macroscopic architec-

tures are connected (Scheme 2). For materials synthesis

applications, high yields and chemoselectivity are neces-

sary, and the concept ofmodularity is crucial. Furthermore,

the more easily the required functional groups can be

introduced into potential building blocks, the more

structurally and chemically diverse the material that

can be synthesized. Because azides and alkynes are readily

attached to molecular scaffolds via a variety of simple

techniques, and are stable toward a wide variety of

solvents and reaction conditions, CuAAC allows the user to

bring almost any necessary building block to the problem

at hand without worrying about the connection reaction.

We focus here on the efforts of our laboratories and

others to employ the CuAAC reaction for the construction

of materials, but references are also provided for a number

of recent materials modification applications which utilize

DOI: 10.1002/marc.200800208


Scheme 3. Representative polymeric architectures in order ofincreasing complexity. Red and blue regions correspond to thefundamental material building blockswhichmay be comprised ofpolymers themselves or small molecules. Materials constructionconcerns the efficient connection of these building blocks, achallenge uniquely met by CuAAC. Synthesis of brush (graft)polymers and star polymers is viewed as a modification in thisreview because both situations involved attachment of polymersto a polymer backbone or multifunctional core, respectively.

CuAAC. In many cases, a reaction can be seen as both a

modification and a construction reaction. For example, the

attachment of alkyne end-functionalized polymers to

azide side-chain derivatized polymers to yield graft

copolymers can be considered both the modification of

the azide derivatized polymer and the construction of a

graft copolymer. Due to space limitations, such cases are

considered modification reactions and only limited

examples are given.

A triazole-containingmaterialwill be defined as resulting

from CuAAC ‘‘construction’’ if at least one triazole within

the structure can be traced in every direction along the

structure to another triazole. For the graft copolymer

example given above, every triazole in the structure is the

result of a modification reaction because it can be traced

directly to the end of the alkyne end-functionalized

polymer. Even within this subset of CuAAC construction

our review is not comprehensive, but instead summarizes a

number of interesting applications of CuAAC to materials

synthesis starting from the construction of linear polymers

and progressing to complicated cross-linked networks of

nanocrystals and nanotubes (Scheme 3). And since the

interactions of click chemistry with materials science are

only beginning, we also look forward to the many new and

exciting architectures and materials that will be made

accessible by CuAAC in the years to come.

Scheme 4. Schematic of linear polymer construction using CuAAC.Such materials have been prepared by addition type polymeri-zation of AB (i) or AA and BB (ii) type monomers, or by iterativeCuAAC/end-group transformation reactions (iii).

Linear ‘‘Click’’ Polymers and Oligomers(From Small Molecule Precursors)

If materials construction is viewed as progressing from

simpler to more complex structures (Scheme 3), then it

should come as no surprise that CuAACwas first applied to



materials synthesis in the construction of linear polymers

and oligomers and has since been employed in a variety of

unique ways for the synthesis of such materials

(Scheme 4). The earliest example, from 2004, was reported

by Finn and coworkers as a control reaction in their

discovery of metal adhesives. The authors showed that a

bis-azide and bis-alkyne formed a soluble linear polymer

thus confirming their hypothesis that CuAAC could be

used for addition polymerizations (Scheme 5, 24).[24]

Further details of this work, along with a recent article

by Ravelo and coworkers describing linear CuAAC poly-

mers incorporated into networks (Scheme 5, 25),[25] will be

discussed later in the section on network synthesis.

In 2005, Angelo and coworkers reported using an

iterative diazo-transer/CuAAC process to construct pepti-

domimetic oligomers that possessed a ‘‘zigzag’’ secondary

structure resulting from the large dipole moment of the

triazole CuAAC product (Scheme 5, 26).[26] In this work, the

triazoles of 26 were viewed as replacements for the

traditional amide peptide bond, while the R groups

mimicked amino-acid side chains. The authors suggested

that this strategy could lead to peptide mimics with

enhanced stability in in vivo applications. Around the

same time, Reek and coworkers reported the construction

of novel conjugated polymers derived from A,A and B,B

diazide and dialkyne fluorene monomers (Scheme 5,

27).[27] Introduction of bipyridine-type functionalities into

these polymers opened a route to novel metal-coordinated

conjugated polymers.

Meudtner and Hecht recently reported an example of a

triazole polymer which possessed secondary structure and

metal-binding pyridine units. Step-growth polymerization

of 2,6-diethynylpyridines with a bifunctional aromatic

azide yielded linear polymers with 2,6-bis(1,2,3-triazol-

4-yl)pyridine units on the backbone which are known to

adopt an anti–anti conformation thus giving rise to helical

polymers (Scheme 5, 28).[28] Circular dichroism spectro-

scopy confirmed the existence of chiral helices and when a



Scheme 5. Representative structures of linear polymers prepared by CuAAC connection of small molecule building blocks. Triazole unitsmade by CuAAC events are shown in blue. Throughout this review, the numbers listed with structures refer to the reference fromwhich thestructure was taken.

1056

variety of metal salts (Zn2þ, Fe2þ, Eu3þ) were added to

dilute solutions of 28 cross-linking occurred yielding

supramolecular metallogels which have potential as novel

magnetic and/or emissive materials.

In 2006, an interesting one-pot synthesis of triazole

oligomerswas reportedbyAucagneandLeigh (Scheme6).[29]

The authors utilized a trimethylsilyl-protected acetylene

(TMS-alkyne) - azide A,B type monomer which was reacted

withanalkyneunderCuAACconditions.Uponcompletionof

this reaction, a silver(I) salt was added along with a second

azide to the same reactionmixture facilitating deprotection

of the TMS-alkyne and subsequent CuAAC with the newly

addedazide. Thismethodologyhas thepotential to beuseful

in a range of applications including the one-pot synthesis of

ABC block copolymers.

Burgess and coworkers later reported an iterative

construction of oligomers derived from the CuAAC

connection of triethylene glycol (TEG) subunits (Scheme

5, 30).[30] By utilizing TEG fragments possessing an alkyne

on one end and a tosylate on the other, the authors were

able to repeatedly perform CuAAC followed by nucleo-

philic displacement of the tosylate with sodium azide to

grow oligomers which then could be end-functionalized

with any desired moiety via a final CuAAC step (R and R0 in

30 could be varied). The water-solubility of these materials

makes them attractive linkers for bioconjugation applica-

tions. Finally, Qing and coworkers prepared addition

polymers by CuAAC which possessed perfluoro-cyclobutyl

(PFCB) groups along the main chain (Scheme 5, 31).[31] The

Scheme 6. Method presented by Leigh et al. for the one-potconstruction of trifunctional oligomers via CuAAC and Ag(I)-catalyzed deprotection of a terminal alkyne.



resulting polymers were thermally stable up to �400 8Cand were soluble in organic solvents making them

attractive candidates for low dielectric and other high

performance coating applications.

Linear ‘‘Click’’ Polymers and Oligomers(from Polymeric Precursors)

All of the aforementioned examples utilize CuAAC to

couple small molecules together to construct polymers or

oligomers. Because azides and alkynes have such a narrow

spectrum of reactivity, they can also be incorporated into

polymerization initiators to make end-functionalized

macromonomers. The use of such building blocks to yield

high molecular weight block copolymers has been

described by several laboratories. We also include the

formation of circular polymers, derived from end-

functionalized linear macromolecules, in this section.

In 2005, Opsteen and van Hest reported the construc-

tion of a variety of polystyrene (PS), poly(methyl

methacrylate) (PMMA), and poly(ethylene glycol) (PEG)

block copolymers by a click chemistry strategy.[32] Atom

transfer radical polymerization (ATRP) of the selected

monomers followed by end-group transformation of the

terminal bromine to an azide using sodium azide yielded

polymers which were coupled with other ATRP-derived

polymers grown from an alkyne initiator. The same

authors recently reported an extension of this technique

using triisopropylsilyl-alkyne (TIPS-alkyne) ATRP initiators

to prepare a,v-heterobifunctional polymers possessing

TIPS-alkyne on one end and azides on the other.[33] CuAAC

followed by deprotection and subsequent CuAAC with

another azide-terminated polymer yielded ABC triblock

copolymers (Scheme 7, 33). Notably, the authors mention

that ATRP using a TMS-alkyne initiator resulted in a

significant degree of TMS loss during the ATRP process. The

TIPS group, on the other hand, was found to be completely

stable during ATRP. It would perhaps be interesting to see

if these polymers could be used in conjunction with

DOI: 10.1002/marc.200800208


Scheme 7. Representative structures of linear polymers prepared by CuAAC connection of polymeric building blocks. Triazole units, theproduct of CuAAC are shown in blue. The corresponding numbers refer to the reference from which the structure was taken.

Scheme 8. Synthesis of a double-stranded DNA catenane byBrown and coworkers.[38] CuAAC circularization of a single DNAstrand (shown in red) followed by annealing of the complemen-tary strand (shown in blue) and CuAAC gave the desired structure(triazoles represented by blue pentagons).

Scheme 9. Schematic of dendrimer modification versus construc-tion. In this reviewwe only describe dendrimers constructed usingCuAAC. These dendrimers possess triazoles at branching pointswithin the dendrimer structure rather than only at the surface.

Leigh’s method described above (CuAAC followed by Ag(I)

deprotection and CuAAC again) to prepare ABC triblocks in

a one-pot procedure.

Matyjaszewski and coworkers reported the synthesis of

an a,v-heterobifunctional-PS which was prepared by ATRP

from an alkyne initiator followed by nucleophilic substitu-

tion of the bromine end group with sodium azide.[34]

Polymerizationof thesemacromonomers (MACs)byCuAAC

gave high molecular polymer products as well as a small

amount of cyclic material (Scheme 7, 34). The authors

mentioned an attempt to perform a one-pot end-group

exchange/CuAAC coupling without success.

The next year, Laurent and Grayson reported the

synthesis of macrocyclic polymers (Scheme 7, 35) derived

from the same polymers reported by Matyjaszewski and

coworkers above, but under different CuAAC conditions

(i.e., higher dilution to favor the cyclization reaction).[35] In

2007, Tunca and coworkers elegantly achieved a one-pot

click construction of an ABC triblock polymer by utilizing

tandem CuAAC and Diels-Alder reactions to yield

PMMA-PS-PEG triblocks (Scheme 7, 36).[36]

Another example of a CuAAC constructed linear

polymer was reported in 2007 by Wang and coworkers.[37]

The authors coupled alkyne-telechelic PEGs with

2,2-bis(azidomethyl)propane-1,3-diol by CuAAC to yield

higher molecular weight PEG polymers with pendant

functionalities (R groups, Scheme 7, 37) including an

alendronate-PEG for potential bone-targeted drug delivery.

The high yield of CuAAC was demonstrated by the

production of hydrogels if no monofunctional PEG was

added to the polymerization mixture (indicating extre-

mely high molecular weight).

Brown and coworkers have recently described the

fascinatingandpotentiallyveryuseful synthesisofacircular

DNA catenane.[38] The authors prepared a single-stranded

DNAwith a 50-alkyne and a 30-azide. CuAAC coupling under

dilute conditions yielded a macrocyclic DNA. When the

complementary DNA strand, also possessing alkyne and

azide termini, was allowed to anneal to the closed DNA loop

and treated with Cu(I), a double-stranded DNA catenane

resulted,connectedwithtwostable triazoleunits (Scheme8).



Network/Branched Architectures

Dendrimers

Anumberofgroupshave recentlyutilizedCuAAC inelegant

ways to modify the surfaces of discrete molecular objects

like dendrimers.[39–41] In this review we only mention

the use of CuAAC to construct dendritic architectures

(Scheme 9) and direct the reader to the aforementioned

reviews to find a wealth of examples of CuAAC for

dendrimer modification.



1058

The synthesis of dendritic molecules requires extremely

efficient reactions for each iterative step to ensure

quantitative conversion of the geometrically increasing

number of functionalities as the dendrimer grows. For this

purpose, chemists in the field of dendrimer synthesis had

been utilizing click-type reactions for years[42–44] but itwas

Fokin,Hawker, and coworkerswhofirst brought theCuAAC

reaction to the field in 2004.[45] Soon thereafter, theWooley

laboratory reported a complementary divergent synthesis

of triazole dendrimers.[46] Hawker and coworkers then

highlighted the chemoselectivity and efficiency of the

CuAAC reaction in this context by making multivalent,

bifunctional dendrimers that onewould be hard-pressed to

prepare so easily by conventional means (Scheme 10).[47]

The final structure featured 16 surface-active mannose

groups and two fluorescent coumarin units derived from

two dendrons, each made with triazole linkages and then

Scheme 10. Hawker’s multivalent, bifunctional dendrimer bearing pr



subsequently joined by a CuAAC reaction. The resulting

dendrimer was shown to be 240 times more potent than

monomericmannose ina standardhemagluttinationassay

thereby providing a nice demonstration of the polyvalent

effect of highly functionalized macromolecular scaffolds.

CuAAC has repeatedly been shown to be an efficient

way to functionalize solid supports.[48–54] For example,

Santoyo-Gonzalez and coworkers convergently prepared

glyco-dendrimers with a silica core and demonstrated

their effectiveness as materials for affinity chromatogra-

phy separation of proteins (Scheme 11).[55]

A particularly interesting combination of CuAAC and

ATRP for the synthesis of polymeric dendrimers was

introduced by Monteiro and coworkers.[56] In an approach

similar to thatofOpsteen[33] andMatyjaszewski,[34]ATRPof

styrene using a bifunctional initiator provided azido-

telechelic PS. CuAAC capping of each end of this polymer

otein-binding mannose units and fluorescent coumarin moieties.

DOI: 10.1002/marc.200800208


Scheme 11. Triazole (shaded blue) glyco-dendrimers on solid SiO2 supports were shown to be effective stationary phases for affinitychromatography.

with tripropargylamine provided tetra-alkyne terminated

PS, which was then addressed with an azido-terminated

PAA. The result was a polymeric dendrimer possessing a

hydrophobic PS corewith ahydrophilic PAA shell. The same

authors recently expanded this approach by using degrad-

able branching units to yield higher generation polymeric

dendrimers with a cleavable periphery (Scheme 12). These

amphiphilic dendrimers self-assembled into micelles in

aqueous environments, and degradation was achieved

via basic hydrolysis of ester groups built into the structure

at the branching points.[57] This work provides a nice

example of the compatibility of ATRP and CuAAC by

offering a straightforward route to complicated polymeric

dendrimers.

Dendrimer synthesis typically involves iterative

activation-functionalization steps requiring two synthetic

steps per generation. Recently, Malkoch and coworkers

reported a beautifully streamlined scheme for the

Scheme 12. Schematic representation of polymeric dendrimersprepared by Monteiro and coworkers. Three triazoles fromCuAAC, represented by blue circles, are present at each branchingpoint. Connection of the triazole units to the polymers by esterlinkages enabled hydrolytic degradation of the dendrimer struc-ture.



preparation of 2,2-bis(methylol)propionic acid (bis-MPA)-

triazole and benzyl ether (Frechet type)-triazole dendri-

mers.[58] Because neither azides nor alkynes require

protection during etherification or esterification, and

because azide-alkyne ligation can take place in the

presence of the unprotected nucleophiles and electrophiles

required for etherification or esterification, every step in

the synthetic sequence was used to grow the polymer.

Fourth generation dendrimers possessing 24 surface

hydroxyls were prepared in only four steps, thereby

greatly reducing the time required tomake such structures

and increasing their commercial viability (Scheme 13).

Astruc and coworkers have pioneered the use of the

metal binding properties of triazole dendrimers in the field

of catalysis. Recently, they reported the catalysis of a

number of carbon-carbon bond forming reactions using

triazole dendrimer-bound palladium metal.[59] These third

generation dendrimers, with 81 surface ferrocene units,

were prepared by iterative hydrosilylation-CuAAC reac-

tions and represent novel nanoreactors (Scheme 14).[60]

During the preparation of this manuscript, Liu and

coworkers reported a novel synthesis of triazole dendrons

which possessed azobenzene chromophores at each

branching unit.[61] Structures with as many as 15

azobenzene moieties were prepared by iterative CuAAC/

SN2 reactions (Scheme 15), taking advantage of the special

anchimeric assistance reactivity of b-haloamine electro-

philes with azide.[62] It was shown that, despite the steric

hindrance within the dendrimer structure, all of the

azobenzene groups could quantitatively be converted

between cis and trans isomers reversibly using UV and

visible light, respectively. The authors mention the

potential of these dendrimers as fast, nanoscale, photo-

active switches.



Scheme 13. Triazole/benzyl-ether dendrimer prepared by Malkoch and coworkers in four steps.

1060

Other Discreet Polymeric Structures (Hyperbranched,Brush, and Star Polymers).

Hyperbranched polymers possess properties similar to

dendrimers and are typically easier tomake at the expense

of being polydisperse. The only example of soluble

hyperbranched polymer synthesis performed with the

aid of the CuAAC reaction to have appeared so far is found

in a 2007 report by Sumerlin and coworkers.[63] Here, the

click reaction was used to conveniently combine the

sensitive acryloyl and trithiocarbonate groups into an

initiator for reversible addition-fragmentation chain

transfer (RAFT) polymerization. This initiator then pro-

vided hyperbranched triazole-based polymers upon reac-

tion with styrene or isopropylacrylamide under standard

RAFT conditions.

In recent years CuAAC has been utilized by a number of

groups for modular ligation of linear polymers with other

molecules to give novel graft/brush polymers,[64–74] star



polymers,[75–83] and other architectures.[84,85] Since these

can be considered asmodification rather than construction

applications of CuAAC (see Scheme 2), we only highlight a

few interesting examples in this review, with apologies to

those omitted because of space considerations. First,

Lecomte and coworkers have presented novel tadpole-

shaped (Scheme 16)[84] and eight-shaped[85] polymers

using a cyclic tin(IV) dialkoxide initiator for controlled

ring-opening polymerization of e-caprolactones (CL)

including an a-chlorinated monomer. Conversion of the

chlorine groups to azides and subsequent CuAAC with

alkyne-PEG yielded complicated structures with poten-

tially novel properties including unexplored modes of

self-assembly.

Tunca and coworkers have recently presented an elegant

CuAAC-dependent synthesis of star polymers possessing

four chemically different arms (ABCD stars, Scheme 17).[76]

The authors utilized two novel hetero-trifunctional

molecules, the first of which possessed a nitroxide for

DOI: 10.1002/marc.200800208


Scheme 14. Ferrocene-terminated triazole dendrimers used byAstruc and coworkers to bind palladium. The resulting metallo-dendrimers were useful nanoreactors for the catalysis of a num-ber of carbon-carbon bond forming reactions.

nitroxide-mediated radical polymerization (NMRP), an

alcohol for tin(IV)-mediated ring-opening polymerization,

and a bromine for later conversion to an azide for CuAAC.

The second molecule contained an alkyne for CuAAC, an

ATRP initiator, and an alcohol. Ring-opening polymeriza-

tion of CL from the hydroxyl group of the first molecule,

NMRP of styrene from the nitroxide group, and conversion

of the bromine to an azide yielded a PS-PCL diblock

possessing a single azide at the center. ATRP of methyl

acrylate or tert-BA, and carbodiimide coupling of PEG to the

second molecule yielded both PtBA-PEG and PMMA-PEG

diblock copolymers possessing a single alkyne at the center.

CuAAC proved to be an efficient means to couple the

PS-PCL-N3 block to the PtBA-PEG-alkyne or PMMA-

PEG-alkyne block to yield ABCD star polymers with

potentially novel properties.

Nanoscale Objects Constructed by CuAAC

A number of groups have recently utilized CuAAC for the

decoration of biological,[86–95] polymeric,[96–98] inor-

ganic,[99–106] and carbon[107] nanoscale objects, but only a

few examples exist wherein CuAAC was employed for the

direct constructionof suchmaterials.Wooleyandcoworkers

have demonstrated the synthesis of both shell[108] and

core[109] crosslinked polymeric nanoparticles derived from

amphiphilic PS–PAA diblock copolymers possessing

alkynes on a fraction of either the hydrophilic PAA block



or the hydrophobic PS block (for shell and core crosslinking,

respectively). These polymers formed micelles in aqueous

solution and were subsequently CuAAC crosslinked

with bifunctional azides and multifunctional dendritic

azides to form polymeric nanoparticles whichwere further

functionalized with fluorescent moieties (Scheme 18). Liu

and coworkers recently pursued a similar approach by

preparing core crosslinked nanoparticles comprised of

poly(N,N-dimethylacrylamide) (PDMA) and poly(N- isopro-

pylacrylamide-co-azidopropylacrylamide).[110]

Caruso and coworkers reported a fascinating synthesis

of ultrathin microcapsules by a unique layer-by-layer

(LBL)/CuAAC approach.[111] The authors started by making

use of electrostatic and hydrogen bonding interactions

between PAA and silica to deposit a thin layer of PAA,

which had a fraction of its carboxylic acid units converted

to azides (PAA-N3), onto the silica particle. A layer of PAA

displaying alkynes (PAA-alkyne) was then coated and

coupled to the previous layer via CuAAC. This process was

repeated for the desired number of iterations yielding

covalently crosslinked PAA of controllable thickness on the

silica surface (Scheme 19). Fluorescent rhodaminemoieties

were attached to the remaining alkynes for imaging of the

particles. Degradation of the silica interior with hydro-

fluoric acid produced covalently linked capsules which

were shown to swell and deswell reversibly with changing

pH.

Hennink and coworkers recently described the synthesis

of biodegradable microcapsules using CuAAC between

azide- and alkyne-modified dextrans (Scheme 20).[112] The

clickable functional groups were linked to dextran

precursors via hydrolyzable carbonates whichwere shown

to break down under physiological conditions to release

their components at controlled rates. These materials

show promise in drug delivery applications where

controlled delivery of a bioactivemoiety is often necessary.

CuAAC for the Synthesis of Macroscopic ‘‘Infinite’’[113]

Networks

Much of our ownwork on thematerials applications of the

CuAAC reaction has been related to the synthesis of infinite

networks (materials of macroscopic dimensions) from

small molecule and/or polymeric precursors. Such materi-

als require efficient reactions for their preparation as there

is a necessary critical conversion percentage of functional

groups (depending on the branching functionality)

which must be achieved before an infinite network (or

gelation) is reached.[114,115] In this vein, CuAAC provides

a route to diversely functional crosslinked networks for

the same reasons that make it so useful throughout

materials synthesis: ease of functional group introduction,

chemoselectivity, andhighyield. In recent years, CuAAChas



Scheme 15. Azobenzene dendrons prepared by Liu and coworkers via CuAAC.

1062

been employed for the construction and functionaliza-

tion[50,116–118] of a range of macroscopic networks which

have vast potential in applications ranging from tissue

engineering and drug delivery to adhesives and microelec-

tronics. This section is divided into three major categories

which summarize the major classes of infinite networks

Scheme 16. Tadpole-shaped polymers prepared by Lecomte andcoworkers.



which have been prepared by CuAAC: small molecule

covalently linkednetworks, smallmolecule supramolecular

networks, and crosslinked polymer networks.

Small Molecule Covalently Linked Networks

The first example of CuAAC for network synthesis was

reported by Finn and coworkers in 2004[24] and was

recently updated with new results.[119] Taking advantage

of the anticipated affinity of triazoles formetal surfaces, an

array of multifunctional azides and alkynes were prepared

Scheme 17. ABCD star polymer prepared by CuAAC coupling oftwo different block copolymers.

DOI: 10.1002/marc.200800208


Scheme 18. Molecular structure of shell-CuAAC-crosslinked poly-meric nanoparticles prepared by Wooley and coworkers. Bothlinear and dendritic azide linkers (R) were used for the cross-linking. However, only the smallest dendrimer bearing four azidespossessed the necessary valency and solubility to yield stablenanostructures.

Scheme 20. CuAAC-constructed dextran microcapsules withdegradable carbonate linkages.

which were polymerized between copper, brass, alumi-

num, and zinc plates yielding adhesives (Scheme 21). The

addition of copper catalyst was not required for adhesive

formation on metallic copper and brass plates, indicating

that a sufficient amount of Cu(I) is present on the surface to

catalyze the CuAAC reaction. The addition of copper salts

did accelerate the reaction, however, as did performing the

crosslinking at elevated temperatures (although the final

adhesive strength did not depend strongly on tempera-

ture). In the cases where no catalyst was added, the final

crosslinked products contained between 2 and 5 wt.-% of

copper indicating that the triazole products efficiently

leach copper ions from the surface. This study identified a

tetrafunctional alkyne and trifunctional azide combina-

tion that yielded adhesives which were twice as strong as

commercially available metal adhesives in peel tests.

Several crosslinked polymers analogous to the adhesive

Scheme 19. Polymeric microcapsules prepared using LBL assemblyof alkyne- and azide-functionalized PAA on silica particles fol-lowed by CuAAC crosslinking.



materials were made in bulk and characterized by

standard techniques. Interestingly, the glass transition

temperatures, of thesematerials were found to be asmuch

as 80 8C higher than the curing temperatures employed

indicating a high degree of crosslinking even in the

diffusion-restricted glassy state.[120] Potential contributing

factors include the high mobility of catalytic Cu(I) centers

through a developing matrix of triazoles, the great

efficiency of the CuAAC coupling reaction, and the great

amount of energy that it releases (approximately

50 kcal �mol�1). Recently, Katritzky et al. reported a similar

study wherein a library of multifunctional azides and

alkynes were polymerized in solution and characterized by

standard techniques.[121]

Finn and coworkers also utilized two of their previously

studied adhesive molecules, tripropargyl amine with

1,6-diazidohexane, in a solution phase CuAAC reaction

to yield a highly crosslinked polymer which was observed

to reversibly swell and deswell when treated with

trifluoroacetic acid due to the amine functionalities within

the material (Scheme 22).[122] The authors suggest that the

polarity, stability, and p-stacking properties of the triazole

products can potentially be exploited for a range of

applications, a notion that has been abundantly confirmed

by reports that have appeared in the past few years.[2]

Small Molecule Supramolecular Networks

The first example of small molecule supramolecular

hydrogelators prepared by CuAAC was presented by

Kim and coworkers in 2003.[123] The authors appended a

Scheme 21. Schematic structure of crosslinked network derivedfrom triazides and trialkynes which were CuAAC crosslinkedbetween two copper plates.



Scheme 22. Acid-swellable CuAAC-crosslinked network reportedby Finn and coworkers.

1064

variety of groups to the C5 position of 20-deoxyuridines via

the click reaction. They then showed that these molecules

formed lamellar or fibrous hydrogen-bonded gels in water

depending on the nature of the C5 substituent. Gallardo

Scheme 23. CuAAC stabilized organogels reported by Finn and coworthermoreversible gels with greater mechanical stability.



and coworkers have utilized CuAAC to prepare

chiral[124,125] and nonlinear diaryl[126] triazole compounds

which were shown to possess liquid crystalline properties

thus warranting their categorization as supramolecular

infinite networks. The authors note the simplicity of

CuAAC for preparing these compounds and indicate they

are screening a library of triazole structures in a search for

novel properties.

The CuAAC process was used to ‘‘stabilize’’ organogels

by Finn and coworkers in 2006.[127] The authors reasoned

that the introduction of azides and alkynes onto the

termini of the alkyl chains of the undecylamide of

trans-1,2-diaminocyclohexane, a molecule known to self-

assemble into supramolecular networks via hydrogen

bonding, would not disrupt gelation but perhaps provide a

way to strengthen the gel products (Scheme 23). Indeed,

self-assembly followed by CuAAC provided a simple and

novel means to alter the properties (glass transition

temperature and rigidity) of these materials without

sacrificing the thermoreversibility of gelation which is

unique to supramolecular gels.

An interesting example of CuAAC for the synthesis of

metal-organic frameworks (MOFs) was recently reported

by Ferey and coworkers.[128] This work explored the

isoreticular principle—the concept that the size of pores

kers. CuAAC crosslinking of preformed supramolecular gels yielded

DOI: 10.1002/marc.200800208


Scheme 24. Supramolecular networks prepared by interaction between TPP-TS and tetra-functional CDs. Different structures (2-D networkvs. linear) were observed depending on which CD derivative (R) was employed for the crosslinking. CuAAC was utilized to construct theself-assembling building blocks by attachment of CDs to a zinc porphyrin.

in MOFs can be tuned solely by altering the length of a

rigid organic linker connecting the inorganic metal

portions. The authors exploited the synthetic convenience

provided by the CuAAC to test the principle by installing

small flexible units at the ends of rigid organic core

molecules. The resulting materials lacked permanent

microporosity as a result of contraction facilitated by

the small flexible organic components, thereby confirming

that the isoreticular principle is limited to completely rigid

organic linkers.

Ding and coworkers recently described an example of a

different type of supramolecular small molecule network

enabled by CuAAC.[129] The authors prepared meso-

tetraaryl zinc(II) porphyrins decorated with anion-binding

b-cyclodextrin (b-CD) or permethyl-b-CD units by CuAAC

attachment of the tetra-alkyne porphyrin to CD azides.

Addition of tetraphenylporphyrin tetrasulfonate (TPP-TS)

to these compounds resulted in either networks with

tetrafunctional branching points (as observed for the

permethylated CD derivative, Scheme 24) or one-



dimensional nanorods (as observed for the standard CD

derivative, Scheme 24). The difference in network structure

was proposed to depend on the orientations of the

cup-shaped CDs: either ‘‘expansive’’ (all four cups facing

outward) or ‘‘contractive’’ (only two cups facing outward).

The expansive state was observed for the permethyl

derivative, allowing each sulfonate group of TPP-TS to be

bound by a CD host, resulting in a tetrafunctional

branched network. In contrast, the standard CD derivative

was found to be locked in the contracted state, resulting in

the formation of linear networks via binding of only two

TPP-TS moieties in a trans fashion.

Crosslinked Polymer Networks

CuAAC has proven useful for the synthesis of a range of

crosslinked polymeric materials. In 2006, Ossipov and

Hilborn presented the first example of CuAAC for the

synthesis of polymeric hydrogels.[130] By modifying

poly(vinyl alcohol) (PVA) with a fraction of either azide

or alkyne functionalities, the authors showed that



Scheme 25. Representative examples of hydrogels crosslinked by CuAAC. Triazole CuAAC products which are used for network constructionare shown in blue. Gel 135 possesses triazoles for both construction and modification. Gel 136 is a supramolecular network which resultsfrom hydrophobic/hydrophilic interactions at various temperatures.

1066

hydrogel materials with tunable mechanical properties

could be prepared by CuAAC crosslinking with either

bifunctional crossinkers bearing the antagonist azide or

alkyne functionality, or by crosslinking of the azide-PVA

with alkyne-PVA (Scheme 25, 130).

Soonafter thiswork,Hawker and coworkers reported the

first application of CuAAC to the synthesis of end-linked

polymeric ‘‘model network’’ hydrogels. Bifunctional alky-

ne-PEGs were crosslinked with tetrafunctional azide-PEGs

(Scheme25,131),[131] toproducematerialswithmechanical

strengths about ten times greater than conventional

photo-crosslinked PEG materials. Any remaining azide

and alkyne groups could be functionalized by CuAAC

post-gelation to ‘‘decorate’’ the gel with imaging moieties.

Importantly, gels crosslinked by CuAAC in the presence of

additives such as a radical scavenger, carbon black, and

TiO2 still possessed excellent mechanical properties. In

contrast, photocrosslinking under these conditions would

be inefficient due to adsorption of light and quenching of

excited state radicals by the additives. Lastly, PEGs

containing ester linkages were shown to yield hydro-

lytically degradable materials whereas ether linked gels

were completely stable to changes in pH.

A recent article by Lamanna and coworkers describes

the CuAAC synthesis of novel hyaluronan hydrogels from



azide and alkyne-modified polymers (Scheme 25, 132).[132]

Crosslinking in the presence of the drug molecules

benzidamine and doxorubicin yielded loaded gels which

released the drugs at rates dependent on the degree of

crosslinking. Furthermore, CuAAC crosslinking in the

presence of yeast cells provided porous materials with

homogeneously distributed live cells. This report contra-

dicts the conventional wisdom that the copper AAC

catalyst is toxic to in vivo applications of the reaction.

While this expectation is certainly reasonable and is

undoubtedly true in some circumstances, it has yet to be

conclusively tested, especially in the presence of

Cu-binding ligands. Furthermore, one can certainly expect

many cells to survive exposure to Cu-containing media,

since copper is a common element and cells possess

effective means to regulate Cu trafficking. Thus, work by

Lamanna, and other reports in nonmaterials areas,[133–135]

suggest that CuAAC in the presence of live cells is a

promising approach to biocompatible scaffolds for tissue

engineering, among other biomaterials applications.

Recently, Lecomte and coworkers utilized ring-opening

polymerization of an a-chloro caprolactone followed by

conversion of the halides to azides to obtain azide-

functionalized PCL. These materials were then subjected

to CuAAC crosslinking in one pot with a PEG dialkyne and

DOI: 10.1002/marc.200800208


Scheme 26. Photodegradable PtBA model networks reported by Turro and coworkers.

N,N-dimethyl propargylamine to yield amphiphilic mate-

rials with grafted amine functionalities (Scheme 25,

136).[136] The authors demonstrated the pH-dependent

swelling of the final materials as well as the pH-dependent

release of a model dye cargo. This work provides another

example of the tailoring of physical properties of networks

such as hydrogels by the use of alternately functionalized

click components (alkynylamines in this case) in the

CuAAC step.

A very recent publication by Baker and coworkers

described an interesting synthesis of biodegradable

propargyl glycolide polymers (Scheme 25, 137).[137] By

CuAAC grafting of different ratios of decyl and PEG chains

to the glycolide backbone, polymer brushes that displayed

lower critical solution temperature (LCST) behavior were

produced. LCST occurs when polymers form a supramo-

lecular crosslinked gel driven by the expulsion of water as

temperature is lowered. The cloud point of these materials

was found to vary between 25 and 70 8C in direct

proportion to the percentage of PEG chains (from 55 to

90%, respectively) employed, and the authors suggest that

expanding these boundaries may be possible. Such

materials provide novel, biodegradable, and thermore-

sponsive hydrogels which may be useful for a range of

biomedical applications.

Anseth and coworkers have reported the synthesis of

PEG-peptide model hydrogels derived from tetra-

azido-terminated PEG star polymers coupled with linear

alkyne-telechelic peptides.[138] The peptide domains fea-

tured photo-reactive alloxycarboxyl (Alloc) groups which

were coupled to fluorescent, cysteine-containing peptides

via transparency-based photolithography to yield intern-

ally patterned materials and gradient-functionalized

hydrogel networks. The latter are of biological importance,

as cell migration can often be controlled using chemical

gradients. Although we do not describe it in this review,

our laboratories are pursuing an alternate pathway to

model networks having chemical and mechanical gradi-

ents by photolithography of materials possessing selec-

tively photodegradable units.[83]



The above examples all describe hydrogel networks,

however, a number of groups have reported examples of

other polymeric crosslinked networks prepared from click

chemistry. Turro and coworkers have utilized CuAAC to

prepare novel degradable end-linked PtBA model net-

works.[139] ATRP polymerization of PtBA from a bifunc-

tional initiator containing an internal double bond, and

subsequent end-group transformation with sodium azide

yielded ozone-cleavable a,v-azido-PtBA macromonomers.

CuAAC crosslinking with tri- and tetra-functional alkynes

yielded end-linked model networks that possessed pore

sizes related to the molecular weight of the starting

macromonomer. Ozonolysis of thesematerials yielded star

polymer products of defined molecular weight, as deter-

minedbySECanalysis, dependingonwhichcrosslinkerwas

used. The same authors later reported an extension of this

work wherein the ozonizable double bond was replaced

with a photocleavable nitrobenzyloxycarbonyl linkage to

yield photodegradable materials of defined structure.[83] In

this article, they also demonstrated the first tandem

CuAAC/ATRP reaction for the assembly of clickable four-

armed structures. In this case, the resulting tetra-

azido-terminated photodegradable star polymers were

crosslinked with a bifunctional alkyne to give photode-

gradablematerials in a route complementary to that based

on linear polymers described above (Scheme 26).

In 2007, a paper by Yagci and coworkers highlighted the

ability of CuAAC to introduce orthogonal functionality for

post-polymerization processing in a convenient fashion, in

this case for the production of thermally curable PS.[140]

First, a PS-co-poly(chloromethylstyrene) random copoly-

mer was prepared by NMRP. The p-chloromethyl groups

were exchanged with azides by nucleophilic substitution

which was followed by CuAAC to attach alkyne-

functionalized benzooxazine moieties. Benzooxazines are

known to polymerize under thermal conditions and the

resulting crosslinked networks (Scheme 27) obtained upon

heating of the benzooxazine-functionalized PS showed

strongermechanical properties than networks prepared by

typical copolymerization with divinyl monomers.



Scheme 28. Model liquid crystal networks prepared by CuAACcrosslinking of azido-telechelic poly(cyclooctene) derivatives andtripropargylamine.

Scheme 27. Thermally cured PS networks presented by Yagci andcoworkers.

1068

Ravelo and coworkers recently utilized diazide and

dialkyne organogelators to prepare novel organogels.[25] In

this case, however, the CuAAC reaction was performed

prior to gelation yielding linear polymers which were then

shown to form thermoreversible gels by hydrogen bonding

in dimethylsulfoxide (DMSO) and other DMSO-organic

solvent mixtures. Interestingly, two unexpected require-

ments of gel formation were the presence of an SO2 group

on the backbone of the polymers and the presence of some

residual copper from the CuAAC reaction. The presumed

interaction of Cu2þ with the triazole products of CuAAC

modification is thought to facilitate gelation, allowing

these materials to be considered as ‘‘metallogels’’.

Grubbs and coworkers recently reported the synthesis of

liquid crystal gel networks which were shown to be

reversible electro-optic switcheswhich converted between

a ‘‘scattering polydomain state’’ and a ‘‘transmissive

monodomain state’’ in the presence of an electric field.[141]

These gels were prepared by CuAAC crosslinking of

azido-telechelic poly(cyclooctene) polymers which pos-

sessed a mesogenic cyano-biphenyl group on each repeat

unit (Scheme 28). As the authors note, the modularity of

the synthetic methodmakes it possible to study the effects

of polymer chain length and structure on the electro-

optical properties of liquid crystals.

Crosslinked Polymer Surfaces and Thin Films

Thin polymer films are important in a range of applica-

tions including sensors, electronics, displays, and gas

separation. An obvious approach would be covalent LBL

construction, but relatively few examples exist due to a

lack of orthogonal, high-yielding reactions capable of

producing such materials. As a result, most LBL surfaces

rely on noncovalent interactions such as hydrogen

bonding or electrostatic attraction between polymers,

and so their mechanical properties and chemical diversity

may be limited for certain applications. Recently, CuAAC

has provided a unique route to covalently linked thin films

and has effectively opened the field of LBL synthesis to

nearly any polymeric precursors.



The first example of CuAAC for LBL construction of thin

films was reported by Caruso and coworkers in 2006.[142]

The authors utilized PAA-N3 and PAA-alkyne to iteratively

CuAAC-couple PAA layers onto a variety of macroscopi-

cally flat surfaces. UV-Vis and FTIR measurements con-

firmed the increase in film thickness with each subsequent

CuAAC reaction as well as the high yield of the CuAAC

process. This methodology was later used for the synthesis

of ultrathin spherical capsules[111] as mentioned above

(Scheme 19).

Polyethylene (PE) is well known to be resistant to LBL

modification, but Chance and coworkers recently incorpo-

rated CuAAC into such a scheme.[143] Oxidation of PE with

CrO3/H2SO4 and functionalization of the resulting car-

boxylic acids with alkynes provided a substrate that could

be addressed with water-soluble azide and alkyne-

functionalized poly(alkylacrylamides) (PAM) in an LBL

fashion. The resulting PAM-coated PE materials were

further derivatized with small molecules in a final CuAAC

step. As is frequently the case, the CuAAC chemistry here

was performed in water, a reaction medium of increasing

interest in materials processing because of its perceived

environmental benefits.

Hawker and coworkers recently reported LBL film

synthesis using dendritic alkynes and azides

(Scheme 29).[144] The authors hypothesized that the

monodispersity and high degree of functionality of

dendrimers should provide for stable films with greater

control over the thickness growth with each layer. Indeed,

DOI: 10.1002/marc.200800208


Scheme 29. LBL assembly of dendrimers on silicon wafers using iterative CuAAC/wash steps with alternating azide and alkynesurface-functionalized dendrimers.

by ellipsometrymeasurements the authors confirmed that

the film thickness increase with each layer was dependent

on the generation of dendrimer used and was a constant

for each new layer. Interestingly, the fifth generation

bis-MPA dendrimers give a drastic increase in thickness

due to the ‘‘dendritic’’ effect, in which steric hindrance

causes the structure to avoid compression and remain

spherical. As expected, linear polymeric azide and alkyne

analogs gave much larger and more variable increases in

thickness for each LBL step.

Figure 1. Construction of covalently linked gold nanorod chains byCuAAC. Image taken from ref. [145].

Crosslinked Structures Derived from NanosizedBuilding Blocks

Covalent crosslinking of nanoscale objects is a blossoming

field which promises to give rise to novel materials

possessing potentially unprecedented properties. Rao and

coworkers have recently studied the structural diversity of

CuAAC covalently crosslinked nanorods, nanoparticles,

and nanotubes.[145] An interesting example was provided

by their observation that thioazide- and thioalkyne-

capped gold nanorods formed chain-like structures

(Figure 1) whereas spherical gold particles formed an

organized network. The authors suggested that the rods

form chain structures because the thiol linkers prefer to



bind to the ends of the gold rods where the (1,1,1) face of

gold is available. These results hint at the diversity of

phenomena to be uncovered in the exciting field of

covalent nanostructure assembly. These investigators

have also provided exciting TEM images of CuAAC

crosslinked CdSe nanocrystals showing the formation of

periodic arrays as well as the marriage of alkyne-



1070

functionalized gold nanoparticles with azide-

functionalized carbon nanotubes to yield novel nanoscopic

hybrid structures.

Conclusion

The CuAAC reaction has proven effective for a broad range

of materials construction applications. From small mole-

cules to linear polymers to branched polymers to

nanoscale and macroscopic materials, the CuAAC process

has been successfully applied to building blocks of every

scale and chemical functionality. Furthermore, structure–

property relationships of many complicated materials (for

example the electro-optic properties of liquid crystals as a

function of polymer chain length[141]) can now be studied

in great depth, as the synthesis of the required polymeric

precursors is made reliable by CuAAC. Lastly, the process is

user friendly: many first-time attempts are successful,

with off-the-shelf and inexpensive catalyst components.

These features place even greater emphasis on the

function of the materials that can be envisioned, rather

than on the potential problems of their construction. We

are excited to see the continued use of CuAAC for an

increasingly creative and diverse array of materials

applications.

Received: April 5, 2008; Accepted: April 25, 2008; DOI: 10.1002/marc.200800208

Keywords: alkyne; azide; click; CuAAC; dendrimers; functionali-zation of polymers; hydrogels; organogels

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