DNA-Functionalized Carbon Nanotubes: Synthesis, Self-Assembly, and Applications

DOI: 10.1002/ijch.201000034

DNA-Functionalized Carbon Nanotubes: Synthesis,Self-Assembly, and ApplicationsLenibel Santiago-Rodr�guez,[a] Germarie S�nchez-Pomales,[a] and Carlos R. Cabrera*[a]

1. Introduction

Carbon nanotubes (CNTs) have been extensively studieddue to their exceptional structural, electronic, and me-chanical properties, and their potential in applications asdiverse as hydrogen storage and biosensing has beenshown. For example, the number of published reports onCNTs for sensing applications has significantly increasedin the past decades. Nevertheless, in order to use CNTs asstandard materials for sensors and to take full advantageof their unique properties, several problems must besolved.

One of the main challenges is to develop functionaliza-tion chemistries that result in increased solubility of theCNTs without altering their properties, which will simpli-fy their use as chemical reagents. To date, the most suc-cessful approach to this challenge has been chemicalfunctionalization of CNTs by either covalent[1,2] or non-covalent approaches.[3,4]

Another primary concern is the production of largeamounts of impurities, such as amorphous carbon, carbonnanoparticles, and metal particle, during the synthesis ofthe CNTs. It is therefore crucial to develop a simple andeffective purification procedure, which could minimizeboth the amount of impurities and the structural changesthat CNTs undergo during typical purification proce-dures.

An additional critical challenge, especially in the elec-tronics and sensing fields, is the integration of CNTs withother circuit elements and their attachment to solid sub-strates. Sensors based on CNTs have shown excellentpromise, but the typical methodologies used to assemblethe nanotubes on solid substrates still hamper the optimi-

zation of these sensors. Therefore, the development of astraightforward methodology for the ordered and con-trolled attachment of CNTs on solid substrates is a verydesirable goal.

During the past few years, our group has demonstratedthat chemical functionalization of CNTs with DNA, incombination with self-assembly, provides a feasible solu-tion to the previous challenges. Herein, we will discuss indetail our main findings, as well as provide a brief over-view of the state of the field.

2. Carbon Nanotubes

Carbon nanotubes (CNTs) were discovered in 1991 byIijima.[5] They consist of graphene sheets (one atom thicklayer of hexagonally bonded carbon atoms, e. g., a graph-ite layer) rolled up as cylinders. CNTs are divided intotwo categories: single-walled carbon nanotubes(SWCNTs), which consist of one cylindrical graphenesheet, and multi-walled carbon nanotubes (MWCNTs),which are SWCNTs with different diameters concentrical-ly arranged one inside the other.

Abstract : Carbon nanotubes (CNTs) possess outstandingstructural, mechanical, and electronic properties. Neverthe-less, to achieve the full potential of CNTs, researchers mustdevelop new purification methodologies or improvements inthe existing purification and separation protocols, designand study novel functionalization chemistries that result inincreased solubility of the CNTs without altering their prop-erties, and devise a straightforward methodology for the at-

tachment of aligned CNTs on solid substrates. To addressthese challenges, our group has studied the chemical func-tionalization of CNTs with deoxyribonucleic acid (DNA)—bycovalent and non-covalent approaches—in combinationwith the self-assembling technique. In this short review, wewill present an overview of DNA-functionalized CNTs, focus-ing on the main findings of our group, and the applicationof the DNA-CNT complexes as electrochemical biosensors.

Keywords: DNA · methylene blue · monolayers · self-assembly · single-walled carbon nanotubes

[a] L. Santiago-Rodr�guez, G. S�nchez-Pomales, C. R. CabreraDepartment of Chemistry, P.O. Box 70377,University of Puerto Rico, R�o Piedras Campus,San Juan, Puerto Rico 00936-8377phone: +1 787 764-0000 1-4807fax: +1 787 756-8242e-mail: [email protected]

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Review

Each carbon atom on graphite consists of planar sp2

hybrid orbital with three s bonds and an out-of-plane p

orbital.[6] Each sp2 bonding carbon atom in graphite pos-sesses an energy of 420 kcal/mol, in comparison to dia-mond with a sp3 configuration that is 320 kcal/mol.Graphite has demonstrated to be stronger than diamonddue to its sp2 bonding.[6] SWCNTs are hollow cylindersformed by rolling graphene sheets. The curvature of theSWCNTs distorts the sp2 bonding configuration of graph-ite by causing the s bonds to be slightly out-of-plane, andconsequently the p orbital to be delocalized outside thenanotubes, which has been called s–p rehybridization.This makes the SWCNTs mechanically stronger, elastic,electrically and thermally more conductive, and chemical-ly and biologically more active than graphite.[6] Moreover,

SWCNTs have been demonstrated to have a ballisticelectron transport through individual nanotubes and highcurrent density, properties that makes them ideal materi-als for electronics and electrochemical applications.[7] Forexample, SWCNTs can carry current densities up to 109

A/cm2, which is more than the current densities that ametal can carry: approximately 105 A/cm2.[8] The combi-nation of high conductivity (1.0 � 106–3.0 � 106 S/m)[9,10]

with their nanoscale size makes SWCNTs a good materialto be used as molecular wires in electrochemical applica-tions and electronics.

SWCNTs have been selected to be covalently attachedto solid surfaces instead of MWCNTs because they canbe cut and oxidized in a reproducible way. Also, the di-ameter of SWCNTs grown under the same conditions isvery similar. This will prevent the introduction of a varia-ble parameter that could not be easily controlled withMWCNTs. Additionally, the small diameter of theSWCNTs makes them an ideal material for the construc-tion of a nanoelectrode array and can enhance the surfacearea of the electrode (compared with planar surface) forthe covalent attachment and detection of biomolecules.The advances in SWCNT functionalization with singlemolecules open the possibility to use SWCNTs as individ-ual electrodes or nanoelectrodes.

The most commonly used methods for CNTs growth in-clude arc discharge, chemical vapor deposition, and laserablation.[11] Another widely used method for SWCNTsgrowth is high pressure carbon monoxide (HiPCO) dis-proportionation. One of the advantages of HiPCO is thatSWCNTs can be produced on a large scale and with ahigh degree of purity, >90 %.[12]

Lenibel Santiago-Rodr�guez receivedher B.S. degree in Chemistry from theUniversity of Puerto Rico(UPR) atCayey in 2003 and finished her Ph.D.degree in 2009 at UPR’s R�o PiedrasCampus with Dr. Carlos R. Cabrera.Her thesis research was about thecharacterization and preparation ofgold substrates modified with single-walled carbon nanotubes for DNA hy-bridization sensing. After her Ph.D. sheworked as a post-doctoral researcherwith Dr. Kai Griebenow at UPR’s R�oPiedras Campus on the functionalization of proteins to increasetheir stability for bioelectrochemical applications. Recently, she ob-tained a post-doctoral research position at UPR’s Mayag�ezCampus with Dr. Carlos Rinaldi, where she will be studying the cel-lular uptake mechanism of superparamagnetic nanoparticles incancer cells. Her research interests include analytical chemistry, ma-terial science, nanotechnology, self-assembly, DNA sensing, proteinfunctionalization and cancer research.

Germarie S�nchez-Pomales graduatedMagna Cum Laude with a B.S. inChemistry from the University ofPuerto Rico (UPR), R�o PiedrasCampus in 2002. As a graduate stu-dent, Germarie worked at the Electro-chemistry and Interfaces Laboratory di-rected by Dr. Carlos R. Cabrera, study-ing the non-covalent functionalizationof carbon nanotubes by DNA, and re-ceived a Ph.D. degree in AnalyticalChemistry from the UPR, R�o PiedrasCampus, in 2009. Also in 2009, Ger-marie received a National Research Council (NRC) Research Associ-ateship Program Award, and she is currently working as a postdoc-toral research associate under the supervision of Dr. Michael J.Tarlov at the National Institute of Standards and Technology(NIST). Germarie’s research interests include bioanalytical chemis-try, electrochemical and surface characterization of nanomaterialsand metallic surfaces, self-assembled monolayers, carbon nano-tubes, biosensors, DNA arrays, and glycoproteomics.

Professor Carlos R. Cabrera obtained aB.Sc. in Chemistry at the University ofPuerto Rico, R�o Piedras Campus, in1982, and continued towards a Ph.D.in Chemistry at Cornell University. InJuly 1987 he joined Dr. Allen J. Bard’sgroup at the University of Texas atAustin as a postdoctoral research asso-ciate. In 1989, Dr. Cabrera joined theUniversity of Puerto Rico, R�o PiedrasCampus, as an Assistant Professor,and currently he is Professor ofChemistry there. His group works in re-newable energy and nanotechnology-related research. Over 50 un-dergraduates, 25 graduate students, and 10 postdoctoral researchassociates have been part of his research group. In 2000, Dr. Cab-rera obtained a NASA Administrator Fellowship to work at NASAGlenn Research Center in Li battery systems. Currently, he is the Di-rector of the Center for Advanced Nanoscale Materials, sponsoredby NASA. In addition to several hundred research papers and pre-sentations over the last 21 years, he is co-author of four chapterson fuel cells, education, and nanotechnology books and, currently,he is editing a book on advanced nanomaterials for aerospace ap-plications.

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Review L. Santiago-Rodr�guez et al.

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All the existing methods for CNT preparation producenanotubes with a variety of impurities. The impurities as-sociated with the growth method are: graphite sheet,amorphous carbon, fullerenes, carbon nanoparticles, andmetal catalyst particles. There are several ways to purifythe CNTs, divided into: (1) gas-phase and (2) liquid-phase. At the same time, they can be subdivided intochemical, physical, and a combination of both processes.For a complete review of the purification methods, pleaserefer to Hau et al.[13] and to Ismail et al.[14]

Gas-phase oxidation includes the treatment of CNTs inair and oxidative plasma. The main disadvantage of gasphase oxidation is that it cannot remove metal catalyst.This property of gas-phase purification methods is unde-sirable for the electrochemical application of SWCNTs,where metal catalysts should be avoided due to their elec-troactivity. Another disadvantage of gas-phase oxidationis the poor control of the reaction process, which canresult in over-oxidation of the CNTs and severe damageto the CNT structure. For these reasons the use of liquid-phase methods that simultaneously remove the metal cat-alyst and carbonaceous material are preferred.

The most used liquid-phase method to remove impuri-ties involves the use of strong oxidants, such as acids. Thebasis for the use of strong oxidizing agents as purifiers isthe difference in oxidation rates between carbonaceousmaterials and the CNTs. Amorphous carbons, for exam-ple, oxidize readily due to their high content of tanglebond, while highly curved carbonaceous particles oxidizebetter than CNTs.[14] Then, by filtration the highly oxi-dized and soluble impurities can be easily removed.Other purification techniques include: ultrasonication,microfiltration, ferromagnetic separation, chromatograph-ic techniques, and microwave heating, among others.[15–18]

One of the advantages of the acid treatment is that it sub-stantially removes the metal catalyst and carbon impuri-ties without destroying the CNTs� structure in a signifi-cant way.

One of the most used acids for SWCNT purification isnitric acid (HNO3), because it has demonstrated to be amild oxidant. The use of HNO3 oxidizes SWCNTs at theend caps and defect sites without destroying the nano-tubes; only small-diameter SWCNTs have been found tobe destroyed after the HNO3 treatment.[19] During the ox-idation process, functional groups such as carboxylic acid,quinone, phenol, ester, and zwitterions, among others, arecreated on the nanotubes surface.[20] Additionally thenitric acid resulted to be non-toxic, inexpensive, and ca-pable to remove the metal catalyst and carbonaceous im-purities without adding more impurities.[13]

Covalent functionalization of SWCNTs requires the in-troduction of chemical groups to the SWCNTs� defectsites. Liu and collaborators have been pioneers in thisarea.[21] They use a mixture of concentrated HNO3/H2SO4

in a 1 :3 volume ratio to shorten, open the nanotube ends,and to introduce carboxylic acids in the end and defect

sites of the SWCNTs. The SWCNTs are shortened duringsonication on the acid mixture due to the collapse ofhigh-temperature bubbles which allows the sonochemicalattack of NO2

+ .[20] The mechanism of action of the acidmixtures proceeds as follows:

HNO3 þ 2H2SO4 $ NO2þ þ H3Oþ þ 2HSO4

� ð1Þ

The NO2+ (electrophilic group) produced by the mix-

ture of acids attacks the p electrons on the CNT�s rings,which leads to a strong adsorption of the NO2

+ group tothe CNT�s surface, and its subsequent oxidation.[22] In ad-dition, this type of purification and oxidation method hasproven to be more effective than nitric acid treatment inremoving impurities, because it is known that the mixtureof acids tends to intercalate and exfoliate graphite.[13, 20]

Nevertheless, extensive oxidation of the CNTs can altertheir electronic and mechanical properties.[23]

3. Self-Assembled Monolayers

Self-assembly, a process that occurs in nature, refers tothe phenomenon in which independent molecules sponta-neously form highly organized structures. Specifically, theformation of a monolayer by self-assembly of moleculeson a surface is referred to as self-assembled monolayers(SAMs). The chemical affinity that the molecule has forthe substrate is the main driving force for the formationof a SAM. SAMs have been extensively studied becauseof the many advantages that they offer: they are easy togenerate, densely packed, well-oriented, and highly or-dered monolayers. Also, the thickness of SAMs can beeasily controlled and the properties of SAMs can bechanged by synthetic methods. The metal where theSAMs are formed can act as an electrode for the trans-duction of signals in a recognition process by electro-chemical methods. Some of the applications from ourgroup and others include the use of SAMs as corrosioninhibitors,[24] surface derivatization,[25,26] molecular recog-nition,[27] biosensors,[28] and others.[29]

The substrate most commonly used for the formationof SAMs is gold surfaces. Gold substrates have beenoften used in the literature during the history of SAMsdue to their relative chemical inertness, the straightfor-ward preparation of gold films, and also because it can behandled under atmospheric conditions. Gold does nothave a stable oxide; as a result it can be cleaned easilyjust by mechanical means. In addition, the substrate forSAM formation can be planar or curved, depending onthe application for which the SAMs are used.[30]

Nuzzo and Allara were the first to report the formationof a SAM on gold surface in 1983.[31] Since then, modifi-cation of gold surfaces with organosulfur compounds hasbeen an area of extensive research. Organosulfur com-pounds such as alkanethiols, dialkyl disulfides, dialkyl sul-fide, alkyl xanthate, and dialkylthiocarbamate are some

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DNA-Functionalized Carbon Nanotubes: Synthesis, Self-Assembly, and Applications


of the compounds that readily form self-assembled mono-layers on metal substrates such as gold.[23] Specifically, themost studied and understood organosulfur compoundsused for SAMs formation are n-alkanethiols. The interac-tion between sulfur and gold is considered to proceed viaan oxidative addition of the thiol (–SH) group to the met-allic gold surface (Au0) followed by the reductive elimina-tion of hydrogen:

R� SH þAu0n ! R� S�Auþ �Au0

n þ 1=2H2 ð2Þ

where R – SH represent the n-alkanethiols molecules,Au0 is the metallic gold surface, and R –S–Au+

* Au0 cor-respond to the thiolate bond formation.[32] Another possi-bility is the oxidative conversion of hydrogen intowater.[33] The spacer component of the monolayer is theskeleton of the adsorbed molecule, and it interacts withother neighboring molecules by van der Waals interac-tion, and in some cases hydrogen or p–p interactions.These interactions between the spacers contribute to theorganization of the monolayer. The tail group refers tothe terminal group of the molecule, which is exposed tothe surface after the monolayer formation. This part is in-volved in subsequent reactions and also contributes inchanging the surface properties.

Functionalization of the tail group of SAMs is com-monly practiced in surface science to impart the desiredproperties to the substrate surface. Two main strategiesfor chemical functionalization of monolayers are avail-able. The first strategy involves direct reactions with out-ermost functional groups on the SAMs. For a review onthis type of strategy, the reader is referred to Sullivan andHuck.[34] The second strategy makes use of reactive inter-mediates. Herein, only those reactions that involve theamine and carboxylic acid coupling to form an amidebond will be discussed.

Carbonyl activation of the carboxylic acid moiety usingcoupling agents such as 1,3-dicyclohexyl-carbodiimide(DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodii-mide (EDC) is commonly encountered in literature forattachment of molecules, such as proteins and deoxyribo-nucleic acid, to substrates. In summary, the mechanism ofDCC as peptide coupling agent proceeds as follows: (1)the carboxylate ions react with electrophilic carbon of thediimide to form the O-acylisourea, an activated inter-mediate; (2) the O-acylisourea undergoes aminolysis toform the amide bond where N,N’-dicyclohexyl urea(DCU) serves as an excellent leaving group.[35]

The reaction mechanism of EDC is similar, and it pro-ceeds as follows: (1) EDC reacts with the carboxylategroup to form the active ester intermediate, O-acylisour-ea. This reactive complex can react with the amine groupto form the amide bond, but this intermediate can also behydrolyzed in aqueous solution, which results in the re-generation of the carboxyl group. To increase the stability

of the intermediate, N-hydroxysuccinimide (sulfo-NHS) isused. (2) The hydroxyl group on the sulfo-NHS reactswith the O-acylisourea to form a stable activated carbox-ylate intermediate (sulfo-NHS ester intermediate), whichhas a half-life of hours. Then, (3) the activated carboxyl-ate intermediate reacts with the amine group to form thestable amide bond.[36]

4. Chemical Functionalization of CarbonNanotubes

Chemically functionalized CNTs are very sought-after re-agents, due to their improved solubility and manageabili-ty, and because they combine the unique properties ofCNTs with those of other materials. Advances in thechemical functionalization of CNTs have included studiesin both molecular and supramolecular chemistry. The sol-ubilization of CNTs by chemical functionalization hasbeen achieved by covalent chemical modification,[1,2,37, 38]

surfactant adsorption,[39] adsorption via p interactions ofaromatic compounds,[40,41] and polymer wrapping.[42,43]

Non-covalent supramolecular approaches for the func-tionalization of CNTs can preserve the unique propertiesof the nanotubes, while improving their solubility andmanageability. These valuable properties have advancednumerous proposals for the use of polymers, biomole-cules, surfactants, and polyaromatic compounds to non-covalently functionalize CNTs.[44] The non-covalent inter-action between the functionalizing molecule and theCNTs consists principally of van der Waals forces or p-stacking.

Alternatively, covalent functionalization of CNTs hasbeen studied more intensively and has been used forcountless applications. The main approaches for the cova-lent functionalization of CNTs include chemical modifica-tion at defect sites and at the sidewalls of the nanotubes.Covalent immobilization of CNTs has been performed byhalogenation, hydrogenation, cycloaddition, and radicaladdition, among other techniques, demonstrating the ver-satility of the covalent functionalization chemistries avail-able.[45]

Defect sites offer a promising starting point for the co-valent modification of CNTs due to their higher reactivityin comparison to the sidewalls, which makes covalentfunctionalization of the sidewalls more limited. Duringthe synthesis of CNTs, some defects of the six-member-ring carbon structure can occur, including the presence ofpentagons and heptagons. Other defects, such as theopening of the tube caps and the formation of holes inthe sidewalls can be induced by purification procedures(e.g., acid oxidation). As a result of acid oxidation wecan obtain nanotubes with oxygenated functionalities asmentioned above. For example, Yu and coworkers dem-onstrated that the acid treatment of CNTs easily generat-ed carboxylic acid groups at each end of the tube.[46] Oxi-




dized CNTs can undergo covalent functionalizationmainly by amidation and esterification reactions.[42]

Chemical reactivity of the tubes� sidewalls comes fromthe curvature-induced pyramidalization at the carbonatom and by misalignment of p-orbitals, both causing astrain in non-planar conjugated systems.[47,48] Therefore,only highly reactive reagents can be successfully used toperform covalent modification of the nanotubes sidewalls.Nevertheless, it is essential to perform chemical modifica-tion of CNTs in a controlled fashion—which is not aneasy task—in order to minimize the structural changesthat CNTs may experience during the functionalizationprocess. Direct sidewall modification has been achievedby hydrogenation or reaction with carbenes, nitrenes, rad-icals, and halogens.[49,50]

On the other hand, CNTs can be integrated to a sub-strate for applications such as electrochemical sensors.There are two types of integration methods: (1) direct or(2) indirect. Both types of growth methods depend on thetechnique of synthesis used. The direct methods includethe random and vertically aligned growth of CNTs over asubstrate. In this sense, techniques like arc discharge andchemical vapor deposition have been used, but the CNTsproduced grow randomly tangled or vertically denselypacked (forest-like), and behave as a macro-electrode interms of electrochemistry.[51] Indirect methods use CNTscomposites, which are a mix of CNTs with materials likeepoxy, mineral oil, and Nafion, among others, as the elec-trode. The substrates used include glassy carbon, glass,and metals like gold. Composites possess many disadvan-tages, including the formation of irreproducible films, lowsensitivity, stability, large response times, and high over-potential (additional potential needed to drive a reaction)for electron transfer reactions.[18] All of these parameterscould be improved using CNTs covalently attached on asubstrate, which is expected to be an easy and controlla-ble way to produce CNT-modified substrates to expandtheir applications.

One of the first approaches in the covalent functionali-zation of substrates was performed by Liu and collabora-tors in 2000. They reported a wet chemical techniquewherein they functionalized the SWCNTs with a thiol-ter-minated molecule that self-attaches on gold, creating astable monolayer.[52] They found that SWCNTs self-as-sembled on gold in this way were perpendicularly orient-ed, as observed by AFM images, and that the adsorptionrate varied inversely with the nanotubes� length. Theyalso observed the characteristic infrared stretching bandof the carboxylic acids at 1710 cm–1 for the oxidizedSWCNTs, and when the SWCNTs were attached to theamino group of the thiolated molecule they observed theappearance of the amide I band at 1600 cm–1. Additional-ly, they reported that the self-assembled SWCNTs formstable films that can survive sonication. They used AFMimages to demonstrate that the density of SWCNTs onthe surface increases with reaction time.

In 2002, Nan et al. proposed a different approach to co-valently attach the SWCNTs to the metal substrates.They functionalized the gold surface with 11-amino-1-un-decanethiol (AUT) and then covalently attached the pre-viously oxidized SWCNTs.[53] They observed the charac-teristic Raman band for the SWCNTs on the substratescovalently attached to the SAMs. They proposed a modelof condensation of the SWCNTs on the SAMs which con-sists of the following steps: (1) collision of the activatedcarboxylic acid functionality of the SWCNTs with theamino group in the monolayer, and subsequent reactionor condensation; (2) the already immobilized SWCNTsserves as nucleation center, leading to formation of bun-dles attached normal to the surface. The same approachwas also performed by Diao et al.[54] They reported thatthe SWCNTs were not totally vertically aligned, as ob-served by TEM images, and in fact there are SWCNTstilted on the surface. Using [Ru(NH3)6]Cl3 they reportedan increase in current in the voltamograms after the cova-lent attachment of the SWCNTs, and they ascribed thereappearance of the current to electron transfer betweenthe gold substrate and the SWCNTs via through-bondtunneling. Subsequently, they deposited copper on theSWCNTs to fabricate metal nanowire arrays by using theSWCNTs as templates.

Gooding and collaborators used the SWCNTs covalent-ly attached to gold for the attachment of the protein mi-croperoxidase. They measured its redox activity by cyclicvoltammetry, demonstrating that SWCNTs act as an elec-trical bridge allowing the electrochemical detection ofproteins.[55] Patolsky et al. used the SWCNTs covalentlyattached to gold to attach an amino derivative of theflavin adenine dinucleotide co-factor to the carboxylgroups of the SWCNTs, which was evidenced by cyclicvoltammetry.[56] Subsequently, the flavin adenine dinucle-otide co-factor was reconstituted with apo-glucose ox-idase, which was demonstrated by AFM measurements.They estimated that the surface coverage of the SWCNTsfor the 25 nm average length and with the glucose ox-idase, was 4 � 10–11 mol/cm2 and 1.1 � 10–12 mol/cm2, re-spectively. Also they reported a 1.5-fold enhancement inelectrocatalytic current using the SWCNTs and suggestedthat the electrical communication imparted by theSWCNTs can be explained by back scattering or electronhopping. They suggested that the oxygen moieties addedto the defect sites of the SWCNTs during the oxidationtreatment act as local barriers to charge transport, forcingthe electron to be backscattered or hop over these defect.This explanation was confirmed by the length dependencyfor electrical communication of the SWCNTs.

In 2005, Chou and collaborators demonstrated thatSWCNTs aligned on the surface using cysteamine pre-sented better heterogeneous electron transfer rate thanrandomly dispersed SWCNTs.[57] They demonstrated thatthe end of the SWCNTs with the carboxylate moieties isresponsible for the improved electrochemical response,




like the edge plane of pyrolytic graphite. In this sensethey attributed the advantages of the SWCNTs to theirsmall size, which allows them to penetrate places that py-rolytic graphite cannot reach. In the same year, Diao andLiu studied the electrochemistry of SWCNTs chemicallyassembled on gold via 11-amino-1-undecanethiol mono-layer. They suggested that the SWCNTs act as Coulombicislands or electron transfer stations, which conduct elec-trons between the gold and the redox species in solution.The electron transfer occurs as follows: (1) electron tun-neling from gold to the SWCNTs, (2) electron transferwithin the SWCNTs and (3) electron transfer from sidewalls and ends of the SWCNTs to the electroactive spe-cies in solution. They explained that the large p-conjugat-ed system on the SWCNTs allows them to act as electronacceptors and donors. They explained that the SWCNTspossess large number of occupied and unoccupied statesthat allows and facilitate both the electron transfer be-tween the SWCNTs and the redox couple, and betweenthe SWCNTs and the metal substrate. They reported thatthrough-space tunneling is the only electron transfermechanism possible between the SWCNTs and 11-amino-1-undecanethiol, because in their experiments there areno chemical bonds between the redox species and theelectrode.

In 2005, Rosario-Castro et al. from our group demon-strated the covalent attachment of SWCNTs to a 4-ami-nothiophenol monolayer on platinum.[58,59] They present-ed a step-by-step characterization of the surface using in-frared spectroscopy and X-ray photoelectron spectrosco-py. Huang et al. demonstrated that SWCNTs covalentlyattached to gold exhibit better electrochemical behaviorin comparison to bare gold.[60] They demonstrated thatthe density of the SWCNTs increases with reaction timeand concentration. Additionally, they observed SWCNTslying down on the surface having a length of more than250 nm, and that the shorter tubes appear to be verticallyaligned. A surface with high density of SWCNTs demon-strated slow electron transfer rates in comparison to asurface modified with lower density of SWCNTs. Thisreport suggested that by controlling the density of theSWCNTs the electrochemical behavior of the surfacescould be controlled, as well.

In 2006, Huang et al. showed that chemically assem-bled SWCNTs on 11-amino-1-undecanethiol form a net-like electrode in which SWCNTs appear lying down onthe surface.[61] They use the as-described electrode foruric acid analysis. They suggested that charge transport ofuric acid to the substrates can occur due to penetration ofthe uric acid into the film, movement of uric acid througha pinhole or channel in the AUT film, or by electrontransfer from the defect sites in tube sides and ends touric acid, in addition to the electron transfer mechanismexplained above. They observed that the electrochemicalactivity of the oxidized SWCNTs is better than that ofthe raw SWCNTs, even when they observed a net-like ar-

rangement of the SWCNTs in both cases. This observa-tion supports the hypothesis that the better electrochemi-cal behavior of the SWCNTs is indeed imparted by theoxygenated functionalities.

Ozoemena et al. used cysteamine to attach theSWCNTs and then they covalently attached cobalt(II)te-tra-aminophtalocyanine to the SWCNTs.[62] They foundthat, on phosphate buffer, the substrate modified with theSWCNTs and the redox molecule have a reversible elec-trochemistry. Due to poor electron transfer, the electro-chemical response of the cobalt(II)tetra-aminophtalocya-nine species does not present a well-resolved voltammo-gram, which confirms that SWCNTs improve the commu-nication between the substrate and the cobalt(II)tetra-aminophtalocyanine. They found that the electrode modi-fied with the SWCNTs, or with the SWCNTs and cobal-t(II)tetra-aminophtalocyanine, exhibited a catalytic re-sponse toward dopamine, which was attributed to possiblepenetration of dopamine into the SAM film pinholes.Their work also supports the through-space tunnelingmechanism of electron transfer between the SWCNTsand the substrate with the monolayer.

Other groups have used mixed monolayers of 4-amino-thiophenol with octadecanethiol to attach MWCNTs, andthey found that the nanotubes tend to organize in smallislands that behave electrochemically like nanoelectro-des.[63] Recently, Lin and collaborators chemically trans-ferred well-aligned SWCNTs obtained by chemical vapordeposition and, after functionalizing them in situ, pro-ceeded to covalently attach them to a gold surface previ-ously modified with 4-mercaptobenzoic acid.[64] They pre-sented a different method to covalently attach the nano-tubes to the desire substrate, but additional studiesshould be performed.

Guiseppi et al. created a microdisc electrode array ofgold that consisted of 1296 microdiscs and compared thecovalent immobilization of SWCNTs on cysteamine and11-amino-1-undecanethiol monolayers.[65] This group usedEDC and NHS as coupling reagents, instead of DCC, thelinker agent used until now. They found that theSWCNTs attached using cysteamine enhanced the effec-tive electrode area by 200% due to the lower passivatingproperties and disorder formation of the cysteamine mon-olayer. The SWCNTs attached to cysteamine were foundto be vertically aligned. Nevertheless, when they used 11-amino-1-undecanethiol monolayer to attach the SWCNTsthey reported that some of the SWCNTs lay down withinthe monolayer and only enhanced the area of the elec-trode by 100%.

Furthermore, the oxidized SWCNTs can be integratedto a surface by electrostatic interactions.[66] Chen et al.reported that an electric field enhanced the electrostaticattachment of the SWCNTs to the 11-amino-1-undecane-thiol SAM on gold.[67] Wu et al. used the property of thecarboxyl group, which can spontaneously adsorb to asilver substrate to vertically attach the previously oxidized




SWCNTs. They observed that shorter SWCNTs success-fully bind in a vertical orientation, but longer one tendsto be adsorbed with some tilting.[68]

5. Deoxyribonucleic Acid (DNA)

DNA is the basic building block of life, since hereditaryinformation is encoded in the chemical language of DNA.The DNA molecule is a polymer in which the monomericunit is the nucleotide. It has a double helix structure, con-sisting of two polynucleotide chains that run in oppositedirections. A nucleotide consists of a nitrogenous hetero-cyclic base, a ribose sugar (deoxyribose sugar for DNA),and a phosphate group (Figure 1). Each strand of thedouble helix is a linear chain consisting of a phosphate–sugar backbone, to which four bases are attached: the pu-rines, adenine (A) and guanine (G), and the pyrimidines,cytosine (C) and thymine (T) (Figure 2). In a process

known as hybridization, two complementary single-stranded DNA (ssDNA) strands are joined into thedouble stranded configuration of the DNA (dsDNA) bythe specific binding of hydrogen bonds between cytosineand guanine, and between adenine and thymine.

The remarkable structural properties of DNA and theability of controlled growth of nucleotide sequences havestimulated growing interest in DNA for nanotechnologyapplications. For example, DNA can be chemically modi-fied with the purpose of providing functional groups thatcan serve as linkers for the covalent attachment of nano-particles or other structures and molecules. Furthermore,due to its hybridization properties, DNA can serve as atemplate to organize the linking of different structures inspecific patterns. Therefore, the design and study ofDNA-based nanostructures, including CNTs, are fields ofincreasing popularity.

6. Non-Covalent Functionalization of CarbonNanotubes by DNA

The supramolecular complexes formed by the non-cova-lent interaction between DNA and CNTs have been in-tensively studied in recent years, and their main proper-ties and applications have been previously reviewed byour group.[69,70] DNA-wrapped CNTs take advantage ofthe exceptional properties of the nanotubes and the re-markable recognition capabilities of DNA. They exist asa well-defined chemical entity in aqueous solution due tothe strong non-covalent interaction between the DNAand the CNTs.[71] Compared to other polymers used,DNA offers the advantage of defined length and se-quence, high dispersion efficiency, and well-developedchemistries for further functionalization of the DNA-wrapped CNTs via covalent or non-covalent functionali-zation approaches.[72]

The synthesis of DNA-wrapped CNTs was first report-ed by several groups in 2003.[72–76] DNA-wrapped CNTsare prepared by combining CNTs with an aqueous solu-tion of DNA and stirring, sonicating, and/or milling[77] thecomponents of the mixture. In DNA-wrapped CNTs, thearomatic hydrophobic DNA bases interact with the side-walls of the CNTs via p-stacking, whereas the hydrophilicsugar–phosphate backbone of the DNA strand interactswith the aqueous solvent (Figure 3).[72,78]

DNA-wrapped CNTs have been synthesized with dena-tured calf thymus DNA,[73,74] DNA from salmon testes,[75]

short synthetic oligonucleotide sequences,[72,76] denaturedgenomic DNA,[73,74, 79] short fragmented DNA,[80, 81] DNAsynthesized by asymmetric polymerase chain reaction(PCR),[82] and single-stranded DNA obtained by rollingcircle amplification.[83] Alternatively, long denatured frag-ments of lambda DNA[79] and double-stranded DNA pro-duced by symmetric PCR[84] lack the capability to effi-ciently wrap around CNTs. Optimization of the disper-

Figure 1. Typical representation of a single strand of DNA.

Figure 2. Chemical representation of the bases that form the DNAmolecule.




sion efficiency of CNTs in DNA solutions by changingthe DNA sequence, DNA length, sonication time, type ofCNTs, and solvent conditions has been reported.[72,76,84–88]

The main properties of these complexes have beenstudied by using techniques that include atomic force mi-croscopy (AFM)[75,76,89, 90] transmission electron microsco-py (TEM),[75, 83,91–94] Raman spectroscopy,[75,76,78, 95–98] Fouri-er transform infrared spectroscopy (FTIR),[75,76] absorp-tion spectroscopy,[72,75,76, 92,99,100] scanning electron micros-copy,[101–105] fluorescence spectroscopy,[102,106–109] scanningtunneling microscopy (STM),[110,111] dichroism,[91,112, 113]

small angle neutron scattering,[107] optical microsco-py,[114, 115] photoluminescence spectroscopy,[108,116,117] energydispersive spectroscopy (EDS),[101, 104] capillary electro-phoresis,[118] and electrochemistry,[104,115, 119,120] amongothers.

Furthermore, several studies have shown that non-co-valent functionalization of CNTs by DNA also has thebenefit of purifying the nanotubes.[89, 91,121] For example,our group performed an in-depth study of the DNA-as-sisted purification of SWCNTs, and we demonstrated thatsonication and centrifugation of SWCNTs in the presenceof DNA serves as a crude purification procedure for thenanotubes. TEM, Raman spectroscopy, SEM, and EDSresults showed that DNA-assisted purification of theSWCNTs decreases the quantity of amorphous carbonand catalyst particles in the dispersion, and at the sametime decreases the degree of aggregation of the nano-tubes. Therefore, non-covalent functionalization ofSWCNTs by DNA provides an easy and simple way topurify SWCNTs at room temperature, without alteringtheir properties.

6.1. Non-Covalent Complexes of DNA and Carbon NanotubesAssembled on Solid Substrates

Individually dispersed DNA-wrapped CNTs have beenassembled on solid substrates, in order to facilitate theircharacterization or to be used as a sensing material.These DNA–SWCNT complexes have been deposited asa film on substrates such as glassy carbon,[105] glass,[106]

gold,[122, 123] and a SiO2 surface with a gold boundary.[124]

Furthermore, our group was the first to form SAMs ofvertically aligned DNA-wrapped SWCNTs on gold surfa-ces.[125–128]

Our group demonstrated the feasibility of immobilizingSWCNTs on gold by the self-assembly of the supramolec-ular complex formed between disulfide-modified DNAstrands and the SWCNTs (Figure 4). Mixed self-assem-

bled monolayers, containing aggregates of DNA–CNT hy-brids covering from 1 to 10% of the surface, were ob-tained, as evidenced by AFM (Figure 5).[128,131] TheDNA–SWCNTs were attached in a perpendicular fashionto the gold electrodes; such an unusual geometry had pre-viously been obtained only by direct growth of the CNTson a surface by chemical vapor deposition, or by post-synthesis attachment of oxidized/activated CNTs by cova-lent means on pre-formed self-assembled monolayers(SAMS). The methodology developed by our group rep-resents a practical alternative to the traditional methodsfor the attachment of SWCNTs to solid substrates, sincethe procedure is not time-consuming and does not requirethe use of expensive instrumentation.

Additionally, our group was able to tailor the surfacecoverage by varying the initial concentration of DNA–SWCNTs or by using reductive electrochemical desorp-tion.[126, 128] We used electrochemical techniques to deter-mine that the blocking properties of the DNA–SWNTSAM increase with increasing concentration of the immo-bilizing species. Also, we demonstrated the feasibility of

Figure 3. Graphical representation of an ss-DNA-wrapped single-walled carbon nanotube. Reprinted with permission from ref. [78]� 2006, American Chemical Society.

Figure 4. Schematic representation of the non-covalent functional-ization of SWCNTs by DNA, and the DNA-mediated attachment ofSWCNTs on gold. (The figure does not necessarily represent thecorrect ratio between the species chemisorbed on the gold sur-face, and the drawings are not to scale.)




using electrochemical desorption to vary the surface cov-erage or to perform the complete removal of the SAMsfrom the surface. The surface coverage of the SAMs canbe controlled by varying the number of desorption cyclesor by stopping at different desorption potentials (seeFigure 6).[129] Alternatively, electrochemical desorptionusing a large number of cycles can be used as a cleaning

procedure to completely remove all the immobilized spe-cies, allowing the electrode to be reused, and thus reduc-ing analysis time and costs.

On the other hand, we analyzed the mixed SAMsformed and we compared both DNA–SWCNT and DNAareas of the mixed SAMs to traditional DNA SAMs.[127]

Surface analysis and electrochemical results showed theformation of a more compact, ordered, and denselypacked DNA layer for the DNA–SWCNT system, incomparison with a traditional DNA SAM. The use ofDNA–SWCNT hybrids to form SAMs on gold substratesthus represents a new approach to improve the immobili-zation of DNA strands on gold, and will therefore helpwith the development of enhanced DNA sensors.

Overall, these results suggest that DNA–SWCNT com-plexes are promising materials for the design of novelnanodevices and sensors. For example, vertically alignedSAMs of DNA–SWCNTs on gold, prepared by Viswana-than and coworkers, were subsequently coated with poly-aniline, modified with acetylcholinesterase, and used as anovel biosensor for the detection of pesticides such asmethyl parathion and chlorpyrifos.[130]

7. Covalent Functionalization of CarbonNanotubes by DNA

Our first approach to electrochemically sense the DNAhybridization on a gold surface modified with a self-as-sembled monolayer and SWCNTs was performed in2007.[131] We demonstrated by cyclic voltammetry, XPS(X-ray photoelectron spectroscopy), and grazing-anglespecular reflectance that a reproducible monolayer of 4-aminothiophenol (ATP) was successfully formed overgold. The cyclic voltammogram of the 4-ATP monolayeron gold showed a characteristic peak at approximately0.85 V that comes from the oxidation of the monolayeron 1.0 m H2SO4. In addition, we found that the surfacecoverage of the monolayer formed from gold immersedin 10 mM 4-ATP solution after 24 h was (1.0 � 0.3) �10–9 mol/cm2. Using XPS we found three peaks in the C1s region that were assigned to C–C (284.5 eV) comingfrom aryl carbon of benzene ring, C–S (285.5 eV), and C–N bond (286.6 eV), respectively. Moreover, these bandsin combination with the disappearance of the thiol bond(at 2,554 cm–1) vibrational mode after the formation ofthe monolayer, confirmed the modification of the surface.

The SWCNTs were covalently attached to the 4-ATPmonolayer via amide bond formation between the aminegroup of the 4-ATP and the carboxylic group of theSWCNTs. The formation of the amide bond was con-firmed by XPS and infrared spectroscopy. The C 1sregion curve fitting showed six bands at 284.5, 285.6,286.6, 287.9, and 288.8 eV that have been attributed to C–C, C–OH, C=O, N–C=O, and O–C=O bonds. Theband at 287.9 eV, assigned to an amide bond, evidenced

Figure 5. Tapping mode atomic force microscopy image (top) andsection analysis (bottom) of a 0.04 mM DNA–SWNT SAM on gold.(Each x, y scale division equals 2 mm for the image (top), and eachz scale division equals 100 nm.) Reprinted with permission fromref. [131], � 2007, Elsevier.

Figure 6. Comparison of the cyclic voltammograms (scan rate: 50mV/s) in K3Fe(CN)6 (1 M in 0.1 m KCl) for bare Au (a), and a 0.04 mMDNA–SWCNT SAM sample before (b) and after (c) one cycle of elec-trodesorption.




the condensation of the oxidized SWNT to the 4-ATP im-mobilized on gold. These results were confirmed by infra-red spectroscopy, by the appearance of the amide vibra-tional modes at 1650, 1515, and 1418 cm–1. Then, the co-valent attachment of a single-stranded DNA consisting of15 bases of thymine was monitored by infrared spectros-copy. The spectrum shows the vibrational modes of u

asymmetric PO2 and u symmetric PO2, at approximately1257 and 1079 cm–1, respectively. Also, we found the thy-mine band at 1647 cm–1. A specific peak for carbonylgroup (C=O) in thymine spectra attributed to non-chem-isorbed thymine to gold was found at 1742 cm–1.

Our second approach was based on a gold surface self-assembled with a monolayer of 11-amino-1-undecanethiol(AUT) covalently bound to SWCNTs and ssDNA(Figure 7).[132,133] Cyclic voltammetry was used to charac-

terize the as-described substrate on 1 mM [Fe(CN)6]3–/

[Fe(CN)6]4– in phosphate buffer at pH 7 (see Figure 8).

We observed a decrease in current after AUT monolayerformation due to the blocking effect that AUT moleculesexerts against the electroactive species in solution, whichisolates the gold surfaces. After the attachment of theSWCNTs, a significant increase in current was observed.Several theories had been established to explain that in-crement in current. The first theory suggests that electrontransfer occurs in the SWCNTs via their conjugatedsystem. The second one suggested that electrons aretransferred via a tunneling mechanism between theSWCNTs and gold. The third theory suggested that back-scattering or electron hopping is the prevalent mechanismat defect sites for the charge transfer. Electron transfervia the oxygenated sites has also been suggested. Afterincreasing the scan rate, we found a sigmoidal shaped vol-

tammogram that suggested that the active sites of the sur-face modified with the SWCNTs presented a nanoelec-trode behavior. By intercalating methylene blue (MB),we monitored the DNA hybridization process, whichunder high ionic strength conditions favors the intercala-tion of MB with the ssDNA guanine bases. By squarewave voltammetry we observed a decrease in MB electro-chemical response after DNA hybridization with it com-plementary ssDNA, due to less accessibility of guaninebases to intercalate the MB molecules. This MB differen-ces in current between ssDNA and dsDNA confirmed thepossibility of using the SWCNTs-modified substrate forelectrochemical DNA hybridization sensing.

The gold surface modified with AUT and covalentlyfunctionalized with SWCNTs-ssDNA was used as a tem-plate to study the DNA hybridization by using the redoxcouple [Fe(CN)6]

3–/4– as an ion marker. To follow theDNA hybridization on the as-described substrate we usedelectrochemical impedance spectroscopy, which is an elec-trochemical technique that allows us to measure the fara-daic and non-faradaic current. We observed an increasein charge transfer resistance (RCT) as the gold surfacemodified with the SWCNTs–ssDNA was hybridized withthe complementary ssDNA (see Figure 9). That increasein RCT can be attributed to the repulsion between thephosphate chain of the DNA and the negative charge ofthe electroactive species in solution, which increases afterthe double-strand DNA formation. As expected, as theconcentration of the complementary ssDNA increased,the repulsion between the dsDNA and [Fe(CN)6]

3–/4 in-creased and, as a consequence, the RCT increased as well.By plotting the ratio of RCT dsDNA to RCT ssDNA vs. thelogarithm of the complementary ssDNA concentration (y= 1.163 log x – 1.669, R2 = 0.991) we found a linearrange between 250–1000 mM with an estimated detectionlimit of 48.8 nM. The selectivity of the substrate towardnon-complementary ssDNA and a three-bases mismatchssDNA resulted in an increase in RCT as follows: RCT

Figure 7. Representation of the gold electrode surface modifica-tion with a self-assembled monolayer of 11-amino-1-undecatethiol(AUT) followed by covalent functionalization with single-walledcarbon nanotubes (SWCNTs) and a single-stranded DNA (ssDNA)which were subsequently used as an impedimetric hybridizationsensor (The figure does not necessarily represent the real nano-structured electrode).

Figure 8. Cyclic voltammograms of bare gold (-&-), 1 mM 11-amino-1-undecanethiol (-*-) after 24 h immobilization, withSWCNTs covalently attached (-~-) and after sequence A attach-ment and hybridization with sequence B (-^-) in 1 mM K3Fe(CN)6/K4Fe(CN)6 in phosphate buffer (pH, 7) solution at 50 mV/s.




non-complementary, followed by three bases mismatchand complementary ssDNA. This approach demonstratedthat the prepared electrode could be reused at least onceafter denaturation.

8. Summary and Outlook

Carbon nanotubes are a unique type of nanomaterial andthe number of reports of their possible applications hascontinued to increase in the past decades. Their structuralheterogeneity, purity, and poor solubility are some oftheir drawbacks; however, chemical functionalization hasbeen effectively used to address these issues. Specifically,functionalization with biomolecules, such as DNA, hasopened the door for the use of CNTs in biomedical appli-cations. Chemical functionalization of CNTs with DNA,by either covalent or non-covalent approaches, is particu-larly attractive because the DNA–CNT hybrids combinethe unique properties of nanotubes and the outstandingrecognition capabilities of DNA.

Due to their versatility, DNA–CNT hybrids have beensuccessfully used as sensors for biomolecules, ions, andgases; as biosensors for DNA hybridization; and as bio-logical transporters, among others. Biosensors based onDNA–CNT complexes provide advantages such as goodstability, low detection limits, and good sensitivity. Fur-thermore, DNA–CNT hybrids are more manageable andeasier to assemble into solid substrates than pristineCNTs. Nevertheless, controlled and orderly integration ofDNA–CNT hybrids into solid substrates is not a trivialtask. We have provided an alternative to this challenge byusing self-assembled monolayers coupled with CNTsfunctionalized by covalent and non-covalent approaches.Our group was able to vary the surface coverage of theDNA–CNT complexes by using reductive electrochemicaldesorption or by changing parameters as simple as theconcentration of DNA–CNTs in solution. Additionally,we have also used SAMs of DNA–CNT complexes asnovel electrochemical biosensors for DNA hybridization.

Opportunities for future work include the applicationof SAMs of DNA–CNT complexes as biosensors for thedetection of viruses, bacteria, antibodies, proteins, gases,and toxic chemical agents, just to name a few. Specifically,the modification of CNTs with DNA aptamers and mo-lecular beacons, and their application as biosensors, arean interesting potential area of research. Also, the inte-gration of DNA-CNTs into microarrays or as field-effecttransistors should be further explored. Moreover, addi-tional studies leading to a clearer understanding of the in-teractions involved during DNA hybridization on surfacesmodified with DNA–CNTs will enable the developmentof improved DNA hybridization sensors.Acknowledgments

This work was supported in part by the Center of Ad-vanced Nanoscale Materials, NASA Grant numbersNCC3-1034 and NNC08BA48A. GSP and LSR acknowl-edge support from an NSF-EPSCoR Institute for Func-tional Nanomaterials Fellowship, Grant Number OIA-0701525, and a Puerto Rico Industrial DevelopmentCompany (PRIDCO) Fellowship.

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Received: May 17, 2010Accepted: July 27, 2010

Published online: October 1, 2010




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DNA-Functionalized Carbon Nanotubes: Synthesis, Self-Assembly, and Applications