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than non-covalent functionalization, can be done in organic solvent or even without solvent, and o ers a huge plethora of functional groups that can be used [44]. All these benefits highly assist the potential use of carbon nanotubes in biomedicine.

Briefy, covalent functionalization can be classified depending on whether the modifications are performed at the sidewalls or in defect sites.

2.1.1 Side Wall Functionalization

The sidewalls of carbon nanotubes are considered to be very inert, so their direct functionalization will only occur if a highly reactive agent is used [45]. Singh et al. [46] widely describe the main side-wall derivatization strategies in SWCNTs, including halogenation, arylation, nucleophilic addition, radical addition, cycloadditions, and carboxyl chemistry reactions. Here we present the most commonly used strategies in preparing CNTs in order to increase their solubility and dispersivity [34], decrease the inherent toxicity [47], and improve their biocompatibility with biomedical purposes.

2.1.1.1  Halogenation  Fluorination was first used to overcome the lack of CNT reactivity using elemental fuorine at temperatures between 25 and 600 °C [48, 49]. These new C-F bonds are weaker than those in alkyl fuorides [50] and can be employed for further functionalization [51], replacing fuorine with amines [52], alcohols [53], or alkyl groups using Grignard [54] or organolytic reagents [55] (Scheme 1). Besides fuorination, chlorination and bromination of CNTs can also be achieved using electrolysis [56].

2.1.1.2  Electrophilic and Nucleophilic Additions  Electrophilic addition of alkyl halides results in the formation of alkyl and hydroxyl groups, whereas nucleophilic addition of amine-based nucleophiles leads to amino-functionalized CNTs (Scheme 2). As an example of electrophilic reaction, Friedel–Crafts acylation between MWCNT

Scheme 1  Fluorination and further functionalization of carbon nanotubes

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and p-aminobenzoic acid in the presence of polyphosphoric acid renders MWCNTNH2 (Scheme 2a), which can be used for further functionalization with poly(l-lac- tide) polymer [57] or with collagen using glutamic acid as a crosslinker [58]. As an example of nucleophilic addition, SWCNT can be alkylated by the treatment with t-butyllithium and subsequent reoxidation of the intermediates to obtain neutral CNTs decorated with tert-butyl moieties [59].

2.1.1.3  Radical Additions  Originally, this approach was developed using substituted aryl diazonium salts electrochemically reduced in organic media (Scheme 2c) [60, 61]. The electron transfer between the CNT and the aryl diazonium salt triggered the formation of the aryl radicals. Posterior developments allowed performing this reaction in water [62] and to generate highly functionalized carbon nanotubes using micelle-coated CNTs [63, 64]. In situ generation of the diazonium salt provided functionalized well-dispersed nanotubes in organic solvents [65, 66], in aqueous solutions [67] and in solvent-free conditions [68]. Finally, electrochemistry allows both the reductive and the oxidative attachment of substituted phenyl groups [69, 70].

Scheme 2  Surface derivatization of CNT: a Friedel–Crafts acylation; b electrophilic aromatic addition; c radical additions using diazonium salts reaction; d ozonolysis

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