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2.1.1.4  Cycloaddition  Cycloadditions are another important way of functionalizing the walls of nanotubes to tune their biocompatibility and biodegradability, both crucial characteristics to perform in vivo studies. Delgado and colleagues [71] described for the first time the [4 + 2] Diels–Alder reaction of o-quinodimethane assisted by microwaves on SWCNT surface (Scheme 3). More recently, anhydride-functional- ized CNTs were produced using a cascade of Diels–Alder cycloaddition reactions employing 1,3-butadiene generated from 3-sulfolene in the presence of atmospheric oxygen [72].

A very versatile methodology uses 1,3-dipolar cycloadditions between the nanotube and azomethine ylides generated in situ by condensation of α-amino acids and aldehydes [73, 74]. This approach yields bi-substituted pyrrolidines and highly functionalized CNTs (Scheme 4) [75, 76]. Using this strategy, Calcio Guadino et al. [77] obtained multi-decorated SWCNTs in a single step. Single microwave-assisted grafting reaction labels nanotubes’ surface with amino acidic β-cyclodextrin derivative and the (1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid monoamide) moiety with a 1:1 ratio.

2.1.2 Defect Functionalization

Defect functionalization makes use of the structural weaknesses of CNTs to create new bonds. Although nanotubes are highly unreactive, all the preparation methods to obtain them leave some defects in their structure, both in the lateral walls and in the tips. Among the lateral walls, these defects include dipoles of heptagon–pentagon pairs in the hexagonal network called Stone–Wales defects, sp3-hybridized defects, and vacancies in the sp2 network [45]. The nanotube’s ends are usually closed with fullerene, presenting mixed pentagonal–hexagonal structures more reactive than the pristine lateral walls [45]. Defect functionalization employs these intrinsic defects or generates new ones on the nanotube structure, normally by aggressive oxidative processes either in liquid or gas phase, or by electrochemical oxidation [78]. This approach has the advantage of generating more functional groups, but also implies higher structural damage. Using less aggressive oxidative approaches, the structural damage is minimized preserving CNT’s properties [79]. Defect functionalization can be classified according to the nature of the chemical transformation occurring at the defect sites, like oxidation, amidation, thiolation, etc. These attached functional groups are normally used as the starting point for further derivatization [80].

Oxidation and carboxyl-based coupling constitutes one of the most relevant strategies for CNTs functionalization, including the formation of esters [81, 82], amides [83], and ammonium carboxylate salts [84]. This modification is achieved in a twostep process. The first one often involves the treatment of commercially available carbon nanotubes with a mineral acid [85] such as nitric acid [86] or a sulfonitric mixture [87]. This step shortens CNTs, narrowing length distribution [88], and reduces the metal concentration left from their synthesis, decreasing toxicity and improving the preclinical possibilities. Nanotube defects will su er the e ects of the oxidant creating carboxylic and other oxygen-bearing groups [85]. The second step occurs via carboxylic acid formation, and can be carried out using two methodologies: (1) employing in situ acid chloride formation with thionyl chloride and

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Scheme 3 [4+2] Diels–Alder reaction of o-quinodimethane assisted by microwaves on SWCNT surface

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Scheme 4  1,3-Dipolar cycloaddition reaction between carbon nanotubes’ surface and azomethine ylide generated in situ

subsequent reaction with a primary amine or alcohol (Scheme 5a) [87]; (2) using activating agents, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysulfosuccinimide sodium salt (NHS), and subsequent reaction with a primary amine (Scheme 5b) [89].

2.2 Non covalent Functionalization

Non-covalent functionalization does not imply the formation of new chemical bonds. The linkage with the nanotube is achieved through van der Waals forces,– interactions, hydrogen bonds, and/or electrostatic interactions, preserving the CNT’s structure intact. As a result, non-covalent functionalization ensures the sp2-hybridized six-membered ring network and the extended -conjugation, maintaining the physical, electric, thermal, and optical properties of CNTs. However, this comes at the cost of a weaker anchoring of the functional groups that can be detached by changes in environmental conditions, as modifications in pH, temperature, or solvent. This weaker bonding could be transformed into an advantage, making this functionalization reversible, something especially useful for therapeutic and

Scheme 5  Functionalization of carbon nanotubes through carboxylate via acid chloride (a) and EDCNHS (b)

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