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1.2. Polymer Sidechain Modification

1.2.2. Covalent Strategies

Unlike non-covalent strategies for polymer functionalization, the use of covalent bonds is desirable when high conversions and robust methods are essential. In particular, some of the characteristics of covalent strategies imply not only excellent yields, but also mild conditions and readily removable by-products. Although, technically, all organic chemistry transformations could be applied for polymer modification, not all are compatible with the higher

molecular weight or the purification techniques of such macrostructures compared to smaller organic molecules.[73] For this reason, over the years, certain strategies have become more popular than others, allowing for both efficiency and compatibility. Among the favoured covalent approaches used in polymer modification, cycloaddition reactions, such as Diels-Alder and 1,3 dipolar reactions, have received the most attention.[74]

The high efficiency of Diels-Alder reactions makes them an appropriate tool for polymer post-functionalization. In particular, maleimides 47 are most commonly used as the electron-poor dienophile due to the possibility to attach various substituents to the nitrogen atom (Figure 24). Common electron-rich dienes used in Diels-Alder polymer conjugations are anthracenes 48, furans 49, and cyclopentadienes 50 to obtain, after reaction with 51, products 52-53, respectively, as shown in Figure 24. While the reaction normally proceeds at elevated temperature of more than 110 °C for an extended time (36 to 120 h) without a catalyst,[74] the use of cyclopentadienes, for example, enables to avoid these harsh conditions. [75]

Figure 24. Diels-Alder reactions between maleimide 47 and polymers containing anthracene 48, furan 49 and pentadiene 50 to obtain sidechain-modified 51-53, respectively. Figure adapted from reference.[74]

While in all these cases a mixture of endo and exo addition products is obtained, the use of benzaldehyde derivative 54 favours the formation of only the endo product (Figure 25). Indeed, the photoisomerization of 54 leads to the Z isomer of enol 55, stabilized by hydrogen-bonding, which can subsequently engage in the Diels-Alder reaction with arginine-rich maleimide 56. Polymer 57 is obtained as a single isomer, in quantitative yield, at room temperature in less than 15 minutes and the cycloaddition can also be carried out in water.[76]

n

47 N O

O

48

n

49 O

n

50

n

51 N

O O

n

52 O N

O

O

n

53 N O

O

Figure 25. UV-light induced formation of 55 from 54 and subsequent Diels-Alder reaction with 56 to obtain arginine-rich endo polymer 57. Figure adapted from reference.[75]

Another important covalent strategy is the 1,3-dipolar cycloaddition. The thermal reaction between a 1,3-dipole and a dipolarophile was investigated extensively by Huisgen and coworkers in the 1960s to obtain five-membered heterocycles.[77] Common 1,3-dipoles are azides, nitro and diazo compounds, while the dipolarophiles are usually alkenes and alkynes. Triazoles, such as 60, are among the heterocyles that were synthesized using the cycloaddition between azide 58 and alkyne 59, using elevated temperatures to obtain usually a 1:1 mixture of the 1,4- and 1,5-regioisomers

,

as shown in Figure 26.[78]

O O

Figure 26. 1,3-Dipolar cycloaddition of 58 and 59 to give triazole 60 as a mixture of regioisomers. Figure adapted from reference.[78]

1,4-Regioselectivity was then achieved by Fokin and Sharpless in 2002 by introducing a copper(I) catalyst,[78] as well as by Meldal and coworkers on a solid support.[79] It was found that the Cu(I) species is best generated in situ by Cu(II) salts, such as copper sulfate (CuSO4×H2O), using a reductant like sodium ascorbate. The reaction proceeds with high yields, in water and at pH values ranging from 4 to 12. Moreover, the reaction tolerates bulkier reactants and a wide variety of functional groups.[78] Over the years, this copper-catalyzed azide-alkyne cycloaddition (CuAAC) became part of the so-called “click” reactions due to its versatility, broad scope, simplicity and biocompatibility.[80]

The most recent proposed mechanism, reported in 2013, involves two copper atoms, as depicted in Figure 27. Starting from alkyne 59, the first copper atom coordinates to the π-system to give 61 and then a second copper atom is introduced leading to acetylide 62. At this point, the π-bound copper coordinates to azide 58 giving complex 63 in which the β-carbon of the acetylide attacks the azide forming the first covalent C-N bond of the six-membered metallacycle 64.

Ring contraction of 64 leads to triazole derivative 65 which then, after protonolysis, gives 1,4-triazole 60.[81]

N N N R2

R1

N

N R2 N

R1

1 4

N N R2 N

1 5

+ R1 58

59 60

Figure 27. Proposed catalytic mechanistic model for CuAAC. Figure adapted from reference.[81]

CuAAC has been applied for the labelling of proteins,[82] DNA,[83] RNA,[84]

receptors in living cells,[85] but alsonanotubes[86] and surfaces[87]. It has also been widely used as a covalent strategy for polymer functionalization, as depicted in Figure 28.[74]

Figure 28. Schematic representation of polymer functionalization achieved using CuAAC. Figure adapted from reference.[74]

There are many examples in the literature where azides or alkynes are introduced as pendants on the polymer backbone to introduce a wide range of functionalities: metal complexes,[88] receptors,[89] dendrimers,[90-92] PEG chains,[93-94] as well as exploited as a strategy to synthesize block copolymers.

[95-98]

CuAAC was also adopted to readily functionalize the polymer sidechain of 66 equipped with an alkyne, with carbohydrates bearing azides such as α-mannose 67 and β-galactose 68, to obtain glycopolymer 69 (Figure 29) which was then selected as the best ligand for the selective recognition of a mannose-binding lectin.[99]

N NN N N N NN N

N NN N N N

NN N Sidechain Functionalization

N NN Block Copolymers

Dendronized Polymers

N NN

N NN N

N N Polymer Bioconjugation

N NN

Figure 29. CuAAC reaction between alkyne polymer 66 and azides 67-68 to obtain glycopolymer 69. Figure adapted from reference.[99]

Moreover, compatibility with polypeptides (Figure 30) enabled to introduce guanidinium groups, as shown in polymer 70, for DNA and siRNA delivery through counterion-mediated uptake,[100] or to obtain biotinylated polymers, such as 71, for further functionalization with streptavidin.[101]

Figure 30. CuAAC reaction on poly(peptide)s to introduce guanidinium and biotin residues, 70-71, respectively. Figure adapted from reference.[100-101]

O

Finally, thiols represent a powerful tool for polymer sidechain engineering due to their compatibility with many functional groups, polymerization methods, simplicity of the conjugation strategies and the commercial availability of thiol-related products.[74] The strategies involving thiol chemistry will be dealt in section 1.4.2. concerning the conjugation of polymers with proteins.

In conclusion, several strategies, whether non-covalent, dynamic or covalent, have been developed to functionalize polymers at the sidechain level.

When considering a possible post-polymerization modification of the CPDs, the use of orthogonal DCBs, such as hydrazones, can be appealing to obtain fully dynamic systems, as well as covalent approaches like the cycloaddition reactions shown in the last part of this chapter. The next chapter, on the other hand, will deal with the modification of delivery systems, for example polymers, with carbohydrates to promote cellular uptake through the use of the abundant carbohydrate receptors.