3.1. Divergent Technique

The first attempt at the synthesis of SBDs was reported by Prof. Vögtle et al., who obtained sulfonamide-substituted G2-G4 polypropylene amine (POPAM) dendrimers by N-monosulfonylation and N-bissulfonylation [40]. Prof. Vögtle et al. proposed using sulfonic acid chlorides (sulfonyl chlorides) for the mono- and bifunctionalization of dendrimers. Arylsulfonyl chlorides are commercially available, making these dendrimers synthetically accessible and increasing the potential structural variability of dendritic sulfonimides. They reported the first N-sulfonylation of poly(propyleneimine) (PPI) dendrimers and suggested using this method to synthesize higher-generation SBDs [32].

The next synthetic approach for obtaining dendrimers with sulfonimide units at the branching points was reported by Prof. Vögtle et al. in 2004 [41]. Prof. Vögtle et al. developed a method that allows the controlled functionalization of oligoamines such as tris(2-aminoethyl) amine by persulfonylation using sulfonyl chlorides. Thus, the sulfonylation reaction can be controlled by changing the reaction conditions, for example, the amount and nature of the reagents, as well as the time and temperature of the reaction. The selectivity of the persulfonylation has opened up possibilities for the synthesis of new types of SBDs with more complex structures and different functional groups through sulfonylation of the amine, by not only the addition method 1→1 but also using the more effective way 1→2 [42]. The selectivity of the sulfonylation reaction may also depend on the nature of the base used; for example, the reaction of tris (2-aminoethyl) amine with arylsulfonyl chlorides in dichloromethane (CH₂Cl₂) or CHCl₃ in the presence of a base catalyst leads to the formation of sulfonamides according to the addition scheme 1→1. The same reaction can lead to sulfonimide according to the 1→2 addition scheme if cesium carbonate is used as the base. The yields of sulfonimide depend on the nature of the sulfonyl chloride. Along with the influence of the base’s nature, sulfonyl chloride's choice affects the sulfonylation reaction. Scheme 1 shows that the sulfonylation of a sulfonamide with six terminal amino groups using sulfonyl chlorides containing methyl and tert-butyl groups in the presence of triethylamine unexpectedly allowed the sulfonylation of all external amino groups. Thus, using the 1→2 branching scheme will enable one to quickly and efficiently obtain chemically stable dendrimers with sulfonimide branches.

Scheme 1. Controllable per-functionalization (persulfonylation) of dendritic oligoamines.

The commercial availability and widespread popularity of polypropylene-amine dendrimers (POPAM) [43] and polyamidoamine dendrimers (PAMAM) [44] are the main factors for studying persulfonylation using these types of dendrimers to obtain higher-generation products. The interaction of the G1 POPAM dendrimers with tosyl chloride was carried out in the presence of cesium carbonate as a base to produce sulfonimide, as shown in Scheme 2 [45]. In addition to the target product, by-products of incomplete substitution of the hydrogen atom of the amino group can also form with the formation of a mixture of sulfonamides. Since the molecular weight of the unsubstituted products is compared to the target dendrimer, sulfonamides can be easily separated using conventional silica gel column chromatography.

Scheme 2. Persulfonylation of a G1 polypropylene-amine (POPAM) dendrimer.

Interestingly, subjecting the G2 POPAM dendrimer to the same sulfonylation procedure with tosyl chloride does not lead to the expected products. Under these conditions, the G2 POPAM dendrimer's further sulfonylation yielded a complex mixture of products consisting of various sulfonylated fragments not subject to separation and purification. Similar to POPAM dendrimers, outer shell PAMAM dendrimers contain aliphatic amino groups. However, the G2 PAMAM dendrimers' sulfonylation with sulfonyl chlorides in the presence of cesium carbonate resulted in octasulfonamide rather than hexadecasulfonimide. The method proved to be of limited use because it could only be applied for the peripheral decoration of G1 branched oligoamines. The partial persulfonylation of the oligoamines makes product separation difficult. Therefore, future investigations on the sulfonylation of amine-terminated dendrimers of other sulfonyl chlorides may lead to the development of new approaches to selective functionalization with the creation of new dendritic structures with useful properties. Based on the previous N-bis-sulfonylation (persulfonylation) results, Oleg Lukin et al. described the synthesis of a newly designed type of dendron that carries sulfonimide functional groups at every branching point. The selectivity of the primary amines persulfonylation in combination with a repeating methodology allows the creation of selectively decorated and shape-changing dendritic sulfonimide structures from simple building blocks [6]. Taking into account the limitations of the peripheral decoration of aliphatic amines, Oleg Lukin et al. employed an amine persulfonylation, which results in a 1→2 branching addition in a repeating manner that would lead to dendritic sulfonimides. The synthetic procedures are shown in Scheme 3 [6]. The main reactions involved are the persulfonylation of amines and the reduction of nitroaromatic compounds.

Oligosulfonimides were synthesized in two steps: by treating N-octylamine with sulfonyl chloride with the nitro group in the presence of triethylamine and catalytic reduction of the nitro moieties to the corresponding amines. Octylamine was selected as the core molecule because of intermediate sulfonimides' good solubility compared to similar primary amines with different alkyl chains [46]. The octylamine was persulfonylated in one step using an excess of the corresponding sulfonyl chloride.

In the last step, the dendrimer was functionalized by persulfonylation with chemically inert tosyl chloride, giving a G3 symmetrical dendrimer with methyl groups at the ends. Thus, the divergent approach shown in Scheme 3 is one of the most effective methods for producing repeating branched structures based on sulfonimide with various functional groups at the ends. Another advantage of this method is the simplicity of the procedure for purification of the obtained dendrimers by simple recrystallization in suitable solvents with a satisfactory yield. The synthesis of SBDs is attractive from the commercial availability of various arylsulfonyl chlorides, which allows one to quickly obtain different types of high-generation SBDs decorated with the desired functional groups. Compared with previous works, this new one-step persulfonylation for primary amines by only heating with an excess of both the arylsulfonyl chlorides and bases affords much better yields than the reaction requiring a longer reaction time with cesium carbonate in acetonitrile. The ability to control the sulfonylation reaction allows one to obtain dendrimers having incompletely substituted branches in their structure; the presence of such defects can be programmed for certain tasks. In Scheme 4 [6], at the first stage, the only sulfonamide was prepared from octylamine and then further sulfonylated with a large excess of sulfonyl chloride, which led to full persulfonylation. The repetition of these steps afforded unsymmetrical sulfonimide.

Scheme 4. Synthesis of SBDs with structural asymmetry. (a) 4-NO₂C₆H₄SO₂Cl, Et₃N, CH₂Cl₂ (b) SnCl₂, HCl, EtOH, reflux; (c) CH₃C₆H₄SO₂Cl, Et₃N, CH₂Cl₂, reflux.

Intermediate sulfonamide can be sulfonylated at the arylamine position or at the sulfonamide position with different sulfonyl chlorides to obtain an asymmetrically branched structure. The first molecule of sulfonyl chloride reacts with the amino group. Then the second molecule of sulfonyl chloride reacts in the same position, even if the sulfonamide position is present in the molecule. This selectivity can be explained based on fundamental organic chemistry; the amino group attached to the aromatic ring is more nucleophilic than the sulfonamide (–SO₂NH) because its nitrogen lone pair is delocalized in the amide bond. Due to unsymmetrical synthesis with different functionalities, dendrimers with similar interiors but different exteriors called Janus-type dendrimers [47] were obtained. This synthetic approach has the advantage of having a wide range of affordable, inexpensive sulfonyl chloride reagents that can produce chemically stable SBDs of various designs that do not require sophisticated purification methods. Despite this advantage, several shortcomings were limiting the synthesis of SBDs. For example, with an increase in dendrimer generation, its molecular weight also increases, which can significantly reduce the product’s solubility and prevent further synthesis and the target product's purification procedure. In addition, the catalytic reduction reaction was not fully reproducible and led to an increase in the number of defects and by-products. The reduction of p-nosyldecorated dendritic sulfonimides with tin chloride (SnCl₂) instead of Pd or Raney-Ni catalysts in boiling EtOH gives a full reduction but with subsequent cleavage of the p-aminobenzenesulfonyl groups to quantitatively form the corresponding amino sulfonamides. It was found that the use of a mixture of EtOH and CH₂Cl₂ in equal proportions is the way to the pure reduction of nitro groups. To reach a higher generation of SBDs, Oleg Lukin et al. investigated the influence of different arylsulfonyl chlorides under the same reaction conditions. Investigations indicated that para- and meta-substituted arylsulfonyl chlorides that lead to G3 and G4 compounds are usually high yielding. The reactivity of aromatic and aliphatic sulfonamides and aromatic amines is different and decreases with the increasing aliphatic part: ArSO₂NHAr ‘> ArNH₂> ArSO₂NH-Alk [48].

In 2010, a group of chemists described the synthesis of G1 and G2 methacrylate monomers containing sulfonimide units at each branch and their radical polymerization to the corresponding sulfonimide-based polymers [36].

Scheme 5 [36] highlights the main reactions, including the sulfonylation of amino groups and the reduction of nitro groups and esters. The G1 monomers’ syntheses started from commercially available ester, which was sulfonylated with arylsulfonyl chlorides. The ester groups were cleanly reduced with diisobutylaluminum hydride (DIBAL-H), affording corresponding alcohols. In the last step, methacrylate was added by reacting alcohols with methacrylic acid chloride (MAC). The synthesis procedures of monomers of the G2 and G3 were similar to the above. These procedures can be repeated, leading to a G3 monomer MG3(CH₃). For the polymerization reaction, the monomers were dissolved in DMF, and the solution was heated under nitrogen in the presence of azoisobutyronitrile (AIBN). The highest G5 SBD decorated with 32 naphthyl terminal groups was prepared using divergent techniques [20] with two steps, similar to that mentioned in Scheme 3. 3-Methoxypropylamine was used as the starting material and persulfonylated with a p-nosyl sulfonyl chloride. The nitroaromatic compounds were reduced with tin (II) chloride because other reducing reagents, such as Fe/NH4Cl, Zn/CH₃COOH, and others, led to mixtures of products. The two-stage approach has significantly increased the production of higher-generation SBDs. Thus, the G3 was obtained on a scale of 7 g in one synthetic cycle, while the species of the G4 were obtained on a scale of 5 g, and the G5 SBD shown in Table 1 was obtained on a 2 g scale [20].

Scheme 5. Synthesis of macromonomers MG1 and MG2. (a) ArSO₂Cl, Et₃N, CH₂Cl₂ (b) diisobutylaluminum hydride (DIBAL-H), tetrahydrofuran (THF) (c) SnCl₂/HCl, EtOH: dichloromethane (DCM); (d) MAC, trimethylamine (TEA), THF.

3.2. Convergent Technique

Typically, SBDs, as well-known commercially available dendrimers such as PAMAM and POPAM, are synthesized using a divergent procedure [49], which has the disadvantage of significantly reducing the yield with increasing dendrimer generation and the accumulation of statistical defects in higher generations. A convergent procedure is usually used to simplify the synthesis and purification and provide better yields of high-generation dendrimers. A convergent approach to the preparation of dendrimer structures is based on the production of branched compounds bearing the active functional group, which can be involved in covalent attachment with the core molecule. A vast number of multifunctional compounds can be used as cores for dendrimers, such as biphenyl, terphenyl, pentaphenylene, and triazine core molecules. Scheme 6 [6] shows the use of tosyl-decorated sulfonimide dendrons to synthesize terphenyl-cored dendrimers using double Suzuki cross-coupling (SCC) reaction.

Scheme 6. Synthesis of a terphenyl-cored SBDs using 1,4-phenylene diboronic acid diester, Pd[(P(pTol)3]3, THF/H₂O.

Surprisingly, sulfonimide derivatives with nitroaromatic groups on the periphery do not react under Suzuki conditions. Although there were several reports of dendrimers obtained by such a one-stage assembly method, they did not receive further development due to the following restrictions: getting hyperbranched polymers [50] with an increase in molecular weight (>2 kDa) instead of dendrimers, or poor chemical stability [51]. Thus, the development of simple methods for obtaining structurally advanced high molecular weight dendrimers remains a problem. Using the previously reported stepwise persulfonylation of octylamine with various sulfonyl chlorides by sequential reactions, a G4 dendron with a 4-bromobiphenylsulfonyl unit in the focal position was achieved. The double cross-coupling reaction of the dendrons with 1,4-phenylenediboronic acid can give the pentaphenylene cored dendrimer with a molar mass exceeding 10 kDa [52].

Rozhkov et al. proposed the synthesis of new branched arylsulfonyl chlorides, which can be further used as reagents for the convergent synthesis of SBDs [53]. As shown in Scheme 7, the synthesis begins with the target molecule, in which the more reactive nitro groups located in the ortho position are used for substitution. The para position’s remaining nitro group was reduced to the amine group using tin (II) chloride. The amine was persulfonylated in a single step with tosyl chloride to give the sulfonimide, which was further converted to bis-sulfonyl chloride with a chlorinating reagent.

Scheme 7. Synthesis of bis-sulfonyl chloride. (a) benzyl mercaptan, K₂CO₃, DMF (b) SnCl₂, i-PrOH (c) CH₃C₆H₄SO₂Cl, Et₃N, CH₂Cl₂ (d) N-chlorosuccinimide, HCl, CH₃COOH.

The new sulfonimide branched arylsulfonyl chlorides, which can be useful reagents for the convergent synthesis of multifunctionalized core compounds, were obtained in good yield and purity. [53] The convergent route reaches its limit at G3 species, whereas the divergent approach can prepare higher-generation sulfonimide-based dendrons.

3.3. Click Chemistry

Tewari et al. synthesized azide-functionalized persulfonylated termini with sulfonimide groups, as outlined in Scheme 8 [54], which were linked together using click chemistry [55]. However, only the G1 dendrimers were obtained using this procedure, emphasizing the initial divergent or convergent approaches' importance.

Scheme 8. Synthesis of persulfonylated azide-functionalized dendron and the convergent synthesis of persulfonylated G1 dendrimers.

The synthesis of dendrimers and dendrons with sulfonimide units at each branch point is based on a series of repeating sulfonylation reactions of amines and sulfonamides followed by reduction of the nitro group into an amino group. Such a combination allows precise control of the form of dendrimers, the number of branches in each generation, and their peripheral design with functional groups. Using the selectivity inherent in reactions eliminates the group's sophisticated protection strategy. Currently, dendrimers' construction and functionalization have been achieved through a set of high yielding, fast, inexpensive, and operationally simple. Therefore, sulfone-based moieties in that category, especially N-monosulfonylation and N-bissulfonylation-based reactions, fulfill all the high-efficiency criteria and cost-effective novel dendrimer synthesis. Nevertheless, the synthesis of SBDs is limited to the G5 and requires further development. Since there has been exponential growth in newly synthesized chemical compounds [56], their preparation methods are still essential. Research and development aimed at improving the synthesis have not lost their relevance. The lack of chemical diversity of SBDs and the limited synthesis methods currently available show that the chemistry of SBDs has not been sufficiently studied. In addition to increasing the diversity of structures and increasing the yield of synthesis reactions, special attention must be paid to dendrimers with large aromatic and form-stable branches. It is expected that such rigid, inert structures will have high melting and glass transition temperatures, opening up new possibilities for chemical modification and application. Despite numerous works on the synthesis of dendrimers, much work remains to be done in this regard. As indicated by the number of works and the results obtained, the divergent method remains the preferred synthesis method today, but this does not reduce other approaches' importance. There is still a need for even higher generations of all types of dendrimers, as well as for high-performance and optimized syntheses of individual families of dendrimers to access targeted mono- and multifunctionalized products. The development of various new and innovative building blocks for the synthesis of dendrimers is also important.