Synthesis of novel AB 2 monomers for the construction of highly branched macromolecular architectures

A series of novel, structurally related AB 2 monomers was synthesized and incorporated into branched materials. Size exclusion chromatography was used to compare these systems based on their relative hydrodynamic volumes. The results of these studies indicated an increased hydrodynamic volume of bis-benzyl amine based AB 2 monomer relative to analogous bis-benzyl ether structures. In order to further explore the bis-benzyl amine AB 2 structural motif, additional monomers were synthesized, leading to new branched materials and hyperbranched polymer structures.


Introduction
Highly branched macromolecular structures such as dendrimers 1 and hyperbranched polymers 2 have gained considerable attention for their potential in applications such as drug delivery, 3 molecular recognition, 4 catalysis, 5 and organic electronic devices. 6To expand the repertoire of highly branched systems with varying functionalities, new monomers need to be synthesized and analyzed.The AB 2 motif is common in macromolecules due to its branching and symmetry.For example, Fréchet introduced the bis-benzyl ether AB 2 monomer 1 for the synthesis of dendrimers 7 and hyperbranched polyesters. 8Using the bis-benzyl ether monomer 1 as a starting point, new monomers 2-6 were designed to increase the variety of AB 2 building blocks for use in macromolecular design.Herein, the synthesis of these novel monomers is reported, and studies involving the preparation of highly branched structures from 2-6 are disclosed.
Initially, 2-4 were targeted because of their similarity to the known bis-benzyl ether monomer 1: 2 has reversed the ether linkage position relative to 1, 3 is the bis-cyclohexyl analog, and 4 is the corresponding bis-amine analog.It was hypothesized that modest changes embodied by 2-4 would lead to differences in the resulting macromolecular properties.To test this hypothesis, branched materials constructed from 2-4 were prepared and studied as a first step towards designing more advanced AB 2 monomers for larger hyperbranched structures.

Results and Discussion
The synthesis of monomer 2 was previously reported as an intermediate step in the preparation of glucokinase activators. 9In this previous disclosure, methyl 3,5-bis(hydroxymethyl)benzoate, an expensive starting material, underwent a Mitsunobu reaction with two equivalents of phenol as the key step in the synthesis of 2. In the present study, an alternative approach was used in order to use a more economical starting material and avoid the triphenylphosphine oxide byproduct from the Mitsunobu reaction (Scheme 1).Scheme 1. Preparation of AB 2 monomer 2 from commercially available 7.
Beginning with methyl 3,5-dimethylbenzoate 7, a free radical halogenation reaction afforded the dibromide 8 10 which was reacted with two equivalents of phenol in the presence of potassium carbonate to provide the diether 9. Hydrolysis of the methyl ester in 9 resulted in the carboxylic acid monomer 2.
Monomer 3 was prepared as described in Scheme 2. Dialkylation of methyl 3,5-dihydroxybenzoate 10 with excess of bromomethyl cyclohexane (11) proceeded slowly relative to alkylation of 10 with benzyl bromide.This rate difference presumably is due to the increased steric bulk of bromomethyl cyclohexane and its reduced solubility in polar solvents.In practice, it was more convenient to isolate the mono-alkylated product 12 by column chromatography (SiO 2 ) and then subject this intermediate to an alkylation with 11, giving the desired 13 as a crystalline solid upon trituration. 11Hydrolysis of 13 to form 3 required higher temperatures compared with similar conditions used to prepare the standard benzyl ether monomer 1. 7 The difference in hydrolysis reactivity is proposed to be due to the hydrophobic cyclohexane rings reducing solubility of the parent methyl ester.The bis-benzyl amine monomer 4 and its synthesis were reported in an earlier publication. 12Scheme 2. Preparation of AB 2 monomer 3 containing cyclohexane units.
Monomers 1-3 were combined with 1,1,1-tris(4-hydroxyphenyl)methane 14, DCC and (dimethylamino)pyridinium 4-toluenesulfonate (DPTS), 13 to form the branched materials 15-17, respectively (Schemes 3 and 4) which were purified by either column chromatography (SiO 2 ) or size exclusion chromatography (SEC). 14The triphenylmethane core employed in the synthesis of 15-17 has been used previously used in the synthesis of hyperbranched polymers 15 and selfassembled liquid crystals. 16Its use in the synthesis of benzyl ether-type dendrimers has not been described, although structures closely related to 15 have been reported. 7Thus, 15-17 represent novel structures which have not been disclosed elsewhere.The preparation of the benzyl amine 18 from monomer 4 and 14 was accomplished using our previously described method. 12Branched materials were also synthesized from monomers 2 and 3 with two other tri-phenol cores (19 and 20) and their experimental data are reported in the supplemental information. 17Benzyl amine based branched structures were not obtained from the reaction of 4 with cores 19 and 20 since it appeared that macromolecules were formed but underwent degradation before isolation was possible.
The model branched materials 15-18 were compared using analytical SEC (Figure 1) using styrene divinylbenzene columns in series and THF as the eluent.Typically a macromolecule with a higher molecular weight has a larger hydrodynamic volume, leading to an earlier retention time. 18Upon running the SEC, the two benzyl ether positional isomers 15 and 16 eluted with identical retention times.The cyclohexyl system 17 and benzyl amine system 18 shifted to shorter retention times, corresponding to larger apparent molecular weights.These results could be explained by examining the correlation between SEC retention time and hydrodynamic volume. 18Branched materials 15-16 have the same molecular weights (Table 1) and thus presumably a similar hydrodynamic volume and retention time.The smaller retention time of 17 relative to 15-16 can be justified by the larger molecular weight of 17 and the greater steric demand of the cyclohexyl groups, leading to a larger hydrodynamic volume.The rationale of the smaller retention time of the benzyl amine system 18 was less clear, especially since the molecular weights of 15, 16, and 18 are very similar.Based on the experimental data, 18 should have a smaller hydrodynamic volume relative to the cyclohexane system 17 due to its lower molecular weight.However, the two compounds eluted at nearly identical times on SEC.It is possible that increased repulsions between the internal amine groups within the branches of 18 in THF lead to a more extended conformation and subsequently a larger hydrodynamic volume.Thus, the branched structure constructed from the bis-benzyl amine 4 appeared to have unique properties which warrant further study of the bis-benzyl amine AB 2 motif in novel branched macromolecular structures.As noted above, the reaction of other tri-phenol cores such as 19 and 20 with monomer 4 in the presence of DCC and DPTS did not lead to branched materials.Two strategies were devised to obtain new branched systems from the bis-benzyl amine AB 2 motif.First, hybrid monomer 21 was prepared containing both ether and amine functionalities.Hybrid dendrimers were successfully synthesized from this monomer, and the results of these studies are reported elsewhere. 12In another approach, an amide bond between 4 and the core was proposed to improve the stability of the resulting system relative to the ester linkages in 18.A new branched material 22 was designed in which amide bonds link the core with the monomer.
Ethylenediamine was utilized as the core because it was hypothesized that amide bonds to an alkyl amine containing core would be more stable than amide bonds with a di-or tri-aniline containing core.The methyl ester groups present at the periphery of 22 were incorporated to provide a functional handle to build larger dendrimers and hyperbranched structures.
Monomer 5, designed for the synthesis of the model system 22, was prepared following Scheme 5. Two equivalents of aldehyde 23 were condensed with 3,5-diaminobenzoic acid (24) and the resulting mixture was treated with NaBH 4 followed by concentrated HCl.The desired bis-benzylamine monomer 5 was isolated in 44% yield with sufficient purity that additional chromatographic purification was not required.To form the two arm system 22, a DCC coupling reaction was performed using two equivalents of monomer 5 and ethylenediamine (25).Purification by column chromatography (SiO 2 ) resulted in 22 and its purity was confirmed by SEC (Figure 2).Branched material 22 had improved chemical stability compared to 18 and thus could be isolated and characterized.The improved stability of 22 was evident by SEC analysis which showed a single peak comparable in peak shape to the parent monomer 5.In contrast, the esterlinked bis-benzyl amine system 18 exhibited peak broadening (Figure 1).The improved stability of 22 suggested that larger branched architectures could be constructed from bis-benzyl amine monomers constructed through amide bonds to a core.Additional branched macromolecular structures were designed based on the bis-benzyl amine monomer motif to make more stable macromolecules.A hyperbranched polymer was proposed from the polycondensation of the triacid monomer 6 and a diamine.Novel hyperbranched polymers containing amine groups are of interest because they are proposed to have favorable properties for applications such as encapsulation, drug delivery, and waste water remediation. 19heme 6. Preparation of hyperbranched polymer 28 by condensing 6 with 27.
Monomer 6 was prepared according to Scheme 6. Condensation of 3,5-diaminobenzoic acid (24) with two equivalents of 4-carboxybenzaldehyde 26 was followed by an in situ reduction of the resulting imine intermediate with NaBH 4 .After acidification with 2N HCl, 6 was isolated in 86% yield by filtration with no additional purification required.Polycondensation of 6 with 4-(aminomethyl) piperidine 27 was attempted in the presence of P(OPh) 3 and pyridine using NMP as a solvent 20 and the reaction was monitored over 24 hours.As time progressed a polymer was visually observed to precipitate.After 24 hours, a white precipitated solid and clear supernatant were observed (Figure 3).Although the solubility of the polycondensation reaction product was limited in organic solvents, preliminary analysis using SEC and 1 H Nuclear Magnetic Resonance (NMR) spectroscopy was attempted.Unfortunately, the polymer was not sufficiently soluble in THF or other suitable solvents to give reliable SEC traces.NMR analysis revealed significant peak broadening, suggesting that higher molecular weight structures formed.One possible product of the polycondensation reaction is represented by structure 28.Studies were done to examine the stability of the resulting polymer in the presence of different solvents.The polymer was found to be stable under various organic and aqueous solvents, even upon extensive sonification.Degradation began after the polymer was in the presence of concentrated HCl at 25 ˚C for 24 hours.

Conclusions
Several novel AB 2 monomers were synthesized and incorporated into branched materials.These branched materials were used as model systems to make direct comparisons between structures resulting from the different monomers.Analytical SEC indicated that 17, constructed from the bis-benzylamine monomer 4, had a larger hydrodynamic volume than analogous ether systems, even though it had a smaller molecular weight.Based on this finding, monomers 5 and 6 were efficiently synthesized in order to study further the formation and properties of macromolecular structures containing the benzyl amine AB 2 motif.The bis-benzyl amine monomer 5 could be introduced into a branched system successfully through amide linkages with an aliphatic core.Furthermore, the amide-linked structure 22 exhibited improved stability relative to the esterlinked structure 18.A polycondensation reaction between monomer 6 and an aliphatic diamine lead to the formation of a hyperbranched polymer.Dendrimers and other branched macromolecules based on the bis-benzyl amine AB 2 monomer have the potential for unique properties and applications involving encapsulation, host-guest complexation, and waste water remediation. 19Studies are underway to explore further the formation of dendrimers and other hyperbranched macromolecules containing the bis-benzyl amine motif, and these structures will be exploited for the removal of common environmental pollutants.

Experimental Section
General.All reactions were performed under an argon gas atmosphere with oven-dried glassware unless otherwise noted.Reagents were obtained from Aldrich or TCI America.2-(Dimethylamino)pyridinium p-toluenesulfonate (DPTS) was prepared as reported previously. 13olvents and reagents were used without further purification except for the following: CH 2 Cl 2 was distilled from CaH 2 , phloroglucinol dihydrate was azeotroped five times with toluene prior to use, and N-bromosuccinimide was recrystallized from water and dried in vacuo prior to use.Reactions were monitored by TLC using silica gel 60 F 254 glass plates.TLC bands were visualized by UV and phosphomolybdic acid (PMA) stain.Eluent solvent ratios are reported in v/v. 1 H NMR spectra were recorded at 300 MHz and 13 C NMR spectra were recorded at 75 MHz on a Bruker AV-300 high performance digital NMR spectrometer.Chemical shifts were reported in parts per million (ppm) and coupling constants were reported in Hertz (Hz). 1 H NMR spectra obtained in acetone-d 6 were referenced to 2.50 ppm, spectra obtained in CDCl 3 were referenced to 7.26 ppm, and spectra obtained in DMSO-d 6 were referenced to 2.05 ppm. 13C NMR spectra obtained in acetone-d 6 were referenced to 29.84 ppm, CDCl 3 were referenced to 77.2 ppm and DMSO-d 6 were referenced to 39.50 ppm.Mass spectra were obtained from University of Illinois Mass Spectrometry Center (Micromass Q-TOF Ultra, ESI).Preparative size exclusion chromatography (SEC) was performed using a 2 cm × 50 cm column of Bio-Rad BioBeads S-X1 beads (200-400 mesh) in toluene.Analytical SEC data was obtained using a Dionex Ultimate 3000 with Styragel HR 3 (7.8× 300 mm) and Styragel HR 4E (7.8 × 300 mm) columns in series in THF.Melting points were obtained using an OptiMelt Automated Melting Point System and are uncorrected.

Cyclohexane based monomer and corresponding branched material synthesis Methyl 3,5-bis(cyclohexylmethoxy)benzoate (13)
. 11 To methyl 3,5-dihydroxybenzoate (5.00 g, 29.7 mmol) in DMF (37.5 mL) was added K 2 CO 3 (8.50g, 61.5 mmol) and the mixture was stirred at 25 ˚C for 2 h.Bromomethylcyclohexane (8.80 mL, 63.1 mmol) was added over 10 min, the reaction was heated at 80 ºC for 3 h.The reaction flask was cooled to 25 ˚C, EtOAc (100 mL) was added and the organic layer was washed with H 2 O (5 × 70 mL) and brine (70 mL).After drying over Na 2 SO 4 and removal of the solvent, the resulting product was purified by silica gel column chromatography (1:1 pet ether:Et 2 O) to separate the desired dialkylated product and the monoalkylated species.The mono-alkylated product was subjected to the above conditions to obtain additional product.Trituration with ice-cold pet ether afforded 13 (4.36 g, 87%) as a white solid. 1

Benzyl amine based monomer and corresponding branched material synthesis 3,5-Bis[[4-(methoxycarbonyl)benzyl]amino]benzoic acid (5).
To a heterogeneous solution of 24 (0.10 g, 0.66 mmol) in MeOH (10 mL) was added 23 (0.23 g, 1.38 mmol).After 20 min, the reaction was cooled to 0 ºC and 0.08 g of NaBH 4 was added in three portions.The reaction was slowly warmed to 25 ˚C and stirred overnight.The reaction was cooled to 0 ºC and H 2 O (1 mL) added dropwise before 2N HCl was added dropwise until the solution reached pH 3. The resulting precipitate was vacuum-filtered and washed with cold MeOH.Upon drying, 5 was obtained as a light gray solid (0.13 g, 44%).mp 182.6-184.7 ºC. 1  Benzylamine branched system 22.To 5 (0.25g, 0.056 mmol) in 5 mL of CH 2 Cl 2 was added ethylenediamine (0.020µL, 2.99 × 10 -4 mmol) and DMAP (0.068 g, 0.557 mmol).After 15 min, DCC (0.12 g, 0.56 mmol) was added and the reaction was stirred for 48 h.The mixture was filtered and the solid was thrice washed with cold CH 2 Cl 2 .After the solvent from the filtrate was removed in vacuo, the resulting solid was purified by silica gel column chromatography (EtOAc) to obtain 22 as an off-white solid (0.13 g, 50%). 1

Figure 1 .
Figure 1.Analysis of the branched materials 15-18 by analytical SEC.

Figure 2 .
Figure 2. Analysis of branched material 22 and the parent monomer 5 using SEC.

Figure 3 .
Figure 3. Formation of a precipitated polymer from the reaction of monomer 6 and 4-(aminomethyl) piperidine 27.Aliquots taken from the polymerization reaction over time.From left to right, aliquots from 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 12 h, 24 h time points are compared.

Table 1 .
17mparison of SEC retention times, SEC derived molecular weights and calculated molecular weights (g/mol) of 15-18.SEC derived molecular weights were determined using a calibration curve obtained from polystyrene standards17