Catalyst Performance in “Click” Coupling Reactions of Polymers

Dirks, A. J.; Van Berkel, S. S.; Hatzakis, N. S.; Opsteen, J. A.; Van Delft, F. L.; Cornelissen, ...... Sudershan R. Gondi, Andrew P. Vogt, and Brent ...
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Macromolecules 2006, 39, 6451-6457

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Catalyst Performance in “Click” Coupling Reactions of Polymers Prepared by ATRP: Ligand and Metal Effects Patricia L. Golas, Nicolay V. Tsarevsky, Brent S. Sumerlin,† and Krzysztof Matyjaszewski* Department of Chemistry, Carnegie Mellon UniVersity, 4400 Fifth AVenue, Pittsburgh, PennsylVania 15213 ReceiVed July 15, 2006

ABSTRACT: CuI-catalyzed azide-alkyne cycloadditions were conducted in organic media under various conditions. The effects of several parameters (ligand, solvent, reducing agent, metal) on these reactions were studied using the step-growth click coupling of low-molecular-weight R,ω-diazido-terminated polystyrene prepared by atom transfer radical polymerization (ATRP). These reactions were typically conducted in DMF, monitored by size exclusion chromatography (SEC), and semiquantitatively analyzed by Gaussian multipeak fitting and subsequent peak integration. Both the electronic properties of the ligand and the number of coordinating atoms had significant influence on the rates of the click coupling reactions. Aliphatic amine ligands led to significantly faster rates as compared to pyridine-based ligands. Faster rates were also observed with tridentate vs tetradentate ligands. A further rate enhancement was observed when the reactions were conducted in a noncoordinating solvent (toluene) vs a coordinating solvent (DMF). Despite the typical susceptibility of CuI complexes to oxidation, the addition of excess hydrazine as a reducing agent allowed click reactions to be conducted under limited amounts of air with decreased catalyst concentrations. A pronounced rate enhancement was observed during reactions conducted in the presence of hydrazine, which could be due to the basicity of hydrazine. Finally, azide-alkyne cycloadditions were successfully catalyzed by oxidatively stable metal complexes, including those of NiII, PdII, and PtII. The PtII catalyst demonstrated the highest catalytic activity relative to those of the other metals.

Introduction Recent years have witnessed rapid development in the field of chemical transformations known as “click” reactions.1 The wide acceptance of these reactions can be attributed to high fidelity, quantitative yields, tolerance to a broad variety of functional groups, and applicability under mild reaction conditions. In particular, the CuI-catalyzed azide-alkyne cycloaddition2,3 has been extensively studied. In biological systems, this particular reaction has been employed for bacterial cell surface labeling;4 conjugation of biological polymers to viruses,5-7 synthetic polymers,8 and solid surfaces;9-11 and the preparation of cyclodextrin12 and cyclopeptide13,14 analogues. In the field of materials chemistry, this reaction has been utilized to functionalize carbon nanotubes15 and polymers16-18 as well as to prepare block copolymers,19 dendrimers,20-22 mechanically interlocked architectures,23 shell cross-linked nanoparticles,24 and macrocyclic polymers.25 Additionally, we previously reported a step-growth polymer coupling process via click chemistry.26 To further understanding of the azide-alkyne click reaction, it is necessary to optimize the conditions under which the reaction is conducted to achieve high rates and yields with minimal synthetic manipulation. Mechanistic investigations27 and reports on azide-alkyne cycloaddition carried out with a variety of ligands28-30 have revealed that the ligand influences the catalytic activity of the CuI complex. However, systematic studies on ligand effects are lacking in the literature, and the majority of these reactions and mechanistic investigations were conducted in aqueous systems.31,32 While this is useful for click chemistry applications such as bioconjugation and cell surface labeling, there have been an increasing number of polymer chemistry † Current address: Department of Chemistry, Southern Methodist University, PO Box 750314, Dallas, TX 75275. * Corresponding author. E-mail: [email protected].

applications that involve macromolecules not soluble in aqueous media.15,16,26 Herein we report the optimization of conditions under which CuI-catalyzed azide-alkyne cycloadditions are conducted in organic systems by systematic variation of the reaction conditions for the step-growth click coupling of homotelechelic polymers prepared via atom transfer radical polymerization (ATRP).33-35 The halogen end groups of polymers prepared by ATRP are easily converted to azido moieties by simple nucleophilic substi-tution.36-38 Thus, polymers prepared by ATRP are particularly well-suited to azidealkyne cycloadditions after appropriate end-group transformation. Another benefit of conducting CuI-catalyzed click reactions with polymers prepared by ATRP is that the predetermined molecular weight and narrow molecular weight distribution facilitate analysis of the reaction products. Although methods such as gas chromatography28 and NMR39 are frequently employed to characterize the products of CuIcatalyzed click reactions of low-molecular-weight compounds, these techniques are generally incompatible with polymer coupling reactions due to high molecular weight of starting materials and products. However, polymer click coupling reactions can be easily monitored by size exclusion chromatography (SEC) and quantitatively analyzed by Gaussian multipeak fitting of the resulting chromatogram.40 Therefore, polymer click coupling reactions are an attractive way to investigate the optimal conditions under which these reactions should be performed, particularly for polymer and materials chemistry applications. One drawback to any CuI-catalyzed process is the oxidative instability of the catalyst under aerobic conditions that results in formation of CuII. This difficulty can be surmounted in aqueous systems by the in-situ generation of CuI from a CuII salt by the addition of an appropriate reducing agent. Excess reducing agent regenerates any catalyst lost to oxidation,

10.1021/ma061592u CCC: $33.50 © 2006 American Chemical Society Published on Web 08/22/2006

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Macromolecules, Vol. 39, No. 19, 2006 Chart 1. Ligands Used during Model Click Coupling Reactions

allowing CuI-catalyzed reactions to be carried out under aerobic conditions. While sodium ascorbate is generally used as an efficient reducing agent for CuII in aqueous media,3,27,41,42 the use of a reducing agent during click reactions in organic solvents has not been reported to the best of our knowledge. Herein, we demonstrate the use of hydrazine as an effective reducing agent for conducting CuI-catalyzed azide-alkyne cycloadditions in the presence of limited amounts of air. Since copper is not the only metal that can coordinate with alkynes, other catalysts can also potentially be used for azide-alkyne cycloaddition. However, in addition to copper, only ruthenium has been reported to catalyze this reaction.43 This investigation details the extension of NiII, PtII, and PdII as catalysts for click coupling reactions of well-defined polymers. The complexes of these metals have the benefit of not being air-sensitive, so azide-alkyne click reactions were conducted with no efforts to exclude oxygen. Experimental Section Materials. Styrene was passed through a column filled with basic alumina in order to remove the inhibitor prior to its polymerization. The ligands used in this study included N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA), N,N,N′N′′,N′′′,N′′′-hexamethyltriethylenetetraamine (HMTETA), 2,2′-bipyridine (bpy), 2,2′:6′2′′terpyridine (tpy), tris[(2-pyridyl)methyl]amine (TPMA), tris[(2dimethylamino)ethyl]amine (Me6TREN), 4,4′-dinonyl-2,2′-bipyridine (dNbpy), and 4,4′-trinonyl-2,2′:6′,2′′-terpyridine (tNtpy) (Chart 1). TPMA,44 Me6TREN,45 and tNtpy46 were synthesized as previously reported. All other reagents (dimethyl-2,6-dibromoheptanedioate (DM-2,6-DBHD), NaN3, propargyl ether (Pg2O), hydrazine, 2,6di-tert-butylpyridine (dtBupy), tetrabutylammonium hydrogen sulfate (Bu4NHSO4), NiCl2, PtCl2, PdCl2) were used as received from Aldrich or Acros. All solvents and liquid reagents were bubbled with nitrogen prior to use, except for experiments conducted in the presence of hydrazine or with catalysts other than CuBr. Preparation of r,ω-Dibromopolystyrene (Br-PS-Br) via ATRP. Neat styrene (50 mL) was deoxygenated in a Schlenk flask by six cycles of freeze-pump-thaw. The monomer was again frozen, and the flask was filled with nitrogen. CuBr (0.312 g, 2.16 mmol) was added, and the flask was evacuated and backfilled with nitrogen five times. PMDETA (0.45 mL, 2.2 mmol) was injected via nitrogen-purged syringe, and the flask was placed in an oil bath thermostated to 80 °C. The initiator, DM-2,6-DBHD (1.9 mL, 8.7 mmol), was then injected via a nitrogen-purged syringe. Samples were withdrawn periodically during the polymerization. After 515 min, the flask was opened, and its contents were diluted with THF. The mixture was passed through a column filled with neutral alumina, concentrated on a rotary evaporator, and precipitated in hexanes. The final product was filtered, dried under vacuum at 50 °C, and analyzed by SEC: Mn ) 2380 g/mol and Mw/Mn ) 1.07. Synthesis of r,ω-Diazidopolystyrene (N3-PS-N3). Br-PSBr (27.30 g, 11.47 mmol) was dissolved in DMF (50 mL), and NaN3 (2.98 g, 45.9 mmol) was added to the solution, which was

then allowed to stir at room temperature (25 ( 2 °C) for 24 h. The polymer was precipitated in methanol, filtered, dried under vacuum, and analyzed by SEC: Mn ) 2545 g/mol and Mw/Mn ) 1.07. A similar procedure was used to prepare the diazido-terminated polystyrene used for click coupling reactions catalyzed by metal complexes other than CuI (Mn ) 2000 g/mol, Mw/Mn ) 1.08). Click Coupling of N3-PS-N3 with Pg2O. A representative reaction was conducted as follows: N3-PS-N3 (0.64 g, 0.50 mmol -N3) and CuBr (0.0359 g, 0.5 equiv) were added to a Schlenk flask, followed by the ligand if it was solid. The contents of the flask were evacuated and backfilled with nitrogen five times. Solvent (5.0 mL), liquid ligand (1 equiv to CuBr, except for bpy (2 equiv)), and Pg2O (25.8 µL, 1 equiv relative to -N3) were injected via nitrogen-purged syringe. In the reactions that included hydrazine, CuBr was added as 0.1 equiv relative to -N3, no efforts were made to exclude oxygen before the reaction, and the reducing agent was added after Pg2O. The reactions were allowed to proceed at 25 ( 2 °C, and samples were periodically withdrawn using a nitrogen-purged syringe. Each sample was diluted with THF and passed through a 0.2 µm filter prior to analysis by SEC. Samples withdrawn during the reactions that included hydrazine were immediately analyzed in order to prevent reaction during storage. Synthesis of Dimethyl-2,6-diazidoheptanedioate (DM-2,6DAzHD). DM-2,6-DBHD (13.1 mL, 0.06 mol) was mixed with NaN3 (9.75 g, 0.150 mol) and Bu4NHSO4 (3.395 g, 0.01 mol) in a mixture of diethyl ether (50 mL) and water (50 mL). The reaction was allowed to proceed at 25 ( 2 °C upon stirring for 48 h. Diethyl ether (100 mL) was added to the mixture, and the organic layer was extracted with water (3 × 50 mL) and dried over sodium sulfate. Diethyl ether was removed by rotary evaporation. Yield: 15.783 g (0.058 mol, 96.7%). 1H NMR in CDCl3 (δ, ppm): 4.2 (t, 2H, CHN3), 3.8 (s, 6H, OCH3), 2.1 (m, 4H, CH2CHN3), 1.6 (m, 2H, CH2CH2CHN3). Click Coupling Reactions Catalyzed by Other Metals. N3PS-N3 (0.25 g, 0.25 mmol -N3) and Pg2O (12.85 µL, 1 equiv of alkyne groups relative to -N3) were mixed with DMF (2.0 mL). The catalyst (NiCl2, PtCl2, or PdCl2, 1 equiv relative to -N3) was added, and the reactions were allowed to proceed at 80 °C for 20 h. A control experiment was also conducted in which N3-PS-N3 and Pg2O were mixed in DMF at 80 °C, but no catalyst was added. Parts of the solutions were diluted with a 50 mM solution of LiBr in DMF, passed through a 0.2 µm filter, and analyzed by SEC. A series of click coupling reactions were conducted in an analogous manner between a low-molecular-weight diazide and dialkyne, namely DM-2,6-DAzHD and Pg2O. Analyses. Apparent molecular weights were determined by SEC using a series of Styragel columns (Polymer Standards Services (PSS), 105, 103, 100 Å), THF (35 °C) or 50 mM LiBr in DMF (50 °C) as the eluent, PS standards as calibration, and toluene as the internal standard.

Results and Discussion The click coupling of N3-PS-N3 with Pg2O was chosen as a model to investigate the effect of catalyst on azide-alkyne

Macromolecules, Vol. 39, No. 19, 2006 Scheme 1. Model Polymer Click Coupling Reaction. Synthesis of r,ω-Dibromopolystyrene, Nucleophilic Substitution with Azide, and Click Coupling of Diazido-Terminated Polystyrene with Propargyl Ether

coupling reactions.26 ATRP was used to prepare low-molecularweight Br-PS-Br. The bromo end groups were transformed to azido groups by simple nucleophilic substitution, and the resulting N3-PS-N3 was coupled by reaction with Pg2O in DMF with a CuBr catalyst (Scheme 1). Ligand Effect. Polymer coupling reactions were monitored by SEC and semiquantitatively analyzed by Gaussian multipeak fitting (Figure 1) and integration of the resulting chromatograms. This strategy was employed to investigate the effects of a variety of ligands (Figure 2) on the rates of click coupling reactions in organic media. These results were compared to those from a control reaction conducted without ligand, since CuBr is sufficiently soluble in DMF, and no additional ligand is required. The results demonstrated the nature of the ligand had a substantial impact on reaction rate (Figure 2). The quantitative analysis of the SEC traces for all reactions after select times is shown in Table 1. Reaction conversion was determined by comparing the SEC peaks areas of the N3-PSN3 “monomer” and the products. The values for apparent number-average molecular weight and molecular weight distribution correspond to the final peak after subtraction of the monomer peak from the entire trace. Aliphatic amine ligands consistently produced significantly faster reaction rates compared to pyridine-based ligands. For each of the aliphatic amine ligands used in these experiments (PMDETA, HMTETA, and Me6TREN), the click coupling reactions are essentially complete (>85% conversion) in no more than 30 min. However, in the presence of pyridine-based ligands such as bpy and TPMA, the initial reaction rates are slower than those conducted with no ligand. Tpy produced intermediate reaction rates, but these were still significantly higher than with no ligand. The low-molecularweight polymer did not completely disappear, which has been demonstrated to be due to the formation of cyclic polymers.25,26,47 In fact, cyclization during polymer click reactions has recently been confirmed and used to efficiently prepare macrocyclic polymers.25 Ligand denticity also affected the rate of the click reactions. Although reactions conducted in the presence of tpy were slower than those in the presence of aliphatic amine ligands, they were faster than reactions using bpy or TPMA. Tetradentate ligands coordinatively saturate the CuI catalyst and therefore may interfere with the coordination to the alkyne, which is an essential reaction step.27,32 This effect was not initially noticeable in the reactions employing aliphatic amine ligands because these reactions were too fast for any significant difference to be measured after 30 min. However, when samples were analyzed after shorter reaction times during the reactions with PMDETA, HMTETA, and Me6TREN, the results indicated that tridentate amine ligands produced faster rates than tetradentate amine ligands, consistent with the effect of denticity observed for pyridine-based ligands. In fact, click coupling with PMDETA

“Click” Coupling Reactions of Polymers 6453

was complete (87% conversion) in no more than 5 min. The reaction conducted in the presence of Me6TREN was slower than the reaction with HMTETA, but this could be due to the heightened susceptibility of the CuBr/Me6TREN complex to oxidation by trace amounts of air. To quantify the differences in click reaction rates produced by various ligands, the inverse of monomer concentration was plotted as a function of time for each system (Figure 3). The slopes of these plots correspond to the apparent rate constants (kapp) of each reaction (Table 2). Monomer concentration was calculated by multiplying the initial functional group concentration by the fraction of residual low-molecular-weight polymer and dividing this number by the conversion to high-molecularweight product of each reaction after 48 h in order to account for the presence of low-molecular-weight cyclic products. Cyclic polymers quickly form from linear monomers, and after 48 h the residual low-molecular-weight polymer consists entirely of cyclic species. The latter assumption is confirmed by the 1H NMR spectrum of the product after 48 h, which did not contain peaks corresponding to the azide or alkyne functionality of the reactants. The relative rate constants for different catalytic systems obey the following order: PMDETA (230) > HMTETA (55) > Me6TREN (50) > tpy (8.6) > TPMA (1.7) > no ligand (1) > bpy (0.43). The pronounced rate enhancements observed for polymer click reactions with aliphatic amine ligands as compared to pyridine-based ligands can be rationalized on the basis of considerations of the currently accepted mechanism for CuI catalysis of azide-alkyne cycloaddition. CuI-alkyne π-complexation is proposed to be an important step in this reaction.27,32 The formation of these π-complexes can occur by two mechanisms: electron density donation from the alkyne to the copper center and back-donation from copper to the alkyne.48,49 Both mechanisms contribute to the formation of the catalytic complex during CuI-catalyzed azide-alkyne cycloadditions. However, the fact that electron-deficient alkynes tend to react more quickly50 indicates that back-donation from the copper center to the unoccupied π*-orbital of the alkyne may be the major factor in CuI-alkyne π-complexation. Therefore, the presence of a ligand with electron-donating properties (aliphatic amines) should enhance the formation of this complex and thus also the rate of the click reaction, as observed. The observed rate enhancements could also be partially due to the stronger basicity of aliphatic amine ligands vs pyridinebased ligands. The acceleration of CuI-catalyzed azide-alkyne cycloadditions by the addition of base has been previously observed and is presumably due to favoring the formation of the copper acetylide complex.10,12,32 Finally, aliphatic amine ligands are more labile than pyridine-based ligands, which could facilitate azide coordination to the copper center.32 A more detailed investigation into the kinetics of CuI-catalyzed click reactions will be the subject of a future publication. Solvent Effect. Since ligand coordination characteristics demonstrated a significant impact on the rates of click coupling, it was envisioned that an additional rate enhancement would be observed when the reactions were conducted in the presence of a solvent that did not compete with alkyne coordination. Therefore, click coupling reactions were conducted in toluene (noncoordinating solvent) and DMF (coordinating) using CuBr as catalyst and tNtpy or dNbpy as ligand. These ligands were chosen in order to ensure sufficient solubility of the catalytic complex in both solvents. The click reaction with dNbpy was significantly faster in toluene as compared to DMF (Figure 4). Second-order kinetic plots and

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Figure 1. SEC trace for click coupling reaction of diazidopolystyrene (0.1 M -N3) with propargyl ether (0.1 M -C≡CH) using CuBr (0.05 M) as catalyst and TPMA (0.05 M) as ligand after 3 h, showing (a) original chromatogram and (b) chromatogram after Gaussian multipeak fitting.

Figure 2. SEC traces as a function of ligand for CuBr-catalyzed (0.05 M) click coupling reactions of diazido-terminated polystyrene (0.1 M -N3) with propargyl ether (0.1 M -C≡CH) in DMF at 25 ( 2 °C after 30 min. Table 1. SEC Data from Click Coupling Reactions with Various Ligandsa time, h

ligand

conv, %

Mn,app

Mw/Mn

0.5

PMDETA HMTETA Me6TREN tpy bpy TPMA PMDETA HMTETA Me6TREN tpy bpy TPMA PMDETA HMTETA Me6TREN tpy bpy TPMA

19 86 87 85 40 5 7 50 84 88 86 91 25 46 90 86 87 86 91 90 88

6 540 14 400 13 600 13 700 6 820 5 740 5 790 8 620 14 400 14 400 13 600 19 800 6 380 7 180 16 600 14 400 13 700 12 900 27 100 16 800 14 900

1.13 1.86 1.92 1.78 1.20 1.05 1.05 1.34 1.78 2.00 1.82 2.24 1.14 1.22 2.25 1.83 1.94 1.84 2.35 1.92 1.78

3

24

a Reactions were carried out at initial concentrations of 0.1 M of -N 3 and -C≡CH and 0.05 M of catalyst in DMF at 25 ( 2 °C.

apparent rate constants (Table 3) were obtained for these reactions in the same way as for the reactions with various ligands. It should be noted that the reactions conducted in the presence of the alkylated pyridine-based ligands behave differently than

Figure 3. Kinetics of CuBr-catalyzed (0.05 M) click coupling of N3PS-N3 (0.1 M -N3) and Pg2O (0.1 M -C≡CH) in DMF at 25 ( 2 °C with (a) aliphatic amine and (b) pyridine-based ligands. The kinetics for the reaction with no ligand are plotted in (b) for comparison. All ligands are 1 equiv vs CuBr, except bpy (2 equiv).

those using bpy or tpy. In DMF the reaction with dNbpy was faster than that with bpy, while the reaction with tNtpy was slower than that with tpy. Therefore, the steric environment of the ligand may also have influenced the reaction rates. This effect is difficult to investigate because the steric environment of a ligand also significantly affects the resulting electronic properties.

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Table 2. Apparent Rate Constants of Click Coupling Reactions Catalyzed by CuBr Complexes with Various Ligandsa ligand PMDETA HMTETA Me6TREN tpy a

kapp (M-1 s-1) 10-1

3.2 × 7.7 × 10-2 6.9 × 10-2 1.2 × 10-2

ligand

kapp (M-1 s-1)

TPMA bpy

2.4 × 10-3 1.4 × 10-3 6.0 × 10-4

Same conditions as in Table 1.

Figure 4. SEC traces for click coupling reactions of diazido-terminated polystyrene (0.1 M -N3) with propargyl ether (0.1 M -C≡CH) using CuBr (0.05 M) as catalyst and dNbpy (0.1 M) as ligand in toluene and DMF at 25 ( 2 °C after 1 h. Table 3. Apparent Rate Constants of Click Coupling Reactions in Toluene and DMFa

a

ligand/solvent

kapp (M-1 s-1)

dNbpy/toluene dNbpy/DMF tNtpy/toluene tNtpy/DMF

6.0 × 10-3 5.0 × 10-4 2.7 × 10-3 1.6 × 10-3

Same conditions as in Table 1.

Effect of Hydrazine as a Reducing Agent. CuI-catalyzed click reactions are usually conducted after rigorous deoxygenation procedures or in the presence of a reducing agent that suppresses catalyst loss by oxidation. Reducing agents are frequently employed during click reactions in aqueous systems, but this approach has not been explored for reactions in organic media. Since hydrazine has been successfully used as a reducing agent for ARGET ATRP,51 it was investigated as a reducing agent for the click coupling of N3-PS-N3 and Pg2O. This reaction was investigated in the presence and absence of hydrazine with no effort being made to exclude oxygen other than sealing the vial. When Me6TREN was used as the ligand, the control experiment demonstrated no reaction after 48 h. However, the presence of hydrazine allowed the click coupling reaction to proceed using CuBr/Me6TREN as the catalytic complex. The addition of 2.5 equiv of hydrazine relative to CuBr produced a slow reaction rate, presumably because most of the reducing agent was consumed early in the reaction. In addition, the oxidation of hydrazine produces acid that may destroy the catalyst derived from the basic ligand Me6TREN.52 However, an analogous reaction conducted in the presence of 12.5 equiv of hydrazine proceeded with a rate similar to the reaction in oxygen-free conditions (Figure 5a). Similar results were obtained when TPMA was used as the ligand for click coupling reactions conducted under limited amounts of air, except that a pronounced, unexpected rate enhancement was observed during the reactions utilizing hydrazine (Figure 5b). This could be due to the ability of hydrazine to neutralize any acid produced during the oxidation of the reducing agent. Hydrazine is also known

Figure 5. SEC traces of click coupling reactions of diazido-terminated polystyrene (0.1 M -N3) with propargyl ether (0.1 M -C≡CH) in DMF after 1 h at 25 ( 2 °C using a CuBr (0.01 M) catalyst and varying amounts of hydrazine and (a) Me6TREN or (b) TPMA as ligand.

to coordinate to copper,53,54 and this may influence the nature and activity of the catalyst if hydrazine is present in sufficient excess to displace ligand from the copper center. Finally, the pronounced rate enhancement could be due to the basicity of hydrazine. To gain further understanding regarding the effect of base, a reaction was conducted between N3-PS-N3 and Pg2O in DMF in the presence of CuBr and dtBupy, added as 1 equiv relative to the acetylene group. This proton trap was chosen in an attempt to separate the effect of added base from the effect of added ligand, since dtBupy cannot coordinate with the CuI catalyst. The addition of the proton trap produced a slight rate enhancement, but the effect was not as significant as that observed in the presence of hydrazine. Nonetheless, because hydrazine is a considerably stronger base than dtBupy, it is conceivable that hydrazine can promote and accelerate CuI-catalyzed click reactions under limited amounts of air by acting as both a reducing agent and a base. Click Reactions Catalyzed by Other Metals. Although CuI compounds have proven very efficient catalysts for click reactions, it is desirable to determine whether other metal compounds can also catalyze the process. Such a study is important from both a mechanistic point of view and also as an alternative to the addition of a reducing agent or the deoxygenation procedures often employed for azide-alkyne cycloadditions. NiCl2, PdCl2, and PtCl2 were each investigated as potential catalysts for click reactions. Each of these metals is known to coordinate to alkynes in a manner similar to copper.55-57 The PtII catalyst demonstrated significant catalytic activity relative to a control experiment that was conducted in the presence of no catalyst. This was observed for the coupling of Pg2O with N3-PS-N3 and a low-molecular-weight analogue

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to pyridine-based ligands, and tridentate contributed to faster rates relative to tetradentate ligands. This rate enhancement was augmented by conducting these reactions in a noncoordinating solvent vs a coordinating solvent. Finally, it was shown that deoxygenation procedures can be avoided by the addition of hydrazine as a reducing agent or by the use of metals other than CuI as catalysts. PtII demonstrated the highest catalytic activity relative to the other metals investigated. Acknowledgment. The authors are grateful for financial support provided by the members of the ATRP/CRP Consortium at Carnegie Mellon University and the National Science Foundation (Grant DMR 0549353). Thanks to Guillaume Louche for preliminary experiments and Ke Min for the synthesis of TPMA. Supporting Information Available: Additional SEC traces and quantitative analyses of all click coupling reactions. This material is available free of charge via the Internet at http://pubs.acs.org.

References and Notes

Figure 6. SEC traces of click coupling of (a) N3-PS-N3 with Pg2O and (b) DM-2,6-DAzHD with Pg2O in the presence of NiCl2, PdCl2, and PtCl2 in DMF after 20 h at 80 °C. Concentration of all reagents is 0.125 M.

of diazido-terminated polyacrylate, DM-2,6-DAzHD (Figure 6). (Caution: care should be taken when heating low-molecularweight azides due to the possibility of explosion.) The kinetic plot and rate constant (kapp ) 4.1 × 10-4 M-1 s-1) of the PtCl2-catalyzed polymer coupling at 80 °C demonstrates that this reaction is ∼10 times slower than the CuBrcatalyzed reaction at room temperature. However, the catalytic activity could be influenced considerably by the addition of appropriate ligand. To try to optimize the click coupling reactions promoted by these novel catalysts, the two metal complexes that demonstrated significant catalytic activity (PdCl2 and PtCl2) were used in the presence of a ligand. PMDETA was selected because of its superior performance in CuIcatalyzed azide-alkyne cycloadditions. The addition of PMDETA produced substantially slower reaction rates for both the click coupling of N3-PS-N3 and DM-2,6-DAzHD with Pg2O in DMF. The catalytic activities of the coordinated metal salts were very low, and coupling of N3-PS-N3 with Pg2O was only slightly more pronounced than in the uncatalyzed reaction with PMDETA. Some high-molecular-weight polymer was obtained during the coupling of DM-2,6-DAzHD with Pg2O, but considerably less than what was obtained with noncoordinated metal salts. Additional ligands and solvents will be explored for PdIIand PtII-catalyzed click reactions in order to achieve fast and efficient reactions and elucidate the catalytic mechanism. Conclusions The step-growth click coupling of N3-PS-N3 with Pg2O was employed as a model reaction for studying the effects of several reaction parameters on azide-alkyne cycloadditions. Ligand choice has a dramatic effect on click reaction rates. Aliphatic amine ligands produced significant rate enhancements relative

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