Unusually Stable Chiral Ethyl Zinc Complexes: Reactivity and

Organometallics 2009, 28, 1309–1319

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Unusually Stable Chiral Ethyl Zinc Complexes: Reactivity and Polymerization of Lactide Guillaume Labourdette, Daniel J. Lee, Brian O. Patrick, Maria B. Ezhova, and Parisa Mehrkhodavandi* Department of Chemistry, UniVersity of British Columbia, VancouVer, British Columbia, Canada ReceiVed August 21, 2008

Chiral diaminophenoxy proligands, H(NNR′OR), where R ) t-Bu, H and R′ ) Me, H, have been developed and their respective zinc ethyl complexes, (NNR′OR)ZnEt, 3a (R ) t-Bu, R′ ) Me), 3b (R ) H, R′ ) Me), 3c (R ) t-Bu, R′ ) H), have been synthesized. The reactivity of 3a with alcohols was explored in detail and compared to a compound reported by Hillmyer, Tolman et al., LZnEt (L ) 2,4di-tert-butyl-6-{[(2′-dimethylaminoethyl)methylamino]-methyl}phenolate). Unlike LZnEt, 3a was inert toward ethanol (as well as methanol, isopropanol, and water). It reacted with phenol and with hydrochloric acid to form (NNMeOtBu)ZnOPh, 4a, and (NNMeOtBu)ZnCl, 5a, respectively. Racemic and enantiopure forms of 4a, (()-4a and (R,R)-4a, were synthesized. The phenoxide complex catalyzed the ring opening polymerization of lactide to atactic poly(lactic acid). Introduction Since their early discovery, organozinc compounds and their derivatives have been explored as reagents and catalysts in numerous organometallic and organic transformations.1 Recently, zinc complexes have been studied extensively as catalysts for the ring opening polymerization (ROP) of cyclic esters, such as lactide (LA), to yield biodegradable polyesters, such as poly(lactic acid) (PLA).2,3 In particular, enantioselective polymerization of racemic lactide (rac-LA), with a variety of discrete metal catalysts, has received increasing attention and controlled microstructure PLAs with isotactic,4-14 syndiotactic,15,16 * To whom correspondence should be addressed. E-mail: [email protected]. (1) Seyferth, D. Organometallics 2001, 20, 2940–2955. (2) Dechy-Cabaret, O.; Martin-Vaca, B.; Bourissou, D. Chem. ReV. 2004, 104, 6147–6176. (3) Wu, J. C.; Yu, T. L.; Chen, C. T.; Lin, C. C. Coord. Chem. ReV. 2006, 250, 602–626. (4) Radano, C. P.; Baker, G. L.; Smith, M. R. J. Am. Chem. Soc. 2000, 122, 1552–1553. (5) Chamberlain, B. M.; Cheng, M.; Moore, D. R.; Ovitt, T. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2001, 123, 3229– 3238. (6) Zhong, Z. Y.; Dijkstra, P. J.; Feijen, J. Angew. Chem., Int. Ed. 2002, 41, 4510–4513. (7) Ovitt, T. M.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1316– 1326. (8) Zhong, Z. Y.; Dijkstra, P. J.; Feijen, J. J. Am. Chem. Soc. 2003, 125, 11291–11298. (9) Tang, Z. H.; Chen, X. S.; Pang, X.; Yang, Y. K.; Zhang, X. F.; Jing, X. B. Biomacromolecules 2004, 5, 965–970. (10) Jensen, T. R.; Breyfogle, L. E.; Hillmyer, M. A.; Tolman, W. B. Chem. Commun. 2004, 2504–2505. (11) Zhang, L.; Nederberg, F.; Messman, J. M.; Pratt, R. C.; Hedrick, J. L.; Wade, C. G. J. Am. Chem. Soc. 2007, 129, 12610–12611. (12) Wu, J. C.; Pan, X. B.; Tang, N.; Lin, C. C. Eur. Polym. J. 2007, 43, 5040–5046. (13) Heck, R.; Schulz, E.; Collin, J.; Carpentier, J. F. J. Mol. Catal. A: Chem. 2007, 268, 163–168. (14) Alonso-Moreno, C.; Garces, A.; Sanchez-Barba, L. F.; Fajardo, M.; Fernandez-Baeza, J.; Otero, A.; Lara-Sanchez, A.; Antinolo, A.; Broomfield, L.; Lopez-Solera, M. I.; Rodriguez, A. M. Organometallics 2008, 27, 1310– 1321. (15) Ovitt, T. M.; Coates, G. W. J. Am. Chem. Soc. 1999, 121, 4072– 4073.

and heterotactic5,7,10,14,17-32 architectures have been reported. Early examples of active zinc catalysts for enantioselective lactide ROP, such as β-diiminate complexes reported by Coates et al.,5,17 utilize bulky, achiral ancillary ligands to obtain highly heterotactic polymer via a chain-end control mechanism. This strategy has been used successfully by a number of groups;23,33,34 however, most examples of highly selective catalysts that promote enantiomorphic site control of rac-lactide polymerization are limited to trivalent metals supported by chiral (16) Chisholm, M. H.; Eilerts, N. W.; Huffman, J. C.; Iyer, S. S.; Pacold, M.; Phomphrai, K. J. Am. Chem. Soc. 2000, 122, 11845–11854. (17) Cheng, M.; Attygalle, A. B.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 1999, 121, 11583–11584. (18) Chisholm, M. H.; Gallucci, J.; Phomphrai, K. Chem. Commun. 2003, 48–49. (19) Cai, C. X.; Amgoune, A.; Lehmann, C. W.; Carpentier, J. F. Chem. Commun. 2004, 330–331. (20) Marshall, E. L.; Gibson, V. C.; Rzepa, H. S. J. Am. Chem. Soc. 2005, 127, 6048–6051. (21) Jensen, T. R.; Schaller, C. P.; Hillmyer, M. A.; Tolman, W. B. J. Organomet. Chem. 2005, 690, 5881–5891. (22) Chisholm, M. H.; Gallucci, J. C.; Phomphrai, K. Inorg. Chem. 2005, 44, 8004–8010. (23) Chen, H. Y.; Huang, B. H.; Lin, C. C. Macromolecules 2005, 38, 5400–5405. (24) Amgoune, A.; Lavanant, L.; Thomas, C. M.; Chi, Y.; Welter, R.; Dagorne, S.; Carpentier, J. F. Organometallics 2005, 24, 6279–6282. (25) Amgoune, A.; Thomas, C. M.; Balnois, E.; Grohens, Y.; Lutz, P. J.; Carpentier, J. F. Macromol. Rapid Commun. 2005, 26, 1145–1150. (26) Ma, H. Y.; Spaniol, T. P.; Okuda, J. Angew. Chem., Int. Ed. 2006, 45, 7818–7821. (27) Dove, A. P.; Gibson, V. C.; Marshall, E. L.; Rzepa, H. S.; White, A. J. P.; Williams, D. J. J. Am. Chem. Soc. 2006, 128, 9834–9843. (28) Liu, X. L.; Shang, X. M.; Tang, T.; Hu, N. H.; Pei, F. K.; Cui, D. M.; Chen, X. S.; Jing, X. B. Organometallics 2007, 26, 2747–2757. (29) Chmura, A. J.; Chuck, C. J.; Davidson, M. G.; Jones, M. D.; Lunn, M. D.; Bull, S. D.; Mahon, M. F. Angew. Chem., Int. Ed. 2007, 46, 2280– 2283. (30) Amgoune, A.; Thomas, C. M.; Carpentier, J. F. Pure Appl. Chem. 2007, 79, 2013–2030. (31) Pang, X.; Chen, X. S.; Zhuang, X. L.; Jing, X. B. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 643–649. (32) Ma, H.; Spaniol, T. P.; Okuda, J. Inorg. Chem. 2008, 47, 3328– 3339. (33) Chen, H. Y.; Tang, H. Y.; Lin, C. C. Macromolecules 2006, 39, 5583–5583. (34) Chisholm, M. H.; Lin, C. C.; Gallucci, J. C.; Ko, B. T. Dalton Trans. 2003, 406–412.

10.1021/om800818v CCC: $40.75  2009 American Chemical Society Publication on Web 02/11/2009

1310 Organometallics, Vol. 28, No. 5, 2009

Labourdette et al. Scheme 1. Synthesis of LZnOEt

Scheme 2. Synthesis of Proligands 2a-2b and Ethyl Zinc Complexes 3a-3c

ligands.4,6,8,26,32,35-38 Catalytic systems with enantiomorphic site control are desirable since they have the potential to generate polymer microstructures that are not possible with chain end control mechanism.15 Chiral complexes are required for enantiomorphic site control; examples of zinc catalysts for lactide ROP bearing chiral auxiliaries are rare.39-41 We are exploring the efficacy of chiral zinc complexes as catalysts for the enantiomorphic site control of lactide polymerization. In pursuing this goal it was important to develop a system with minimal chain-end control and high activity. The highly active zinc ethoxide complex, [LZnOEt]2 (Scheme 1) reported by Hillmyer, Tolman et al., which resulted in the conversion of rac-LA to atactic PLA, was chosen as the achiral prototype. This catalyst was formed via the protonolysis of the related ethyl zinc complex with ethanol to result in a zinc alkoxide, [LZnOEt]2, which was shown to be dinuclear in the solid state but mononuclear in solution (Scheme 1).42 Inspired by this work, we sought to investigate a chiral version of this zinc catalyst with the intent of enabling stereoselective polymerization of lactide. We have reported an indium catalyst supported by analogous chiral ligands capable of active, living, and selective ROP of lactide.43 Herein we describe the related zinc chemistry and the surprising differences observed between its reactivity and that of the complex reported by Hillmyer and Tolman. (35) Spassky, N.; Wisniewski, M.; Pluta, C.; Borgne, A. Macromol. Chem. Phys. 1996, 197, 2627–2637. (36) Ovitt, T. M.; Coates, G. W. J. Polym. Sci. Pol. Chem. 2000, 38, 4686–4692. (37) Majerska, K.; Duda, A. J. Am. Chem. Soc. 2004, 126, 1026–1027. (38) Chisholm, M. H.; Patmore, N. J.; Zhou, Z. P. Chem. Commun. 2005, 127–129. (39) Chakraborty, D.; Chen, E. Y. X. Organometallics 2003, 22, 769– 774. (40) Wu, J. C.; Huang, B. H.; Hsueh, M. L.; Lai, S. L.; Lin, C. C. Polymer 2005, 46, 9784–9792. (41) Farwell, J. D.; Hitchcock, P. B.; Lappert, M. F.; Luinstra, G. A.; Protchenko, A. V.; Wei, X. H. J. Organomet. Chem. 2008, 693, 1861– 1869. (42) Williams, C. K.; Breyfogle, L. E.; Choi, S. K.; Nam, W.; Young, V. G.; Hillmyer, M. A.; Tolman, W. B. J. Am. Chem. Soc. 2003, 125, 11350–11359. (43) Douglas, A. F.; Patrick, B. O.; Mehrkhodavandi, P. Angew. Chem., Int. Ed. 2008, 47, 2290–2293.

Results and Discussion Synthesis and Characterization of Proligands and Metal Complexes. The synthesis of proligands is based on a route developed for (()- and (R,R)-N,N-dimethyldiaminocyclohexane reported by Finney.44 Condensation reactions of this asymmetrically alkylated diaminocyclohexane with 3,5-di-tertbutyl-2-hydroxybenzaldehyde or salicylaldehyde form the corresponding diaminophenol compounds, H(NNHOR), where R ) t-Bu and H for 1a and 1b, respectively. Reductive amination of 1a and 1b with NaBH3CN and CH2O forms the proligands H(NNMeOR), 2a and 2b (Scheme 2). Distinctive 1H NMR (C6D6, 25 °C) spectroscopic features of 2a include a doublet at 3.81 ppm (2H, methylene backbone) and two singlets in a 2:1 ratio at 2.12 and 2.08 ppm (N-CH3). Similar features were observed for 2b: a doublet at 3.73 ppm (2H, methylene backbone) and two singlets, in a 2:1 ratio, at 2.09 and 2.02 ppm (N-CH3). The enantiopure compound (R,R)-2a was also synthesized from (R,R)-N,N-dimethyl diaminocyclohexane. Compounds (()- and (R,R)-2a have identical 1H NMR spectra. The reaction of proligands 2a, 2b, and 1a with 1 equiv of Et2Zn forms the ethyl compounds (NNR′OR)ZnEt, 3a (R ) t-Bu, R′ ) Me), 3b (R ) H, R′ ) Me), and 3c (R ) t-Bu, R′ ) H) respectively, in 10-60 minutes at room temperature. The 1H NMR spectrum (25 °C, C6D6) of 3a shows a triplet belonging to Zn-CH2CH3 at 1.76 ppm and a doublet of quartets at 0.54 ppm belonging to Zn-CH2CH3. The latter peak is obscured by ligand peaks, but can be distinguished in a COSY spectrum (see Supporting Information). The backbone methylene protons of the ligand appear as AB doublets at 2.96 and 3.88 ppm and there are three signals belonging to N-CH3 groups at 1.56, 1.85, and 1.86 ppm indicating a desymmetrized ligand. These observations are corroborated by 13C{1H} NMR spectroscopy. Similar peaks are observed for 3b and 3c. Both enantiopure and racemic forms of complex 3a, (()-3a and (R,R)-3a, were synthesized and show identical NMR features. The molecular structures of (R,R)-3a, (()-3a, and (()-3b were determined by single crystal X-ray crystallography (Figures 1-3). The complexes are mononuclear with pseudotetrahedral (44) Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431– 8434.

ReactiVity and Polymerization of Lactide

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Figure 1. Molecular structure of (R,R)-3a with ellipsoids at the 50% probability level. Most hydrogen atoms were omitted for clarity.

Figure 2. Molecular structure of two diastereomers of (()-3a, 3a (left) and 3a-β (right), with ellipsoids at the 50% probability level. Enantiomers for these molecules were also observed in the unit cell; they have been omitted for clarity. Most hydrogen atoms were omitted for clarity.

zinc centers. When (()-(NNMeOR) is coordinated to a metal center, multiple possible sources of chirality arise: from the cyclohexyl ring, the metal center itself, and the chiral central amine. The solid-state structure of (R,R)-3a shows only one complex (Figure 1), although we observe the formation of the related diastereomer stemming from a different chirality at the central amine (N7) in solution (see below). The bond lengths and angles for the racemic analogue (()3a are very similar to those of (R,R)-3a (see SI). However, the solid state structure of (()-3a shows two isomers, 3a and 3a-

β, with different chirality at the zinc center and the central amine nitrogen atoms, N7 and N37 (Figure 2).45 Both diastereomers presented in Figure 2 have the R,R-cyclohexyldiamine backbone. The chirality of the central amine group is best illustrated by the relative position of the central N-Me and the nearest cyclohexyl proton. In 3a C30 and C3-H are cis with respect (45) Since the ligand set is racemic, four isomers are expected to form. We evaluated a given crystal from a batch. All four isormers are observed in the unit cell of a given crystal (see Supporting Information).


Labourdette et al.

Figure 3. Molecular structure of (()-3b with ellipsoids at the 50% probability level. Most hydrogen atoms were omitted for clarity. Table 1. Selected Bond Lengths (Å) and Angles (deg) for Zinc Ethyl Complexes

(R,R)-3a Bond lengths Zn-C1 Zn-O1 Zn-N1 Zn-N2

1.971 1.927 2.152 2.185

Bond angles N1-Zn-N2 N1-Zn-O1 N2-Zn-O1 C1-Zn-N1

82.19 (15) 95.54 (14) 111.61 (16) 124.5 (2)

(6) (3) (4) (5)

(()-3b Zn1

(()-3b Zn2

1.980 1.950 2.121 2.145

1.950 1.930 2.127 2.161

(2) (1) (2) (2)

83.54 (6) 96.29 (5) 103.42 (6) 119.16 (7)

(1) (1) (2) (2)

83.17 (6) 96.06 (6) 106.65 (6) 124.11 (8)

LZnEt 1.997 1.956 2.147 2.128

(4) (2) (3) (3)

84.85 (13) 93.32 (12) 99.76 (12) 117.82 (16)

to each other, while in 3a-β C60 and C33-H are trans. The chirality of the central amine group is important for the solution structures of the complexes bearing this family of ligands; however, it is not always possible to see the different isomers in the solid state. The molecular structure of (()-3b shows the two diastereomers with different chiral centers at zinc and the central amine nitrogen, but with identical configurations (R,R) of the cyclohexane ring (Figure 3). Although the solid-state structures of (R,R)-3a and (()-3b are similar to that of LZnEtsall three zinc centers are pseudotetrahedralsthere are some clear differences (Table 1). The relative positions of the ligand substituents, and as a result the bond angles, are different. An identical viewpoint of both (R,R)-3a and LZnEt shows that in (R,R)-3a the bulky arene ring is pointing away from the Zn-Et group while in LZnEt the ring is closer to the ethyl group (Figure 4). This difference between the two complexes is most pronounced in the N2-Zn-O1 and the C1-Zn-N1 angles, which are significantly larger for (R,R)-3a. A similar bend of the arene group is observed in the less hindered (()-3b. The minor differences

Figure 4. Structural comparison of (a) (R,R)-3a, (b) (()-3b, and (c) LZnEt.

observed in the solid-state structures are not expected to contribute to differences in the reactivity of the dynamic species in solution. When 3a or 3b were synthesized in a variety of solvents, the secondary products 3a-β or 3b-β were formed (less than 15%)



Figure 5. 1H NMR (C6D6, 400 MHz) spectrum of (()-3a after 10 min at 25 °C (bottom) and heating at 80 °C in C6D6 for 72 h (top).

and a new symmetric set of backbone methylene signals in their 1 H NMR spectrum was observed. Analytically pure samples were found to have similar ratios of a secondary product. Formation of 3a-β was studied in more detail; similar results were found with 3b-β. Changes in the reaction time from 10 min to 5 h at room temperature did not change the percentage of 3a-β; the reaction is essentially complete after 10 min. Variable temperature NMR studies (C6D5CD3) from -20 to 80 °C carried out over 2.5 h did not result in significant changes in the isomer mixture. However, after 72 h at 80 °C in C6D6, a 50:50 mixture of 3a:3a-β was observed (Figure 5). This ratio did not change upon cooling to room temperature. Decreasing the reaction temperature to below -90 °C or changing the reaction solvent from diethyl ether to THF, benzene, toluene, or pentane does not significantly change the ratio of 3a to 3aβ. This evidence suggests the existence of an equilibrium between 3a and 3a-β in solution. This equilibrium, in place for all complexes bearing this ligand family, arises from the two isomers of the complex with different chirality on the central amine, as illustrated by detailed NMR studies, see below (eq 1). Hillmyer and Tolman did not report a similar phenomenon for LZnEt;42 in repeating their work we also did not observe the formation of a secondary product. Interestingly, this equilibrium does not reach 50:50 for 3c under similar reaction conditions. Complex 3c has a secondary central amine and presumably can undergo a more rapid inversion than 3a and 3b.

The complexity of a system with four possible stereocenters complicated the characterization of our compounds. However, detailed NMR analysis of 3a and 3a-β revealed significant differences in the stereochemistry of the two molecules in agreement with the solid-state structures. 1H NMR spectra of a mixture of 3a and 3a-β confirmed that both species have an identical molecular skeleton: the number of signals and their multiplicities in 3a-β are identical to 3a. The protons for the dimethyl amine in 3a (C9-H and C10-H) and 3a-β (C39-H and C40-H) were assigned based on COSY and NOE experiments (see Supporting Information). Irradiation of the cyclohexyl

Figure 6. Illustration of the specific chirality of diastereomers 3a and 3a-β based on 1D selective NOE experiment (C6D6, 400 MHz) of a 50:50 mixture of 3a and 3a-β.

proton C3-H in 3a in a 1D selective NOE experiment produced an NOE effect on the C9-H protons, while a similar experiment with the and C33-H protons in 3a-β showed an NOE effect with the opposite methyl group protons or C40-H (Figure 6). This difference is a direct correlation to the relationship between the central N-Me and the cyclohexyl proton. In 3a the C30-H and C3-H are cis while in 3a-β the analogous protons C60-H and C33-H are trans. The solution and solid-state studies confirm the equilibrium proposed in eq 1. The minor isomers generated by inversion of the central tertiary amine are observed in all subsequent complexes bearing the (NNMeOR) ancillary ligands; however, they do not influence the reactivity of the complexes. Reactions of Ethyl Zinc Compounds with Alcohols and Water. In direct contrast to the Hillmyer and Tolman complex, LZnOEt, which was synthesized via reaction of LZnEt with ethanol (Scheme 1), experiments carried at room temperature over 24 h show that 3a is unreactive toward stoichiometric amounts of methanol, ethanol, and isopropanol in a myriad of different organic solvents.42,46 Reactions of 3a with 2 equiv of methanol, ethanol, and isopropanol over one week result in the formation of free ligand, decomposition, and no reaction, respectively. Complex 3a is also inert in the presence of neat water at room temperature. The sterically unencumbered 3b is also inert in the presence of ethanol (room temperature, 15 h). Several different factors were considered in explaining the unusual reactivity of complexes 3a and 3b: (1) There are no significant electronic differences between 3a, 3b, and LZnEt; (2) Complex 3a is more sterically hindered than LZnEt, however the lack of reactivity of the significantly less congested 3b belies a steric argument; and (3) The acidity of the respective alcohol plays an important role in their reactivity with the zinc ethyl complexes. Methanol, ethanol, isopropanol, and water have pKa (46) We have successfully repeated this work.


Labourdette et al.

Figure 7. Molecular structure of (()-4a•phenol with ellipsoids at the 50% probability level. Most hydrogen atoms were removed for clarity.

values of approximately 30 in DMSO47 and are not prone to ready proton dissociation in organic solvents. Phenol is more acidic in such environments (pKa ) 18) and would be expected to promote different reactivity. Reaction of (()-3a with one equiv phenol at room temperature for 9 h forms (()-(NNMeOtBu)ZnOPh (()-(4a) (eq 7). The enantiopure complex, (R,R)-4a, was generated from (R,R)-3a and has identical spectroscopic features. The 1H NMR spectrum of 4a shows the distinctive three peaks for the NCH3 groups at 2.02, 1.94, and 1.43 ppm. The phenoxy peaks are further downfield at 7.40 and 6.82 ppm. There is no evidence for formation of a phenoxy-bridged dimer in solution; however, such a structure cannot be ruled out in light of the aggregation behavior observed for LZnOEt42 and prior observations of the importance of aggregation behavior in related zinc alkoxide catalysts.48 Although we did not observe a dimer in the solid state, we did observe aggregation with excess phenol present in the crystal lattice. The molecular structure of the phenol adduct of (()-4a, (()-4a•phenol, shows a pseudotetrahedral zinc center with a phenoxy ligand in close contact with a second phenol -OH (Figure 7).49 The O(28)-H(36) and O(28)-O(36) bond lengths are 1.9 and 2.67 Å, respectively.

Complex (()-3a also reacts cleanly with HCl•Et2O in 1 h at room temperature to form (NNMeOtBu) ZnCl ((-5a) (Eq 8). The (47) Taft, R. W.; Bordwell, F. G. Acc. Chem. Res. 1988, 21, 463–469. (48) Rieth, L. R.; Moore, D. R.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 15239–15248. (49) The equivalent of phenol can be avoided by strict control of stoichiometry.

1

H NMR spectrum of (()-5a shows the three peaks for the NCH3 groups at 2.01, 1.97 and 1.45 ppm (in C6D6, 25 °C). The molecular structure of (()-5a shows one molecule in the unit cell; dimerization or aggregation is not observed in solution or the solid state (Figure 8). The zinc center is pseudotetrahedral with a slightly smaller O(26)-Zn-N(8) angle (113°) than that of 4a (120°) (Table 2).

Insight into the difference in reactivity of 3a and LZnEt with alcohols can be obtained by considering two possible mechanisms for this reaction depending on the nature of the substrates (Scheme 3). Reactions of ethyl zinc complexes with substrates that easily dissociate a proton under the reaction conditions, phenol and HCl in the case of 3a, proceed via a direct protonation of the zinc ethyl bond. With the less acidic alcohols, coordination to the metal center leading to a decrease in the pKa of the coordinated species becomes increasingly important. We propose that in order for the latter mechanism to be viable in these stable tetrahedral Zn(II) complexes, dissociation of the terminal amine arm of the chelating ligand must occur. To support this proposal, we investigated the lability of the terminal secondary amine in LZnEt and in (()-3a.50 We first attempted to isolate base adducts of the compounds by reacting them with excess pyridine. However, reaction of either LZnEt or (()-3a with 2 equiv of pyridine at room temperature overnight followed by removal of excess pyridine in Vacuo at room temperature for a further 24 h only yielded the starting zinc ethyl complexes. If a pyridine adduct of either complex is forming, it is not stable under the conditions required to remove



Figure 8. Molecular structure of (()-5a with ellipsoids at the 50% probability level. Most hydrogen atoms were omitted for clarity. Table 2. Selected Bond Lengths (Å) and Angles (deg) for One Molecule of (()-4a and (()-5a (+)-4aa

(()-5aa

Zn-N7 Zn-N8 Zn-O26 Zn-O28

Bond lengths 2.094(3) Zn-N7 2.083(3) Zn-N8 1.925(2) Zn-O26 1.920(2) Zn-Cl

2.064(2) 2.067(2) 1.8987(18) 2.2048(7)

O26-Zn-O28 O26-Zn-N7 O28-Zn-N7 O26-Zn-N8 O28-Zn-N8 N7-Zn-N8

Bond angles 119.04(10) O26-Zn-Cl 98.56(11) O26-Zn-N7 120.60(11) Cl-Zn-N7 120.35(11) O26-Zn-N8 107.52(10) Cl-Zn-N8 86.84(11) N7-Zn-N8

120.40(6) 99.99(8) 117.78(6) 112.57(8) 112.79(7) 88.36(8)

a Two enantiomers are present in each structure, data for one presented.

Scheme 3. Possible Mechanisms for the Reaction of Ethyl Zinc Complexes and Acids/Alcohols

excess pyridine. A possible equilibrium between the ethyl species, LZnEt or (()-3a, and pyridine was investigated in situ. As discussed above, the methyl peaks of the dimethylated amine are distinct in both complexes because of the asymmetry of the

system. If the terminal dimethyl amine dissociates in the presence of pyridine, the equilibration of the two signals would be observed by NMR spectroscopy. Two equiv of pyridine were added to a solution of LZnEt or (()-3a and the 1H NMR spectra (CD2Cl2, 20 °C) of the resulting mixtures were obtained prior to addition of base and at 60 min (Figure 9). The spectra for the LZnEt mixture show that the two methyl groups (2.38 and 2.09 ppm) equilibrate and appear as a single broad peak at 2.24 ppm after 60 min while the signal for the central amine methyl group is unaffected.50 Analogous experiments with (()-3a do not show similar changes. Reacting (()-3a with pyridine for longer times (48 h, C6D6, 20 °C) does not result in dissociation of the terminal amine group. It is likely that the diaminocyclohexane backbone of (()3a is rigid enough to prevent substitution of the dimethylated amine by the pyridine ligand. The lack of amine dissociation explains why 3a and 3b are less prone to protonolysis by reaction with ethanol while LZnEt forms the zinc ethoxide complex at room temperature. Lactide Polymerization. The racemic and enantiopure phenoxide complexes, (NNMeOtBu)ZnOPh (()- and (R,R)-4a are catalysts for the ring opening polymerization of lactide (Table 3).51 A comparison of entries 1 and 6 in Table 3 shows that 4a does not achieve the same level of activity as LZnOEt.42 The system is also significantly less active than a related indium catalyst developed in our group (Table 3, entry 5).43 Polymerization of racemic LA with (()-4a did not result in any selectivity (Table 3, entries 2 and 3). The large scale polymerization samples show molecular weights inconsistent with added equivalents of monomer and high molecular weight distributions (Table 3, entries 2-4). We monitored the polymerization activity of (()-4a in the presence of 188 equiv of rac-LA to 96% conversion over a period of 25 h (Table 3, entry 4) via 1H NMR spectroscopy (CD2Cl2, 20 °C, 1,3,5-trimethoxybenzene, TMB, was used as an internal standard). The plot of [LA]/[TMB] shows the progress of polymerization over the reaction period (Figure 10). A 3 h initiation period is followed by polymerization, which reaches greater than 95% conversion after 10 h. The inconsistent molecular weights and high molecular weight distributions may be attributed in part to an incomplete initiation. The causes of the initiation period are not well understood, however the study indicates that LZnOEt is a superior catalyst for the polymerization of lactide.

Conclusions The synthesis and study of a family of chiral zinc complexes as potential catalysts for the ring opening polymerization of lactide are reported. The ethyl zinc complexes are chiral analogues of a highly active, achiral lactide ROP catalyst reported by Hillmyer and Tolman, LZnEt. Upon synthesis of the chiral ethyl zinc precursors, (NNMeOR)ZnEt (R ) H, t-Bu), an equilibrium was observed in solution between diastereomers formed by the central amine. The new zinc compounds were not reactive toward alcohols such as ethanol in direct contrast (50) Unlike 3a, complex LZnEt exhibits fluxional behavior in CD2Cl2 and CD3CN. EXSY experiments (CD2Cl2, 298 K) on LZnEt show a strong exchange cross peak between the two amine methyl groups. The coalescence point for these peaks is above the boiling point of CD2Cl2 the solvent; however, the rate constant for this exchange was estimated by variable temperature 1D proton experiments in CD3CN. In the more polar solvent, the exchange process is faster: at the coalescence temperature (310 K) the exchange rate was 213 s-1 (XG ) 14.2 kcal/mol). (51) Attempts to generate and isolate complexes with other alkoxides or amides to date have been unsuccessful.


Labourdette et al.

Figure 9. 1H NMR spectrum (CD2Cl2, 20 °C) of LZnEt before addition of pyridine (bottom) and 60 min after addition of 2 equiv of pyridine (top). Table 3. Selected Data for Ring Opening Polymerization of rac-LAa entry

Cat

LA/Cat

[Cat] (mM)

[LA] (M)

Time (h)

conversionb(%)

Mn

Mw

PDI

Pmc

1 2 3 4 5 6

(()-4a (()-4a (R,R)-4a (()-4a {In}d LZnOEte

200 200 200 188 200 1500

1.6 1.6 1.6 2.4 2.4 0.69

0.31 0.31 0.31 0.45 0.48 1.0

24 40 40 25 0.8 0.3

96 100 100 96 95 93

16000 46600 94800 32100

8800 21700 45600 26200

1.80 2.15 2.08 1.14

0.54 0.52

a All reactions were carried out in CH2Cl2 or CD2Cl2 at 20 °C. b Determined via integration of the methyl resonances of LA. c Determined from the methine region of the 1H{1H} NMR spectrum. d {In} ) ([NNHOtBu]InCl)2(µ-Cl)(µ-OEt).43 e Reference 42.

Figure 10. Plot of [LA]/[TMB] for polymerization of 188 equiv rac-LA with (()-4a in the presence of 1,3,5-trimethoxybenzene (TMB) as an internal standard. The methine proton of LA was monitored via 1H NMR spectroscopy (CD2Cl2, 20 °C, 400 MHz). [(()-4a]o ) 2.4 mM, [LA]o ) 0.45 M.

to LZnEt, which reacted readily to form the corresponding zinc ethoxide. However, upon reaction of (NNMeOtBu)ZnEt with phenol (pKa ) 18) the phenoxide complex (NNMeOtBu)ZnOPh

was formed. Reaction with hydrochloric acid formed (NNMeOtBu)ZnCl. The reactivity of (NNMeOtBu)ZnEt toward alcohols may be explained by lack of dissociation of the


ancillary ligand, which would prevent coordination and deprotonation of alcohols with high pKa values (∼30). Polymerization of rac-lactide with (NNMeOtBu)ZnOPh produced atactic PLA and showed significant initiation and slow propagation rates, in direct contrast to the highly active LZnOEt. Complications in catalyst synthesis, a slow polymerization time, and a lack of enantioselectivity have prompted us to reevaluate the ligand design to incorporate the chiral moiety in a nonlabile arm of the ligand.

Experimental Section General Considerations. Unless otherwise indicated, all air and/ or water sensitive reactions were carried out under dry nitrogen in an MBraun glovebox or using standard Schlenk techniques. NMR spectra were recorded on Bruker Avance 300, 400, or 600 MHz spectrometers. The chemical shifts in the 1H NMR spectra are given in ppm versus residual protons: δ 7.27 CDCl3, δ 7.16 C6D6, δ 5.34 CD2Cl2, δ 2.09 CD3C6D5 (methyl), δ 1.94 CD3CN. 13C{1H} NMR chemical shifts are given in ppm versus residual 13C atoms: δ 77.2 CDCl3, δ 128.39 C6D6. Mass spectrometry analyses were performed on Kratos MS-80 (low resolution), Bruker Biflex IV (high resolution). Elemental analysis data were obtained from a Carlo Erba Elemental Analyzer EA 1108. All measurements for X-ray crystallographic data were made on a Bruker X8 APEX diffractometer with graphite monochromated Mo KR radiation. Details of the X-ray structure determination of complexes are summarized in the Supporting Information. Materials. All solvents (pentane, toluene, methylene chloride, THF and diethyl ether) were degassed and dried using 3Å molecular sieves in an MBraun solvent purification system. Benzene and THF were further dried with Na/benzophenone before being distilled and degassed prior to use. Deuterated solvents were either dried over calcium hydride (CD2Cl2, CD3Cl, CD3CN) or over Na/benzophenone (C6D6, toluene-d8). Racemic lactide was purchased from AlfaAesar and recrystallized consecutively from toluene then isopropanol. Compounds (()-1a and (R,R)-1a were prepared following literature procedures.43,52 All other compounds were obtained from Aldrich and were used without further purification. 2,4-Ditert-butyl-6-(((2-(dimethylamino)cyclohexyl)(methyl)amino)methyl)phenol, (()-H(NNMeOtBu), (()-2a. (()-1a (19.9 g, 55.2 mmol) was dissolved in acetonitrile (500 mL). 37% w/w aqueous formaldehyde (22.6 g, 278 mmol) was added to the opaque orange mixture, which was then stirred for 30 min at room temperature. The mixture was cooled to 0 °C with an ice-bath and sodium cyanotrihydroborate (7.03 g, 112 mmol) was added with constant stirring. After 30 min stirring at room temperature, glacial acetic acid (10 mL) was added to the mixture dropwise, forming a white foam at the surface of the mixture. After 5 h reaction at room temperature, methanol/CH2Cl2 (400 mL, 2% methanol by volume) was added and the mixture was extracted with 1 M NaOH (3 × 400 mL). The organic layer was concentrated to dryness and the resulting orange solid was recrystallized from acetonitrile to produce white crystals (14.9 g, 39.8 mmol, 72% yield). 1H NMR (400 MHz, C6D6, 298 K): δ 11.24 (1H, s, OH), 7.56 (1H, d, J ) 2.2 Hz, ArH), 7.06 (1H, d, J ) 2.2 Hz, ArH), 3.81 (1H, d, J ) 11.7 Hz, NCH2C), 3.10 (1H, br s, NCH2C), 2.24 (2H, m, CyH), 2.12 (6H, s, N(CH3)2), 2.08 (3H, s, NCH3), 1.76 (9H, s, C(CH3)3)), 1.53 (3H, m, CyH), 1.42 (9H, m, C(CH3)3), 0.84 (3H, m, CyH). 13C{1H} NMR (101 MHz, C6D6, 298 K): δ 155.60 (ArC), 139.96 (ArC), 136.25 (ArC), 125.26 (ArC), 124.01 (ArC), 123.27 (ArC), 64.52 (CyC), 64.42 (CyC), 35.91 (N(CH3)2), 34.07 (NCH3), 32.51 (C(CH3)3), 30.58 (C(CH3)3), 26.25 (CyC), 26.08 (CyC), 24.22 (CyC), 22.41 (CyC). Anal. calcd (found) for C24H42N2O: C 76.9 (77.22), H 11.3 (11.42), N 7.48 (7.77) %. (52) Miqueu, K.; Despagnet-Ayoub, E.; Dyer, P. W.; Bourissou, D.; Bertrand, G. Chem.-Eur. J. 2003, 9, 5858–5864.

Organometallics, Vol. 28, No. 5, 2009 1317 R,R-2,4-Ditert-butyl-6-(((2-isopropylcyclohexyl)(methyl)amino)methyl)phenol, (R,R)-(NNMeOtBu), (R,R)-2a. (R,R)-1a (6.37 g, 17.7 mmol) was dissolved in acetonitrile (150 mL). 37% w/w aqueous formaldehyde (7.29 g, 23.9 mmol) was added to the opaque orange mixture, which was then stirred for 30 min at room temperature. The mixture was cooled to 0 °C with an ice-bath and sodium cyanotrihydroborate (2.39 g, 38.0 mmol) was added with constant stirring. After 30 min stirring at room temperature, glacial acetic acid (10 mL) was added to the mixture dropwise, forming white foam at the surface of the mixture. After 5 h reaction at room temperature, methanol/CH2Cl2 (300 mL, 2% methanol by volume) was added and the mixture was extracted with 1 M NaOH (3 × 400 mL). The organic layer was concentrated to dryness and the resulting orange solid was recrystallized from acetonitrile to produce white crystals (5.99 g, 60.2 mmol, 90% yield). 1H NMR (400 MHz, C6D6, 298K): δ 11.24 (1H, s, OH), 7.56 (1H, d, J ) 2.2 Hz, ArH), 7.06 (1H, d, J ) 2.2 Hz, ArH), 3.81 (1H, d, J ) 11.7 Hz, NCH2Ar), 3.10 (1H, br s, NCH2Ar) 2.24 (2H, m, cyH), 2.12 (6H, s, N(CH3)2), 2.08 (3H, s, NCH3), 1.76 (9H, s, C(CH3)3), 1.53 (4H, m, cyH), 1.42 (9H, m, C(CH3)3), 0.84 (4H, m, CyH). 13C{1H} NMR (101 MHz, C6D6, 298 K): 155.62 (ArC), 139.99 (ArC), 136.28 (ArC), 125.22 (ArC), 124.04 (ArC), 123.29 (ArC), 69.51 (CyC), 67.40 (CyC), 35.82 (N(CH3)2), 34.89 (NCH3), 32.50 (C(CH3)3), 30.57 (C(CH3)3), 26.23 (CyC), 26.06 (CyC), 24.21 (CyC), 22.39 (CyC). Anal. calcd (found) for C24H42N2O: C 76.95 (77.04), H 11.30 (11.35), N 7.48 (7.50) %. (()-(E)-2-((2-(Dimethylamino)cyclohexylimino)methyl)phenol. (()-N,N-Dimethyl diaminocyclohexane (3.29 g, 23.1 mmol) was dissolved in dry methanol (150 mL). Salicylaldehyde (2.37 g, 19.4 mmol) and molecular sieves were added to the mixture. The reaction mixture was stirred for 5 h at room temperature under a static nitrogen atmosphere. The orange product mixture was filtered and the filtrate was dried under vacuum to afford a dark-brown oil (5.27 g, 21.7 mmol, 94% yield). 1H NMR (300 MHz, C6D6, 296 K): δ 14.02 (1H, m, OH), 7.90 (1H, s, N ) CH), 7.13 (1H, 7.02, m, ArH), (7.04, 2H, m, ArH), 6.69 (1H, m, ArH), 2.76 (1H, dt, CyH), 2.32 (1H, dt, CyH), 2.06 (6H, s, N(CH3)2), 1.50 (5H, m, CyH), 0.94 (3H, m, CyH). 13C{1H} NMR (75 MHz, C6D6, 296 K): 163.72 (N ) CH), 162.67 (ArC), 132.46 (ArC), 131.65 (ArC), 120.00 (ArC), 118.69 (ArC), 117.91 (ArC), 69.90 (CyC), 67.12 (CyC), 40.95 (N(CH3)2), 34.93 (CyC), 25.72 (CyC), 25.18 (CyC), 23.63 (CyC). HRMS (MALDI TOF), m/z: calcd for C15H23N2O (H+): 247.1810, found: 247.1808. (()-2-((2-(Dimethylamino)cyclohexylamino)methyl)phenol, (()1b. (()-(E)-2-((2-(dimethylamino)cyclohexylimino)methyl)phenol (3.75 g, 15.2 mmol) was dissolved in acetonitrile (150 mL) and NaBH4 (5.79 g, 15.3 mmol) were added with stirring. After 30 min stirring at room temperature, a catalytic amount of acetic acid (3 mL) was slowly added. The mixture was stirred for 5 h, then diluted with 2% methanol/DCM (150 mL) and washed three times with 1 M NaOH (300 mL). The dark-brown organic layer was water dried with Na2SO4, the solvent was removed under vacuum to yield a light-brown solid (2.88 g, 11.5 mmol, 76% yield).1H NMR (300 MHz, C6D6, 296 K): δ 7.20 (2H, m, ArH), 6.97 (1H, m, ArH), 6.82 (1H, m, ArH), 3.74 (2H, dd, J ) 39.9, 13.9 Hz, N ) CH), 2.49 (1H, br, NH), 2.09 (2H, m, CyH), 1.97 (6H, s, N(CH3)2), 1.50 (3H, m, CyH), 0.94 (5H, m, CyH). 13C{1H} NMR (75 MHz, C6D6, 296 K): 159.87 (ArC), 129.13 (ArC), 128.48 (ArC), 125.11 (ArC), 119.18 (ArC), 117.38 (ArC), 67.05 (CyC), 59.33 (CyC), 51.25 (NCH2C), 40.28 (N(CH3)2), 32.35 (CyC), 25.80 (CyC), 25.23 (CyC), 21.27 (CyC). HRMS (MALDI TOF), m/z: calcd for C15H25N2O (H+): 249.1962, found: 249.1967. (()-2-(((2-(Dimethylamino)cyclohexyl)(methyl)amino)methyl)phenol, (()-(NNMeOH), (()-2b. (()-1b (2.62 g, 10.5 mmol) was dissolved in acetonitrile (200 mL). Aqueous formaldehyde (37% by wt., 4.32 g, 53.2 mmol) was added to the reaction flask with stirring. The mixture was cooled in an ice-bath for 15 min before


Labourdette et al.

sodium cyanotrihydroborate (1.55 g, 0.0247 mol) was added to the mixture. The mixture was stirred for a further 20 min, then a catalytic amount of acetic acid (2 mL) was slowly added. After 4 h reaction, the product was extracted with 2% methanol/CH2Cl2 (200 mL) and washed with 1 M NaOH (3 × 300 mL). The organic phase was collected and the solvent was removed under vacuum. Recrystallization in acetonitrile isolated white crystals in (2.13 g, 8.12 mol, 77% yield). 1H NMR (400 MHz, C6D6, 298 K): δ 10.88 (1H, s, OH), 7.17 (2H, m, ArH), 6.99 (1H, m, ArH), 6.79 (1H, m, ArH), 3.73 (1H, d, J ) 12.7 Hz, NCH2C), 2.86 (1H, d, J ) 12.2 Hz, NCH2C), 2.28 (1H, dt,CyH), 2.15 (1H, dt,CyH), 2.09 (6H, s, N(CH3)2), 2.02 (3H, s, NCH3), 1.61 (4H, m, CyH), 0.82 (4H, m, CyH). 13C{1H} NMR (101 MHz, C6D6, 298 K): 159.14 (ArC), 130.42 (ArC), 129.25 (ArC), 124.69 (ArC), 118.29 (ArC), 117.56 (ArC), 64.74 (CyC), 64.04 (CyC), 52.67 (NCH2C), 38.73 (NCH3), 25.97 (CyC), 25.82 (CyC), 23.16 (CyC), 21.97 (CyC). HRMS (MALDI TOF), m:z: calcd for C16H27N2O (H+): 263.2119, found: 263.2123. (()-[NNMeOtBu]ZnEt, (()-3a. Proligand (()-2a (2.00 g, 5.34 mmol) was dissolved in benzene (10 mL) and cooled to -38 °C. Diethyl zinc (0.560 mL, 5.35 mmol) was added to the solution and the colorless mixture was left for 10 min at room temperature. A white solid was isolated by solvent evaporation under vacuum (2.47 g, 5.28 mmol, 99% yield). Recrystallization in TMS ether led to formation of colorless X-ray quality crystals.

H41), 2.31 (1H, td, J ) 11.5, 3.8 Hz, H33), 2.13 (3H, s, H40), 2.08 (3H, s, H60), 1.91 (1H, td, J ) 11.6, 3.65 Hz, C44), 1.90 (9H, s, C53-55), 1.67 (3H, s, H39), 1.62 (3H, d, J ) 7.9 Hz, M09), 1.54 (3H, t, J ) 7.92 Hz, H59), 1.47 (9H, s, C49-51), 1.4-1.6 (2H, m, H36), 0.71 (2H, m,, H35), 0.47 (2H, q, J ) 7.92, H58), 041 (2H, m, H32). 13C{1H} NMR (101 MHz, C6D6, 298 K): δ 166.09 (C47), 138.29 (C46), 134.61 (C44), 126.40 (C43), 124.35 (C45), 123.36 (C42), 65.16 (C34), 64.32 (C33), 56.01 (C41), 44.77 (C40), 43.22 (C50), 39.14 (C39), 36.26 (C52), 34.55, 34.32, 34.52, 32.75 (C49-51), 30.78 (C53-55), 25.29, 25.08, 24.91, 24.81, 22.49, 22.89, 22.29, 21.83, 14.38 (C59), -3.61 (C58). Anal. calcd (found) for C26H46N2OZn: C 66.72 (66.91), H 9.91 (9.74), N 5.99 (5.92) %. (R,R)-[NNMeOtBu]ZnEt, (R,R)-3a. (R,R)-2a (1.60 g, 4.27 mmol) was dissolved in benzene (10 mL) in a vial and cooled to -38 °C. Diethyl zinc (0.450 mL, 4.30 mmol) was added to this solution and the colorless mixture was stirred for 10 min at room temperature. A white solid was isolated by solvent evaporation under vacuum (1.96 g, 4.18 mmol, 98% yield). Recrystallization in TMS ether led to formation of colorless X-ray quality crystals. NMR assignment for a product mixture with

Unusually Stable Chiral Ethyl Zinc Complexes: Reactivity and

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