Computational Study of the Mechanism of Cyclic Acetal Formation via

This accounts for the experimentally observed H/D exchange at that position. ... (4, 5) The use of transition metal complexes as catalysts is preferre...
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Organometallics 2011, 30, 618–626 DOI: 10.1021/om1009582

Computational Study of the Mechanism of Cyclic Acetal Formation via the Iridium(I)-Catalyzed Double Hydroalkoxylation of 4-Pentyn-1-ol with Methanol Torstein Fjermestad,† Joanne H. H. Ho,‡ Stuart A. Macgregor,*,† Barbara A. Messerle,*,‡ and Deniz Tuna† †

School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, Scotland, U.K., and ‡ School of Chemistry, The University of New South Wales, Sydney, Australia Received October 4, 2010

The mechanism of Ir(I)-catalyzed double hydroalkoxylation of 4-pentyn-1-ol with methanol to form cyclic acetals has been investigated with density functional theory calculations. Using a model [Ir(PyP0 )(CO)2]þ catalyst (PyP0 = 1-[2-phosphinoethyl]pyrazole) the key steps in the first hydroalkoxylation are shown to be (i) electrophilic activation of the alkyne at the cationic Ir(I) metal center; (ii) rate-limiting C-O bond formation via intramolecular nucleophilic attack by the pendant OH group at the C4 position of the bound alkyne; and (iii) facile Hþ transfer to form an Ir-bound cyclic vinyl ether intermediate. The key C-O bond forming cyclization step is greatly facilitated by the presence of an external H-bonded MeOH molecule that stabilizes the positive charge that develops at the hydroxyl proton of the bound alkyne. External MeOH also plays a key role in the Hþ transfer step, for which a number of kinetically competitive pathways corresponding to either retention of the hydroxyl proton in the product or exchange with solvent were identified. The second hydroalkoxylation is initiated from the Ir-bound cyclic vinyl ether intermediate and depends on the ability of that species to access an Ir(I)-alkyl form in which the β-carbon carries a significant positive charge. Reversible C-O bond formation then occurs via nucleophilic attack of MeOH at the β-carbon and proceeds via a novel [3þ2]-addition of the O-H bond over the {Ir-CR-Cβ} moiety. This forms an Ir(III) hydrido-alkyl species, from which reductive elimination yields the final O,O-acetal product. This final reductive elimination is the rate-limiting step within the second hydroalkoxylation component of the cycle. The Ir(I)-alkyl intermediate can also access a MeOH-mediated C-H activation at the Cγ position that leads to exchange with external MeOH. This accounts for the experimentally observed H/D exchange at that position.

Introduction The transition metal-catalyzed addition of oxygen nucleophiles across an unsaturated C-C bond offers a convenient one-step route to the construction of oxygen-containing heterocycles. The addition of alcohols to alkynes can lead to the formation of a wide variety of O-heterocycles, including vinyl ethers,1 and the catalyzed intramolecular addition of two alcohol moieties to alkynes can lead to the formation of bicyclic acetals and spiroketals.2 Pharmacologically, these heterocyclic molecules have been reported to possess highly important biological activities including anti-inflammatory, *Corresponding authors. E-mail: [email protected]; b.messerle@ unsw.edu.au. (1) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079– 3159, and references therein. (2) (a) Messerle, B. A.; Vuong, K. Q. Pure Appl. Chem. 2006, 78, 385–390. (b) Messerle, B. A.; Vuong, K. Q. Organometallics 2007, 26, 3031–3040. (c) Li, X. W.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437–5440. (d) Elgafi, S.; Field, L. D.; Messerle, B. A. J. Organomet. Chem. 2000, 607, 97–104. (e) Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li, Y. Synlett 2008, 6, 940–944. (f) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907–4910. (g) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729–3731. pubs.acs.org/Organometallics

Published on Web 01/18/2011

anticancer, and antitumor properties,3 and, as such, numerous routes have been developed for their synthesis.4,5 The use of transition metal complexes as catalysts is preferred for the promotion of the hydroalkoxylation of alkynes due to the high efficiency and functional group tolerance of these reactions.1,4,6-8 Mo, W,7,9,10 Ru,11-13 and, in particular, Pd complexes1,6,14-18 have been used to catalyze the hydroalkoxylation of alkynes (3) (a) Elliot, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001, 2303–2340. (b) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 2862–2892. (c) Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2000, 1291–1318. (d) Boivin, T. L. B. Tetrahedron 1987, 43, 3309–3362. (e) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–1661. (f) Mead, K. T.; Brewer, B. N. Curr. Org. Chem. 2003, 7, 227–256. (g) Brimble, M. A.; Furkert, D. P. Curr. Org. Chem. 2003, 7, 1461–1484. (h) Schwartz, B. D.; Hayes, P. Y.; Kitching, W.; De Voss, J. J. J. Org. Chem. 2005, 70, 3054–3065. (i) Pietruszka, J. Angew. Chem., Int. Ed. 1998, 37, 2629–2636. (j) Francke, W.; Kitching, W. Curr. Org. Chem. 2001, 5, 233–251. (4) Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons, Inc.: New York, 2001; pp 993-997. (5) Oparina, L. A.; Parshina, L. N.; Khil’ko, M. Y.; Gorelova, O. V.; Preiss, T.; Henkelmann, J.; Trofimov, B. A. Russ. J. Org. Chem. 2001, 37, 1553–1558. (6) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198, and references therein. r 2011 American Chemical Society

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Figure 1. Reaction routes for the metal-catalyzed hydroalkoxylation of alkynes.

forming a range of five- and six-membered O-heterocycles.9-11,13,14,27 Other transition metals used to promote these reactions include Pt,2f,15,19,20 Au,2g,21,22 Ag,23,24 Rh,2d,25,26 and Ir.2c,27-29 More recently, Ln30 complexes have also been reported to be effective catalysts for the formation of vinyl ethers. Widely accepted routes for the one-step transition metalcatalyzed intramolecular hydroalkoxylation reaction of a terminal alkynol are shown in Figure 1. Reaction routes where Pd, Au, Pt, Ag, Ir, and Rh metal centers are used generally involve initial nucleophilic attack of the hydroxy group of the substrate at the π-coordinated alkyne, leading to either the endo-dig or exo-dig products (Figure 1a). Alternatively, reaction pathways involving Mo, W, Cr, and Ru (7) McDonald, F. E. Chem.—Eur. J. 1999, 5, 3103–3106, and references therein. (8) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. J. Angew. Chem., Int. Ed. 2004, 43, 3368–3398, and references therein. (9) McDonald, F. E.; Reddy, K. S. J. Organomet. Chem. 2001, 617, 444–452. (10) Wipf, P.; Graham, T. H. J. Org. Chem. 2003, 68, 8798–8807. (11) Trost, B. M.; Rudd, M. T.; Costa, M. G.; Lee, P. I.; Pomerantz, A. E. Org. Lett. 2004, 6, 4235–4238. (12) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528– 2533. (13) K€ uc€ ukbay, H.; Cetinkaya, B.; Guesmi, S.; Dixneuf, P. H. Organometallics 1996, 15, 2434–2439. (14) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron 2003, 59, 6251–6259. (15) Kadota, I.; Lutete, L. M.; Shibuya, A.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6207–6210. (16) Cacchi, S. J. Organomet. Chem. 1999, 576, 42–64. (17) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845–1852. (18) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. Tetrahedron 1985, 41, 3655–3661. (19) Hartman, J. W.; Sperry, L. Tetrahedron Lett. 2004, 45, 3787– 3788. (20) Kataoka, Y.; Matsumoto, O.; Tani, K. Organometallics 1996, 15, 5246–5249. (21) (a) Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J. P. J. Am. Chem. Soc. 2005, 127, 9976–9977. (b) Hashmi, A. S. K.; Schaefer, S.; Woelfe, M.; Diez Gil, C.; Fischer, P.; Laguna, A.; Blanco, M. C.; Gimeno, M. C. Angew. Chem., Int. Ed. 2007, 46, 6184–6187. (22) Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998, 37, 1415–1418. (23) Kataoka, Y.; Matsumoto, O.; Tani, K. Chem. Lett. 1996, 727– 728. (24) Pale, P.; Chuche, J. Tetrahedron Lett. 1987, 28, 6447–6448. (25) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482– 7483. (26) Yoneda, E.; Sugioka, T.; Hirao, K.; Zhang, S. W.; Takahashi, S. J. Chem. Soc., Perkin Trans. 1 1998, 477–483. (27) Genin, E.; Antoniotti, S.; Michelet, V.; Gen^et, J. P. Angew. Chem., Int. Ed. 2005, 44, 4949–4953. (28) Nakagawa, H.; Okimoto, Y.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2003, 44, 103–106. (29) Masui, D.; Kochi, T.; Tang, Z.; Ishii, Y.; Mizobe, Y.; Hidai, M. J. Organomet. Chem. 2001, 620, 69–79. (30) Seo, S. Y.; Yu, X.; Marks, T. J. J. Am. Chem. Soc. 2009, 131, 263– 276.

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(and in some cases Rh) metal centers include rearrangement of the metal-bound reaction intermediate, forming a vinylidene complex, which undergoes nucleophilic attack by OH at the terminal alkyne carbon, generating only the endo-dig product (Figure 1b). McDonald and co-workers reported the use of Mo(CO)6 and W(CO)6 for the cycloisomerization of alkynols to endocyclic vinyl ethers via a metal vinylidene intermediate.31 They published the only computational studies for the cyclization of alkynols reported to date that showed that the endo-cyclization is kinetically favored when the reaction is metal-catalyzed. Mechanistic insights into Pt(II)- and Au(I)-catalyzed cycloisomerization reactions of internal alkynols were also reported by De Brabander and co-workers, who demonstrated the preferential formation of endocyclic products and suggested that the Hþ transfer step is ratelimiting and selectivity-determining.2f A further mechanistic possibility has been described by Marks and co-workers whereby organolanthanide complexes are effective catalysts for the primary and secondary cyclization of alkynols, forming exocyclic heterocycles via the insertion of CtC into Ln-O bonds.30 Significant advances in double hydroalkoxylation of alkyne diols have also been made, although the mechanism by which these two-step processes occur still remains unsolved. We have previously demonstrated the Rh/Ir(I)-catalyzed double hydroalkoxylation of alkynols for both internal and terminal alkynes with methanol, as well as alkyne diols, and undertaken mechanistic investigations.2a,b,32 We proposed a mechanism based on reaction intermediates observed using low-temperature NMR spectroscopy, as well as deuteration studies that indicated that the initial electrophilic activation of the alkyne is followed by the nucleophilic attack of the alcohol.2b Herein we present a computational study that defines the complete mechanism of Ir(I)-catalyzed double hydroalkoxylation of 4-pentyn-1-ol with methanol.

Results and Discussion Experimental Observations on the Ir-Catalyzed Cyclization of Alkynols to Form O,O-Acetals with Intermolecular Incorporation of an Alcohol. This computational study was based on the experimental Ir(I)-catalyzed double hydroalkoxylation studies described previously.2b Of a series of catalysts tested for the cyclization of 4-pentyn-1-ol (2) to form 2-methyl2-(4-pentynyloxy)-3,4,5-tetrahydrofuran (Scheme 1a) in chloroform solvent at 60 °C, the most efficient was found to be [Ir(PyP)(CO)2]þ, 1 (as the [BPh4]- salt, where PyP = 1-[2(diphenylphosphino)ethyl]pyrazole). When the catalyzed cyclization reactions of the alkynol substrate 2 were conducted in the presence of excess methanol (Scheme 1b), the cyclic acetal product resulting from incorporation of a molecule of methanol was formed. Both processes are consistent with an exocyclic vinyl ether intermediate formed via the first hydroalkoxylation (in parentheses, Scheme 1a). Deuterium labeling experiments were described previously,2b where the catalyzed cyclization of 2 was carried out in the presence of excess deuterated methanol (CD3OD, Scheme 1c). These experiments showed (i) a product with a doubly deuterated exocyclic methyl group where the deuterium (31) Sheng, Y.; Musaev, D. G.; Reddy, K. S.; McDonald, F. E.; Morokuma, K. J. Am. Chem. Soc. 2002, 124, 4149–4157. (32) Ho, J. H. H.; Hodgson, R.; Messerle, B. A.; Wagler, J. Dalton Trans. 2010, 39, 4062–4069.

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Scheme 1

labels must be derived from CD3OD and (ii) a product with a singly deuterated exocyclic methyl group that indicates a degree of retention of the hydroxyl proton of the 4-pentyn-1ol substrate. This latter result was confirmed by running the complementary labeling experiment, where reaction of HCt C(CH2)3OD in the presence of CH3OH led to observation of the deuterium label at the exocyclic methyl group (Scheme 1d). In addition, these labeling studies always exhibited some deuteration at the C3 position in the products. Preliminary Discussion: Is the Second Step Metal-Catalyzed? While it is clear that the initial cyclization of the double hydroalkoxylation reaction is metal-catalyzed, it is important to establish unequivocally that this is also the case for the second hydroalkoxylation. To probe this experimentally, the most direct approach would be to add methanol to the five-membered exocyclic vinyl ether intermediate, in the presence/absence of metal complex. The simple unsubstituted exocyclic vinyl ether ring system is, however, reported to be unstable.33 Marks and co-workers used Ln complexes to catalyze the synthesis of a range of exocyclic vinyl ethers, and, in this case, no further reaction with the alkynol starting material was observed.30,34 Similar results were observed with Au catalysts,33 suggesting that Au and Ln catalysts do not promote a second hydroalkoxylation step. We have previously shown that the Ir(I)-catalyzed addition of methanol to the endocyclic vinyl ether ring system—an isomer of the exocyclic vinyl ether ring system—is very efficient, and also using deuterium labeling showed that this process must be metal- and not Lewis acid-catalyzed.2b In recent work, we have demonstrated the use of mixed Ir(I) and Rh(I) catalysts for the formation of a series of bicyclic acetals and spiroketals.32 As a part of that study, we established that at high temperatures and in the presence of metal catalyst the formation of the bicyclic ring spiroketal system is reversible. Ho has also shown that at high temperature the bicyclic spiroketal ring system does not undergo isomeric exchange or return to starting material in the absence of catalyst.35 These results all indicate that the second step of the double hydroalkoxylation reaction is indeed metal-catalyzed. (33) Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2007, 48, 1439–1442. (34) Yu, X.; Seo, S. Y.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 7244–7245. (35) Ho J. H. H. Ph.D. Thesis, The University of New South Wales, Australia, 2010.

Figure 2. Proposed general mechanism for double hydroalkoxylation of 4-pentyn-1-ol with MeOH.

Computational Study. The computational study of the double-hydroalkoxylation reactions of 4-pentyn-1-ol (2) with MeOH catalyzed by [Ir(CO)2(PyP)]þ (1) was based on a modified version of the previously proposed catalytic cycle (see Figure 2).2b These reactions are performed in excess methanol (often as solvent), and so the organic reactant will be considered to be an H-bonded adduct of 2 and methanol (2.MeOH). Initial binding of 2.MeOH at 1 generates the five-coordinate alkyne complex, 3.MeOH. The first hydroalkoxylation then proceeds via ring closure through the intramolecular nucleophilic attack of the pendant hydroxy group at the C4 position. This generates an alkenyl intermediate, 4.MeOH, where the positive charge is formally located on the ring oxygen. The first hydroalkoxylation is then completed by Hþ transfer to give 5.MeOH, which features an endocyclic vinyl ether moiety bound to a formally cationic Ir metal center. The second hydroalkoxylation proceeds via MeOH attack, forming the second C-O bond and generating an Ir-hydride, 6, from which reductive elimination releases the O,O-acetal product and recycles the catalyst. As well as accounting for the double hydroalkoxylation process, any proposed mechanism must also be consistent with the experimental labeling studies, which indicate the partial incorporation of the alkynol OD label at the exocyclic methyl group, as well as H/D exchange at the C3 position (see Scheme 1). Calculations employed a model ligand, 1-[2-phosphinoethyl]pyrazole, PyP0 , where the Ph substituents of the PyP ligand were replaced by H. Even with this simplified model, each step in Figure 2 is complicated by the number of different isomers available for each intermediate. The conformational flexibility of the PyP0 ring and the bound organic moieties, as well as variations in the precise positioning and orientation of the external MeOH, exacerbates these difficulties. As a result, a number of pathways exist for each step that are often close in energy. We will therefore focus on the lowest energy routes and aim to highlight the general factors that promote reactivity. Alternative pathways will also be discussed when they provide extra insight; for example, the presence of MeOH as an external H-bond acceptor

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Figure 3. Computed reaction profiles (kcal/mol) for ring closure in 30 -MeOH. Selected distances are given in A˚.

significantly affects the energetics of several of the processes, and so comparison of the reactivities of 2.MeOH and 2 (in the absence of MeOH) is particularly relevant.36 Unless otherwise stated, energies are quoted relative to the combined energies of the separate reactants, 10 and 2.MeOH, where the prime indicates use of the simple PyP0 model ligand. 1. First Hydroalkoxylation. (i) Alkyne Binding and C-O Bond Formation via Ring Closure. The most stable form of 30 .MeOH, the five-coordinate species formed between 10 and 2.MeOH, is shown in Figure 3. This isomer (E = -25.0 kcal/ mol) exhibits a P-equatorial/N-axial (Peq-Nax) binding mode for the PyP0 ligand and an equatorial alkyne ligand lying parallel to the equatorial plane, a position that maximizes πback-donation from the Ir center.37 In addition, the terminal carbon (C5) is situated trans to CO, and the -(CH2)3OH.MeOH chain is directed toward the axial pyrazole. Other variations on this structure (i.e., with C5 trans to phosphine and/or the chain oriented to axial CO) all lie within 4 kcal/mol. 30 .MeOH also displays a strong H-bond between the alkynol and MeOH (H1 3 3 3 O2 = 1.79 A˚).38 Ring closure of 30 .MeOH proceeds via TS(30 -40 ).MeOH (E = -13.3 kcal/mol) and entails the approach of O1 toward C4 (O1 3 3 3 C4 = 2.07 A˚) and an elongation of the Ir 3 3 3 C4 distance to 3.01 A˚. The product formed, 40 .MeOH, has a trigonal-bipyramidal structure, with a Peq-Neq binding mode for the PyP0 chelate and the newly formed alkenyl ligand in an axial position. A lengthening of the C4-C5 bond from 1.28 A˚ to 1.36 A˚ is computed, consistent with doublebond character in 40 .MeOH, while rotation about the Ir-C5 bond also occurs such that the alkenyl group lies roughly parallel to the Ir-N axis (H5-C5-Ir-N = -10.1°). The new C4-O1 bond is rather long, at 1.54 A˚. Ring closure also induces a significant lengthening of the O1-H1 bond and a concomitant shortening of the H1 3 3 3 O2 interaction, in both the transition state (1.66 A˚) and, in particular, 40 .MeOH (1.41 A˚). Overall, ring closure in 30 .MeOH entails a barrier of 12.7 kcal/mol and is slightly endothermic (ΔE = þ5.7 kcal/ mol). (36) Under catalytic conditions relatively high concentrations of MeOH or 4-pentyn-1-ol would be expected to be present, and either could play the role of external alcohol. The choice of MeOH in this role is more convenient, as it maintains the same stoichiometry throughout the computational study. (37) Albright, T. A.; Hoffmann, R.; Thibeault, J. C.; Thorn, D. L. J. Am. Chem. Soc. 1979, 101, 3800–3812. (38) Two further geometric isomers of 30 .MeOH were located, again with an equatorial alkyne ligand but now with Pax-Neq or Peq-Neq PyP0 binding modes. The lowest energy forms of these species are 7 or 12 kcal/ mol, respectively, less stable than the structure shown in Figure 1 (see Supporting Information).

Figure 4. Schematic reaction profile for Hþ transfer in 40 in the absence of external MeOH (LnIr = [Ir(PyP0 )(CO)2], energies in kcal/mol and are quoted relative to species 10 and 2 set to zero).

To assess the stabilizing effect of the external H-bond to MeOH on the ring closure process, we recomputed this step with the MeOH-free model, 30 . In this case this process now entails a much larger barrier (ΔE‡ = 18.7 kcal/mol) and is significantly more endothermic (ΔE = þ18.2 kcal/mol).39 Moreover, the five-membered ring formed in the product, 40 , exhibits an even longer C4-O1 distance of 1.66 A˚, and this, along with the minimal barrier to the reverse ring-opening reaction, suggests that ring closure in the absence of external MeOH will be difficult. The role of external MeOH can be explained by the computed natural charges at O1. These see a reduction in negative charge during ring closure, which in turn makes H1 more δþ and hence a better H-bond donor to O2 (30 : qO1 = -0.77, qH1 = þ0.50; TS(30 -40 ): qO1 = -0.58, qH1 = þ0.55; 40 : qO1 = -0.56, qH1 = þ0.56). (ii) Proton Transfer. This step involves the net transfer of a proton from the ring oxygen (O1) in 40 .MeOH to the Irbound carbon (C5) to form intermediate 50 .MeOH (Figure 2). Experimental labeling studies of the double hydroalkoxylation of either 4-pentyn-1-ol with CD3OD or HCtC(CH2)3OD with MeOH suggest a degree of retention of the hydroxyl proton in the exocyclic methyl group of the O,O-acetal product (see Scheme 1). The calculations must therefore define competing mechanisms that are consistent with both label retention (i.e., transfer of H1 onto C5) and label exchange with solvent (modeled by H6 from external MeOH transferring onto C5 and H1 moving onto O2, i.e., net H1/H6 exchange). MeOH-Free Hþ Transfer. One route that would be consistent with label retention is an intramolecular Hþ transfer in 40 , in the absence of any external MeOH. This was shown (39) See the Supporting Information for details.

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Figure 5. Schematic reaction profiles for Hþ transfer in 40 .MeOH along pathways I, II, and III (LnIr = [Ir(PyP0 )(CO)2], relative energies in kcal/mol).

to involve sequential O1-C4 and C4-C5 [1,2]-H shifts (see Figure 4), and, although the overall formation of 50 is extremely favorable thermodynamically (ΔE = -47.6 kcal/mol), the high barrier of the first Hþ transfer step (ΔE‡ = 19.5 kcal/mol) means this process will not be kinetically competitive with alternative MeOH-assisted pathways (see below). This intramolecular route can therefore be ruled out in this case, although it is interesting to note that in the absence of solvents that facilitate Hþ transfer this step may be associated with significant barriers. MeOH-Assisted Hþ Transfer. A large number of pathways were considered for this process, which, in many cases, differed only subtly due to variations in the orientations of the external MeOH molecule or the alkenyl moiety, or in the conformation of the PyP0 ligand. We focus here on three pathways, I-III, that highlight the main factors affecting Hþ transfer and also incorporate the lowest energy H1 retention and H1/H6 exchange routes. These pathways are summarized in Figure 5 and are all based on 40 .MeOH, as shown in Figure 3; other isomers were also considered and showed similar behavior. For pathways I and II computed barriers to Hþ transfer were 14.2 and 4.0 kcal/mol, respectively, both significantly reduced compared to that found in the absence of methanol (ΔE‡ = 19.5 kcal/mol). The particularly low energy of pathway

II reflects the orientation of the methanol moiety in the transition state (TS(40 -50 ).MeOH (II), E = -15.4 kcal/mol, see Figure 6), which allows all potential H-bond donor groups to be saturated. This structure has short H1 3 3 3 O1 and H6 3 3 3 C5 contacts (both 1.75 A˚) and is much more stable than TS(40 -5 0 ).MeOH (I) (E = -2.8 kcal/mol), where H1 has short contacts to O1 and C5 (1.77 and 2.16 A˚, respectively), but H6 is completely exposed. Characterization of these transition states shows that pathway I proceeds with H1 retention, while pathway II is an H1/H6 exchange process. Exchange therefore appears favored; however, inclusion of a second methanol molecule H-bonded to H6 in pathway I halves the barrier to only 7 kcal/mol. Further solvation by methanol would presumably reduce this barrier even further, meaning that these exchange and retention pathways could well become competitive. In pathway III an alternative process occurs where H1 is again removed by external MeOH, but now H6 is initially transferred onto the metal center to generate an Ir-hydride intermediate, 4a0 .MeOH (III) (E = -36.3 kcal/mol). This proceeds via TS(40 -4a0 ).MeOH (III) (E = -15.4 kcal/mol), which features a short H1 3 3 3 O1 contact (1.51 A˚) and interaction of H6 with both C5 and Ir (H6 3 3 3 C5 = 2.16 A˚, H6 3 3 3 Ir = 2.48 A˚; see Figure 6). This network of stabilizing

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Figure 6. Rate-limiting transition states along Hþ transfer pathways I, II, and III. Relative energies are given in kcal/mol and selected distances in A˚.

Figure 7. Computed geometries for 50 .MeOH, formed along Hþ transfer pathways I, II, and III. Relative energies are given in kcal/ mol and selected distances in A˚.

interactions is consistent with a low activation barrier of 4.0 kcal/mol. Comparison of TS(40 -50 ).MeOH (II) and TS(40 -4a0 ).MeOH (III) suggests the key difference is an increase in the trans-N-Ir-C(O) angle, from 139.9° in TS(40 -50 ).MeOH (II) to 164.1° in TS(40 -4a0 ).MeOH (III) (see Figure 6). The sixth coordination site is therefore more available in the latter, and so Hþ transfer to Ir can occur. 4a0 .MeOH (III) retains a close Ir-H1 3 3 3 O2 contact of 2.09 A˚, and from this species two pathways were characterized for the formation of 50 MeOH: (i) a Hþ transfer process in which H1 is delivered to C5 (pathway IIIa via TS(4a0 50 ).MeOH (IIIa), E = -26.1 kcal/mol, overall H1 retention) and (ii) reductive elimination where H6 is transferred onto C5 (pathway IIIb via TS(4a0 -50 ).MeOH (IIIb), E = -25.7 kcal/mol, overall H1/H6 exchange). As both processes have a common rate-limiting step via TS(40 -4a0 ).MeOH (III) at -15.4 kcal/mol, they will be competitive, both with each other and with pathways I and II above. The three forms of 50 .MeOH produced are all very stable (E = -48 to -53 kcal/mol) and feature an exocyclic vinyl ether ligand (see Figure 7). 50 .MeOH (II) and 50 .MeOH (III) are most clearly trigonal bipyramidal with the vinyl ether binding as an η2-alkene, while in 50 .MeOH (I) this moiety appears less strongly bound with long Ir 3 3 3 C5 and Ir 3 3 3 C4 distances (2.38 and 2.89 A˚, respectively). Despite this, 50 .MeOH (I) is actually more stable than 50 .MeOH (II) and 50 .MeOH (III), and the accessibility of this type of geometry is found to be important in facilitating the second hydroalkoxylation step. A representative reaction profile for the first hydroalkoxylation is shown in Figure 8. C-O bond formation in 30 .MeOH to give 40 .MeOH is the rate-determining step

Figure 8. Schematic overall reaction profile for the first hydroalkoxylation of 4-pentyn-1-ol via 30 .MeOH (LnIr = [Ir(PyP0 )(CO)2], relative energies in kcal/mol).

(ΔE‡ = 12.7 kcal/mol), although this is greatly facilitated by the presence of MeOH as an H-bond acceptor. External MeOH also facilitates the subsequent Hþ transfer, which can occur via a number of low-energy, kinetically competitive mechanisms, resulting in either retention or solvent exchange of the original alkynol proton (in Figure 8 energetics are based on 40 .MeOH (II), which gives 50 .MeOH (II) with net Hþ exchange). 2. Second Hydroalkoxylation. (i) C-O Bond Formation and Reductive Elimination. This process involves the reaction of 50 .MeOH such that the O-H bond of methanol adds over the CdC double bond of the vinyl ether ligand to give the final O,O-acetal product and regenerate the catalyst [Ir(PyP0 )(CO)2]þ,

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Figure 9. Computed stationary points for hydroalkoxylation of 50 .MeOH (IV). Relative energies are given in kcal/mol and selected distances in A˚. Scheme 2

10 (see Scheme 2). Anti attack of MeOH at the face opposite the metal was found to involve prohibitively high activation barriers, whether via a direct [1,2]-addition (ΔE‡ > 50 kcal/mol) or after inclusion of a second MeOH molecule to facilitate this process via a proton chain transfer mechanism (ΔE‡ > 35 kcal/mol). Syn attack of MeOH proved to be far more accessible and was shown to involve a [3þ2] addition of the O-H bond over the {Ir-C5-C4} moiety to generate the new C-O bond and a metal hydrido-alkyl intermediate, 60 . The final products can then be formed via reductive elimination. The requirement for syn attack of MeOH in the second hydroalkoxylation means that the reactive forms of 50 .MeOH all adopt square-pyramidal geometries in which MeOH is oriented toward the vacant metal coordination site. We focus on one representative pathway in which the reactant, 50 .MeOH (IV), has MeOH trans to the pyrazole nitrogen and exhibits a significantly elongated Ir 3 3 3 C4 distance of 3.24 A˚ (see Figure 9). Computed natural charges also show that C4 in 50 .MeOH (IV) carries a large positive charge (þ0.55, cf., for example, þ0.29 in 50 .MeOH (II)). 50 .MeOH (IV) could therefore be

considered an Ir-alkyl complex with a formal positive charge at C4, with this site becoming highly susceptible to nucleophilic attack as a result. C-O bond formation proceeds through a five-membered cyclic transition state, TS(50 -60 ) 3 MeOH (IV) (E = -37.1 kcal/mol, ΔE‡ = 10.9 kcal/mol) and is accompanied by O2-H6 bond cleavage and delivery of the methanolic proton to the Ir center to generate the Ir hydridoalkyl, 60 (IV) (E = -49.5 kcal/mol). Reductive elimination from 60 (IV) occurs via TS(60 -10 ) (IV) with a barrier of 21.1 kcal/mol to give 10 and the O,Oacetal product. The transition state exhibits the expected features associated with C-H bond-forming reductive elimination, and the higher energy of TS(60 -10 ) (IV) compared to TS(50 -60 ).MeOH (IV) means that this step will be ratelimiting within the second hydroalkoxylation part of the cycle. Reductive elimination is favorable thermodynamically (ΔE = -12.4 kcal/mol) and so is likely to be irreversible. The overall reaction profile for the second hydroalkoxylation is summarized on the right-hand side of Figure 12. This also emphasizes that the overall double hydroalkoxylation of 4-pentyn-1-ol with MeOH to give the O,O-acetal product is a highly exothermic process (ΔE = -61.9 kcal/mol). (ii) H/D exchange at C3. Experimentally, the double hydroalkoxylation reactions of either 4-pentyn-1-ol in CD3OD or of HCC(CH2)3OD in MeOH both result in some incorporation of deuterium at the C3 position of the O,Oacetal product. We propose that this exchange occurs at intermediates of the type 50 .MeOH. These species readily undergo attack by methanol to give 60 , however, the low barrier and approximately thermoneutral nature of this step, coupled with the relatively large barrier for the subsequent reductive elimination suggest that species such as 50 .MeOH could be sufficiently long-lived to allow H/D exchange to occur. We have defined one mechanism that would account for this, involving a methanol-assisted C-H activation at the C3 position (see Figure 10).

Article

Figure 10. Postulated mechanism for H/D exchange at the C-3 position in 50 3 CD3OD (LnIr = [Ir(PyP0 )(CO)2]).

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Figure 11. Key stationary points for H/D exchange at the C3 position in 50 .MeOH (IV). Relative energies are given in kcal/ mol and selected distances in A˚.

Summary and Conclusions Starting from 50 .CD3 OD the C3-H3 bond is cleaved with H3 transfer to external CD 3 OD and concomitant Dþ transfer to the metal centre to give Ir-deuteride 70 .CD3 OH. Exchange of CD3OH with CD 3OD (which would be present in excess) then gives 7 0 .CD 3OD from which the reverse of the C-H activation step generates 50 .CD3OD with a deuterium now incorporated at the C3 position. This species can then undergo hydroalkoxylation to give the final labelled O,O-acetal product. This C3-H/D exchange mechanism has been computed for 50 .MeOH (IV), and key stationary points are given in Figure 11, while Figure 12 compares the energetics of exchange with the productive hydroalkoxylation reaction. C3-H3 activation occurs through TS(50 -70 ).MeOH (IV) (E = -33.2 kcal/mol) and gives intermediate 70 .MeOH (IV) (E = -40.4 kcal/mol), featuring a C3-C4 double bond (1.36 A˚). Importantly, this process is (i) more accessible than reductive elimination from 60 (IV) and (ii) will be reversible (the barrier for the re-formation of 50 .MeOH (IV) from 70 .MeOH (IV) being only 7.2 kcal/mol). Assuming facile MeOH exchange in 70 .MeOH (IV), this process readily accounts for H/D exchange at C3.

Density functional theory calculations have been employed to define the mechanism of double hydroalkoxylation of 4-pentyn-1-ol with methanol using an [Ir(PyP)(CO)2]þ catalyst. The first hydroalkoxylation proceeds by initial electrophilic activation of the alkyne at the metal center, which promotes nucleophilic attack by the pendant OH group at the C4 position. A number of low-energy and kinetically competitive pathways have been defined for the subsequent Hþ transfer step, which may occur with both retention of the original hydroxyl hydrogen and exchange with solvent. This is consistent with the results of experimental labeling studies. The energetics of both steps in the first hydroalkoxylation process are significantly lowered by the presence of external MeOH. In the key C-O bond forming cyclization, H-bonding between the alkynol and MeOH serves to stabilize the positive charge that develops at the hydroxyl proton upon ring closure. In addition, the participation of MeOH results in low barriers for Hþ transfer and formation of the cyclic vinyl ether intermediate. As a result, C-O bond formation corresponds to the rate-determining step in the first hydroalkoxylation (ΔE‡ = 12.7 kcal/ mol), and this process is found to be significantly thermodynamically favorable (ΔE ≈ -50 kcal/mol). A similar role

Figure 12. Computed reaction profiles for 50 .MeOH (IV): reversible H exchange at C3 vs hydroalkoxylation (LnIr = [Ir(PyP0 )(CO)], relative energies in kcal/mol).

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for external alcohol in promoting Hþ transfer reactions has been computed for the Au-catalyzed hydroalkoxylation of alkenes40 and allenes.41 The cyclic vinyl ether complexes produced in the first hydroalkoxylation can access a range of different structures where the cyclic vinyl ether moiety is bound either as an alkene at a formally cationic metal center or as an Ir-alkyl where the formal positive charge resides on the C4 position. These two structural forms are close in energy, and the accessibility of Ir-alkyl species proved crucial for the C-O bond formation step in the second hydroalkoxylation. This occurs via a syn attack of MeOH and results in a [3þ2] addition of the O-H bond over the {Ir-C5-C4} moiety to generate an Ir(III) hydrido-alkyl species. The final cyclic acetal product is then produced via rate-limiting reductive elimination with a barrier of 21.3 kcal/mol. The second hydroalkoxylation is an exothermic process by ca. 12 kcal/ mol, and the overall double hydroalkoxylation reaction is exothermic by 61.9 kcal/mol. The reversibility of the C-O bond forming step, coupled to the significant barrier to reductive elimination, means that the intermediate cyclic vinyl ether complexes may have significant lifetimes and hence may be implicated in an H/D exchange at the C3 position, evidence for which is seen in experimental labeling studies. One possible mechanism for this process has been defined, whereby MeOH acts as a proton shuttle, facilitating C-H bond activation at C3 via concomitant and reversible protonation of the Ir center.

Fjermestad et al. CHCl3 and MeOH via the PCM approach. The most significant effect was on the relative energies of all the H-bonded adducts, which are destabilized relative to the free reactants and MeOH by ca. 10 kcal/mol in CHCl3 and ca. 14 kcal/mol in MeOH. Computed activation energies, however, were less affected; for example, barriers for ring closure in 30 .MeOH, C-O bond formation in 50 .MeOH (IV), and reductive elimination in 60 (IV) all changed by less than 1.0 kcal/mol in both solvents. Somewhat more variation was seen in the Hþ transfer steps, with the largest change in barrier height being an increase of 3.3 kcal/ mol associated with TS(40 -4a0 ).MeOH (III) in MeOH. More importantly, the identity of the rate-limiting transition states for each of the hydroalkoxylation steps remains unchanged in both solvents. All computed energies are supplied in the Supporting Information, where relative energies computed in the gas phase, CHCl3, and MeOH are compared in Table S1. General Procedure for Catalysis. The experimental procedures for the catalyzed reactions discussed in this publication were described in two previous publications.2a,b The deuteration studies for this publication were carried out using the same general procedures. Specifically, the catalyzed cycloisomerization reactions of 4-pentyn-1-ol in the presence of excess methanol were conducted in NMR tubes fitted with a concentric Teflon valve. The catalyst complex, [Ir(PyP)(CO)2]BPh4 (5 mol %), was dissolved in freshly distilled chloroform (∼0.5-0.6 mL) in the NMR tube. Freshly distilled methanol (5-10-fold molar excess) was added by injection into the NMR tube before the addition of appropriately deuterated 4-pentyn-1-ol (27.0 mg, 0.317 mmol) to the mixture (Scheme 1). The catalytic reaction was performed at 25 to 35 °C in the NMR instrument. Characterization of the products was confirmed by comparison to literature data. Products from reaction Scheme 1d:

Experimental Section Computational Details. All DFT calculations were run with Gaussian 0342 using the BP86 functional. Ir and P centers were described with the Stuttgart RECPs and associated basis sets,43 with added d-orbital polarization on P.44 6-31G** basis sets were used for all other atoms.45 All stationary points were fully characterized via analytical frequency calculations as either minima (all positive eigenvalues) or transition states (one imaginary eigenvalue), and IRC calculations and subsequent geometry optimizations were used to confirm the minima linked by each transition state. Reported energies include a correction for zero-point energies. The role of general solvation was assessed by recomputing the energies of all stationary points in both (40) Kov acs, G.; Lled os, A.; Ujaque, G. Organometallics 2010, 29, 3252–3260. (41) Maseras, F.; Paton, R. S. Org. Lett. 2009, 11, 3352. (42) Frisch, M. J.; et al. et al. Gaussian 03, Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004. (43) Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H.; Preuss, H. Theor. Chim. Acta 1990, 77, 123–141. (44) H€ ollwarth, A.; B€ ohme, M.; Dapprich, S.; Ehlers, A. W.; Gobbi, A.; Jonas, V.; K€ ohler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. Chem. Phys. Lett. 1993, 208, 237–240. (45) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257–2261. (b) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–222.

H NMR (CHCl3, 76.8 MHz): δ 2.04 (t, J = 2.1 Hz, 1D, D3), 1.31 (apparent t, J = 2.0 Hz, 1D, CH2D).

2

Acknowledgment. This work was supported by the Australian Research Council, the University of New South Wales, and Heriot-Watt University. J.H.H.H. is grateful to the University of New South Wales for a University International Postgraduate Award (UIPA). Financial support by the Spanish Ministry of Science and Innovation (MICINN) (T.F.) and by Studienstiftung des Deutschen Volkes and DAAD (D.T.) is also gratefully acknowledged. Supporting Information Available: Computed Cartesian coordinates (A˚), SCF energies and enthalpies (0 and 298.15 K), and free energies (298.15 K, 1 atm) including solvent corrections (CHCl3 and MeOH) are supplied in atomic units for all stationary points including unique imaginary eigenvalues for all transition states. Full ref 42. This material is available free of charge via the Internet at http://pubs.acs.org.