Ivan Keresztes

Characterization of Reactive Intermediates by Multinuclear Diffusion-Ordered NMR Spectroscopy (DOSY)

Nuclear magnetic resonance (NMR) is the most powerful and widely utilized technique for determining molecular structure. Although traditional NMR data analysis involves the correlation of chemical shift, coupling constant, and NOE interactions to specific structural features, a largely overlooked method introduced more than 40 years ago, pulsed gradient spin-echo (PGSE), measures diffusion coefficients of molecules in solution, thus providing their relative particle sizes. In the early 1990s, the PGSE sequence was incorporated into a two-dimensional experiment, dubbed diffusion-ordered NMR spectroscopy (DOSY), in which one dimension represents chemical shift data while the second dimension resolves species by their diffusion properties. This combination provides a powerful tool for identifying individual species in a multicomponent solution, earning the nickname chromatography by NMR. In this Account, we describe our efforts to utilize DOSY techniques to characterize organometallic reactive intermediates in solution in order to correlate structural data to solid-state crystal structures determined by X-ray diffraction and to discover the role of aggregate formation and solvation states in reaction mechanisms. In 2000, we reported our initial efforts to employ DOSY techniques in the characterization of reactive intermediates such as organolithium aggregates. Since then, we have explored DOSY experiments with various nuclei beyond (1)H, including (6)Li, (7)Li, (11)B, (13)C, and (29)Si. Additionally, we proposed a diffusion coefficient-formula weight relationship to determine formula weight, aggregation number, and solvation state of reactive intermediates. We also introduced an internal reference system to correlate the diffusion properties of unknown reactive intermediates with known inert molecular standards, such as aromatic compounds, terminal olefins, cycloolefins, and tetraalkylsilanes. Furthermore, we utilized DOSY to interpret the role of aggregation number and solvation state of organometallic intermediates in the reactivity, kinetics, and mechanism of organic reactions. By utilizing multinuclear DOSY methodologies at various temperatures, we also correlated solid-state X-ray structures with those in solution and discovered new reactive complexes, including a monomeric boron enolate, a product-inhibition aggregate, and a series of intermediates in the vinyl lithiation of allyl amines. As highlighted by our efforts, DOSY techniques provide practical and feasible NMR procedures and hold the promise of even more powerful insights when extended to three-dimensional experiments.

Secondary alkene insertion and precision chain-walking: a new route to semicrystalline "polyethylene" from α-olefins by combining two rare catalytic events.

While traditional polymerization of linear α-olefins (LAOs) typically provides amorphous, low T(g) polymers, chain-straightening polymerization represents a route to semicrystalline materials. A series of α-diimine nickel catalysts were tested for the polymerization of various LAOs. Although known systems yielded amorphous or low-melting polymers, the sandwich α-diimines 3-6 yielded semicrystalline polyethylene comprised primarily of unbranched repeat units via a combination of uncommon regioselective 2,1-insertion and precision chain-walking events.

Evidence for Nonstatistical Dynamics in the Wolff Rearrangement of a Carbene

Two 13C-labeled isomers of the formal Diels−Alder adduct of acetylmethyloxirene to tetramethyl 1,2,4,5-benzenetetracarboxylate have been synthesized. Flash vacuum thermolysis of these adducts leads to various isotopic isomers of acetylmethylketene, the ratios of which have been determined by NMR. The surprising finding that the principal product comes from methylpyruvoyl carbene rather than its more stable isomer diacetylcarbene is explained by MPWB1K density functional calculations, which show that the reactant probably undergoes a unimolecular rearrangement to a norcaradiene derivative prior to its fragmentation. Coupled-cluster calculations on the methylpyruvoyl carbene show that it is capable of undergoing three unimolecular isomerizations. The fastest is 1,2-acetyl migration to give acetylmethylketene directly. The next is rearrangement via acetylmethyloxirene to diacetylcarbene and thence by Wolff rearrangement to acetylmethylketene. The least-favorable reaction is degenerate rearrangement via 1,3-dimethyl-2-oxabicyclo[1.1.0]butan-4-one (the epoxide of dimethylcyclopropenone). The combined experimental and computational results indicate that Wolff rearrangement of the diacetylcarbene occurs with a 2.5:1 ratio of the methyl groups despite the fact that they are related by a twofold axis of symmetry in the carbene. Preliminary molecular dynamics simulations are consistent with this conclusion. Taken together, the results suggest that the Wolff rearrangement is subject to the same kind of nonstatistical dynamical effects detected for other kinds of thermally generated reactive intermediates.

N2 hydrogenation from activated end-on bis(indenyl) zirconium dinitrogen complexes.

Sodium amalgam reduction of the bis(indenyl)zirconium dihalide complexes, (eta5-C9H5-1-iPr-3-Me)2ZrX2 (X = Cl, Br, I), yielded the corresponding end-on dinitrogen complexes, [(eta5-C9H5-1-iPr-3-Me)2Zr(NaX)]2(mu2, eta1, eta1-N2), with inclusion of 1 equiv of salt per zirconocene. The solid state structures of the chloro and iodo congeners establish short Zr N and elongated N N bonds, consistent with modest to strong activation of the coordinated dinitrogen molecule. Exposure of the N2 compounds to 1 atm of dihydrogen resulted in rapid N H bond formation to yield a hydrido zirconocene hydrazido compound concomitant with salt elimination. These studies establish a new structural type of zirconocene dinitrogen complex and demonstrate that side-on coordination of the N2 ligand in the ground state is not a prerequisite for dinitrogen hydrogenation.

Synthetic Approaches to (smif)2Ti (smif = 1,3-di-(2-pyridyl)-2-azaallyl) Reveal Redox Non-Innocence and C-C Bond-Formation

Attempted syntheses of (smif)(2)Ti (smif =1,3-di-(2-pyridyl)-2-azaallyl) based on metatheses of TiCl(n)L(m) (n = 2-4) with M(smif) (M = Li, Na), in the presence of a reducing agent (Na/Hg) when necessary, failed, but several apparent Ti(II) species were identified by X-ray crystallography and multidimensional NMR spectroscopy: (smif){Li(smif-smif)}Ti (1, X-ray), [(smif)Ti](2)(μ-κ(3),κ(3)-N,N(py)(2)-smif,smif) (2), (smif)Ti(κ(3)-N,N(py)(2)-smif,(smif)H) (3), and (smif)Ti(dpma) (4, dpma = di-2-pyridylmethyl-amide). NMR spectroscopy and K-edge XAS showed that each compound possesses ligands that are redox noninnnocent, such that d(1) Ti(III) centers AF-couple to ligand radicals: (smif){Li(smif-smif)(2-)}Ti(III) (1), [(smif(2-))Ti(III)](2)(μ-κ(3),κ(3)-N,N(py)(2)-smif,smif) (2), [(smif(2-))Ti(III)](κ(3)-N,N(py)(2)-smif,(smif)H) (3), and (smif(2-))Ti(III)(dpma) (4). The instability of (smif)(2)Ti relative to its C-C coupled dimer, 2, is rationalized via the complementary nature of the amide and smif radical dianion ligands, which are also common to 3 and 4. Calculations support this contention.

Enediolate–Dilithium Amide Mixed Aggregates in the Enantioselective Alkylation of Arylacetic Acids: Structural Studies and a Stereochemical Model

A combination of X-ray crystallography, (6)Li, (15)N, and (13)C NMR spectroscopies, and density functional theory computations affords insight into the structures and reactivities of intervening aggregates underlying highly selective asymmetric alkylations of carboxylic acid dianions (enediolates) mediated by the dilithium salt of a C2-symmetric chiral tetraamine. Crystallography shows a trilithiated n-butyllithium-dilithiated amide that has dimerized to a hexalithiated form. Spectroscopic studies implicate the non-dimerized trilithiated mixed aggregate. Reaction of the dilithiated amide with the dilithium enediolate derived from phenylacetic acid affords a tetralithio aggregate comprised of the two dianions in solution and the dimerized octalithio form in the solid state. Computational studies shed light on the details of the solution structures and afford a highly predictive stereochemical model.

Rapid synthesis of crowded aromatic architectures from silyl acetylenes.

Congested aromatic systems were prepared by benzannulating silyl-protected arylacetylenes. The silyl groups may be retained in the naphthalene products and transformed into iodides in high yield. The desirable attributes of this strategy, particularly its remarkable tolerance of sterically hindered alkynes, are showcased in the efficient synthesis of a congested, branched oligo(naphthalene). As such, benzannulations of diaryl and silyl-protected acetylenes show outstanding promise for accessing new aromatic architectures.

13 C NMR snapshots of the complex reaction coordinate of pyridoxal phosphate synthase

The predominant biosynthetic route to vitamin B6 is catalyzed by a single enzyme. The synthase subunit of this enzyme, Pdx1, operates in concert with the glutaminase subunit, Pdx2, to catalyze the complex condensation of ribose 5-phosphate, glutamine and glyceraldehyde 3-phosphate to form pyridoxal 5-phosphate, the active form of vitamin B6. In previous studies it became clear that many if not all of the reaction intermediates were covalently bound to the synthase subunit, thus making them difficult to isolate and characterize. Here we show that it is possible to follow a single turnover reaction by heteronuclear NMR using (13)C- and (15)N-labeled substrates as well as (15)N-labeled synthase. By denaturing the enzyme at points along the reaction coordinate, we solved the structures of three covalently bound intermediates. This analysis revealed a new 1,5 migration of the lysine amine linking the intermediate to the enzyme during the conversion of ribose 5-phosphate to pyridoxal 5-phosphate.

Synthesis of a 7-Azaindole by Chichibabin Cyclization: Reversible Base-Mediated Dimerization of 3-Picolines

The lithium diisopropylamide (LDA)-mediated condensation of 2-fluoro-3-picoline and benzonitrile to form 2-phenyl-7-azaindole via a Chichibabin cyclization is described. Facile dimerization of the picoline via a 1,4-addition of the incipient benzyllithium to the picoline starting material and fast 1,2-addition of LDA to benzonitrile cause the reaction to be complex. Both adducts are shown to reenter the reaction coordinate to produce the desired 7-azaindole. The solution structures of the key intermediates and the underlying reaction mechanisms are studied by a combination of IR and NMR spectroscopies.

Addition of Methyl Triflate to a Hafnocene Dinitrogen Complex: Stepwise N2 Methylation and Conversion to a Hafnocene Hydrazonato Compound

Treatment of the hafnocene complex bearing a strongly activated, side-on bound dinitrogen ligand, [(eta(5)-C(5)Me(4)H)(2)Hf](2)(mu(2),eta(2),eta(2)-N(2)), with two equivalents of methyl triflate yielded a mixture of products, one of which was identified as the triflato hafnocene methyl diazenide compound, (eta(5)-C(5)Me(4)H)(2)Hf(OTf)(N(2)(CH(3))), arising from methylation of one of the nitrogen atoms. This reactivity contrasts with that of the zirconocene congener, [(eta(5)-C(5)Me(4)H)(2)Zr](2)(mu(2),eta(2),eta(2)-N(2)), where methyl triflate addition yields a variety of products that lack new nitrogen-carbon bonds. The methylated hafnocene product, (eta(5)-C(5)Me(4)H)(2)Hf(OTf)(N(2)(CH(3))) provides a platform for additional transformations for the functionalized dinitrogen core. Treatment with additional methyl triflate results in a second nitrogen-carbon bond formation to yield a rare example of a triflato hafnocene hydrazonato complex. Loss of methane and formation of the hafnocene bis(triflate) accompany the transformation. Isotopic labeling studies and other experiments are consistent with a pathway involving initial methylation of the unsubstituted nitrogen in the methyl diazenido ligand followed by deprotonation by a triflate anion.