2012 Theses Doctoral

(I) Zinc complexes as synthetic analogues for carbonic anhydrase and as catalysts for H₂ production and CO₂ functionalization . . .

Sattler, Wesley Ian

The multidentate alkyl ligand, [Tptm] ([Tptm] = tris(2-pyridylthio)methyl), provides an organometallic counterpart to the more common tripodal ligands, [Tp] ([Tp] = tris(pyrazolyl)hydroborato) and [Tm] ([Tm] = tris(2-mercaptoimidazolyl) hydroborato). A wide range of [Tptm] zinc complexes have been synthesized, enabling a diverse range of both stoichiometric and catalytic chemical transformations including the production of H₂ and the functionalization of CO₂.

The [Tptm] ligand has been used to isolate the first mononuclear alkyl zinc hydride complex, [κ³-Tptm]ZnH. The hydride complex may be easily synthesized on a multigram scale via reaction of the trimethylsiloxide complex, [κ⁴-Tptm]ZnOSiMe₃, with PhSiH₃. The hydride complex, [κ³-Tptm]ZnH, provides access to a variety of other [Tptm]ZnX derivatives. For example, [κ³-Tptm]ZnH reacts with (i) R₃SiOH (R = Me, Ph) to give [κ⁴-Tptm]ZnOSiR₃, (ii) Me₃SiX (X = Cl, Br, I) to give [κ⁴-Tptm]ZnX and (iii) CO2 to give the formate complex, [κ⁴-Tptm]ZnO2CH. [κ³-Tptm]ZnH is hydrolyzed to give the dimeric hydroxide complex, {[κ³-Tptm]Zn(μ–OH)}₂, which when treated with CO₂, results in the bicarbonate complex, [κ⁴-Tptm]ZnOCO₂H. The halide complexes, [κ⁴-Tptm]ZnX (X = Cl, Br, I), can be used to synthesize the fluoride complex, [κ⁴-Tptm]ZnF, via treatment with tetrabutylammonium fluoride (TBAF).

The bis(trimethylsilyl)amide complex, [κ³-Tptm]ZnN(SiMe₃)₂, which has been prepared directly via the reaction of [Tptm]H with [ZnN(SiMe₃)₂]₂, reacts with CO₂ to give the isocyanate complex, [κ⁴-Tptm]ZnNCO. The formation of the isocyanate complex results from a multistep sequence in which the initial step is insertion of CO₂ into the Zn-N(SiMe₃)₂ bond to give the carbamato derivative, [Tptm]Zn[O2CN(SiMe₃)₂], followed by rearrangement to [κ⁴-Tptm]ZnOSiMe₃ with the expulsion of Me₃SiNCO, which further reacts to give [κ⁴-Tptm]ZnNCO. An important discovery is that the rate of the final metathesis step, to give [κ⁴-Tptm]ZnNCO, is enhanced by CO₂. Specifically, insertion of CO₂ into the Zn-O bond of [κ⁴-Tptm]ZnOSiMe₃ gives the carbonate complex [κ⁴-Tptm]Zn[O₂COSiMe₃], which is more susceptible towards metathesis than is the siloxide derivative.

The [Tptm] ligand has also been effective for other metals, such as magnesium and nickel. While [Tptm] complexes of magnesium exhibit chemistry that is similar to that of zinc, the linear nickel nitrosyl complex, [κ³-Tptm]NiNO, shows diverse reactivity involving its nitrosyl ligand. For example, oxygenation of [κ³-Tptm]NiNO is reversible. The reaction of [κ³-Tptm]NiNO with air gives the paramagnetic nitrite complex, [κ⁴-Tptm]Ni[κ²-O₂N], the latter which may be deoxygenated via reaction with trimethylphosphine.

Additionally, the tetradentate alkyl ligand, tris(1-methyl-imidazol-2- ylthio)methyl, [TitmMe], has been studied as a comparison to the [Tptm] system. The bis(trimethylsilyl)amide complex, [κ³-TitmMe]ZnN(SiMe₃)₂ has been synthesized, and it also reacts with CO₂ to give the isocyanate complex, [κ⁴-TitmMe]ZnNCO.

The hydroxide complexes, [TpBut,Me]ZnOH ([TpBut,Me] = tris(3-t-butyl-5- methylpyrazolyl)hydroborato), and {[κ³-Tptm]Zn(μ–OH)}₂, were used to model transformations with CO2 that are of relevance to the mechanism of action of carbonic anhydrase. Low temperature ¹H and ¹³C NMR spectroscopic studies on solutions of the hydroxide complex, [Tpᴮᵘᵗ𝄒ᴹᵉ]ZnOH, in the presence of 1 atmosphere of CO₂ have allowed for the identification of the bicarbonate complex, [Tpᴮᵘᵗ𝄒ᴹᵉ]ZnOCO₂H. In the presence of less than 1 atmosphere of CO₂, both [Tpᴮᵘᵗ𝄒ᴹᵉ]ZnOH and [Tpᴮᵘᵗ𝄒ᴹᵉ]ZnOCO₂H may be observed in equilibrium, thereby allowing for the measurement of the equilibrium constant for insertion of CO₂ into the Zn–OH bond. At 217 K, the equilibrium constant is 6 ± 2 x 10³ M⁻¹, corresponding to a value of ΔG = –3.8 ± 0.2 kcal mol⁻¹. In addition to the solution-state spectroscopic studies, [Tpᴮᵘᵗ𝄒ᴹᵉ]ZnOCO₂H and [κ⁴-Tptm]ZnOCO₂H have been structurally characterized by X-ray diffraction, thereby providing the first examples of structurally characterized terminal zinc bicarbonate complexes. The bicarbonate complexes afford important metrical data of importance to the critical bicarbonate intermediate of the mechanism of action of carbonic anhydrase. The dimeric hydroxide complex, {[κ³-Tptm]Zn(μ–OH)}₂, is sufficiently reactive towards CO₂ that it is able to abstract CO₂ directly from air to form the bridging carbonate complex, [Tptm]Zn(μ-CO₃)Zn[Tptm]. Both the bicarbonate and carbonate complexes are reduced by silanes to give the formate derivative, [κ⁴-Tptm]ZnO₂CH, a transformation that is significant for the functionalization of CO₂.

The alkyl zinc hydride complex, [κ³-Tptm]ZnH, has also proven to be an effective and robust catalyst for a variety of transformations including (i) the rapid generation of hydrogen on demand, (ii) the hydrosilylation of aldehydes and ketones producing siloxanes and (iii) the functionalization of CO₂ to produce a useful formylating agent, (EtO)₃SiO₂CH. The trimethylsiloxide complex, [κ⁴-Tptm]ZnOSiMe₃, may also be used as an effective precatalyst for these reactions. For example, in the [κ⁴-Tptm]ZnOSiMe₃ catalyzed hydrolysis and methanolysis of PhSiH₃, three equivalents of H₂ are released, with the methanolysis reaction achieving 105 turnovers and turnover frequencies surpassing 106 h-1.

Additionally, [κ³-Bptm*]ZnO₂CH (Bptm* = bis(2-pyridylthio)(p-tolylthio)methyl) has been synthesized using the tridentate [Bptm*] ligand, which has only two chelating pyridyl arms, forbidding a κ⁴-coordination. It serves as a room temperature catalyst for the hydrosilylation of CO₂, resulting in more rapid CO₂ functionalization compared to the [Tptm] system. [κ³--Tptm]ZnH and [κ³--Bptm*]ZnO₂CH provide the first two examples of zinc complexes that catalyze the hydrosilylation of CO₂. These results provide evidence that, in suitable ligand environments, inexpensive and abundant nontransition metals can perform reactions that are typically catalyzed by precious metal-containing compounds.

The use of Li[Me₃SiNR] in order to generate an isocyanide complex from its carbonyl precursor provides a novel, convenient synthetic method that circumvents the use of the free isocyanide as a reagent. Metal isocyanide compounds are most commonly synthesized using the free isocyanide. By contrast, the reaction of transition metal carbonyl compounds, LnMCO, with Li[Me₃SiNR] yields the corresponding isocyanide derivative, LnMCNR. This reaction is driven by the cleavage of a weak silicon-nitrogen bond with concomitant formation of a stronger silicon-oxygen bond. Both sterically hindered and enantiopure isocyanide complexes have been synthesized.

Thimerosal, [(Arᶜᵒ²)SHgEt]Na, an organomercurial utilized since the 1930s as a topical antiseptic, and more recently as a vaccine preservative, previously was not structurally characterized. Therefore, the molecular structures have been determined for thimerosal, its protonated derivative, (Arᶜᵒ²ᴴ)SHgEt, and its mercurated derivative, [(Arᶜᵒ²ᴴᵍᴱᵗ)SHgEt]₂, using single crystal X-ray diffraction. ¹H NMR spectroscopic studies indicate that the appearance of the ¹⁹⁹Hg mercury satellites of the ethyl groups is highly dependent on the magnetic field and the viscosity of the solvent; this observation is attributed to relaxation caused by chemical shift anisotropy. The relative signs of the Hg-H coupling constants (i.e. ²JHg-H and ³JHg-H) have been determined by virtue of the fact that the inner pair of satellites appears as a singlet at 400 MHz. Reactivity studies involving (Arᶜᵒ²ᴴ)SHgEt provide evidence that the Hg-C bond is kinetically stable with respect to protolytic cleavage. Finally, a series of known dithiol compounds have been synthesized for use as mercury chelating agents.