Carolyn S. Higman

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty-Chemicals Manufacturing.

The recent uptake of molecular metathesis catalysts in specialty-chemicals and pharmaceutical manufacturing is reviewed.

Isomerization During Olefin Metathesis: An Assessment of Potential Catalyst Culprits

Two ruthenium hydride complexes commonly proposed as agents of unintended isomerization during olefin metathesis are examined for their activity in isomerization of estragole, a representative allylbenzene. Neither proves kinetically competent to account for the levels of isomerization observed during cross‐metathesis of estragole by the second‐generation Grubbs catalyst. A structure–activity analysis of selected ruthenium hydride complexes indicates that higher isomerization activity correlates with a more electrophilic metal center.

Tandem catalysis versus one-pot catalysis: ensuring process orthogonality in the transformation of essential-oil phenylpropenoids into high-value products via olefin isomerization–metathesis

Conversion of essential-oil allylbenzenes (phenylpropenoids) to high-value fine chemicals via isomerization–metathesis is reported. The target reaction sequence involves isomerization of ArCH2CHCH21 into the corresponding conjugated olefins 2, and ensuing cross-metathesis with acrylates to generate ArCHCHCO2R 3. The second-generation Hoveyda catalyst HII was chosen for the metathesis step. A range of lead candidates was assessed for the isomerization step, of which most active was the Grotjahn catalyst [CpRu(PN)(MeCN)]PF6 ([4]PF6; PN = 2-PiPr2-4-tBu-1-Me-imidazole). The following order of isomerization activity was determined, using the isomerization of estragole 1a to anethole 2a (Ar = p-MeOC6H4) as a probe reaction: [CpRu(PN)(MeCN)]PF6 > RuHCl(CO)(PPh3)3 > Ru(Me-allyl)2(COD) > Pd2Br2(PtBu3)2 > RuHCl(PPh3)3 > RuCl3(μ2-C)(μ2,κ1-C,η6-Mes-H2IMes)Ru(H)(H2IMes) (the “Grubbs hydride”) > RuHCl(CO)(H2IMes)(PCy3) > RuHCl(CO)(IMes)(PCy3) > RuHCl(CO)(PCy3)2. To maximize process efficiency, a systematic comparison of orthogonal tandem catalysis versus sequential catalyst addition was undertaken, using catalysts [4]PF6 and HII. The impact of each process type on product selectivity and catalyst compatibility was assessed. Selectivity was undermined in tandem isomerization–metathesis by competing metathesis of 1. Sequential catalyst addition eliminated this problem. The isomerization catalyst [4]PF6 adversely affected metathesis yields when equimolar with HII, an effect traced to the imidazole functionality in [4]PF6. However, at the low catalyst loadings required for efficient isomerization (0.1 mol% [4]PF6), negligible impact on metathesis yields was evident. The target cinnamates and ferrulates were obtained in quantitative yields by coupling these steps in a one-pot isomerization–metathesis protocol.

Unusually Strong Binding of Dinitrogen to a Ruthenium Center

Metal–dinitrogen complexes are of great interest for their potential to reduce energy costs in ammonia production, and to facilitate access to nitrogen-containing organic compounds. Many examples have been discovered since the 1965 report of [Ru(NH3)5(N2)] . Despite the prominence of iron systems in catalyzing the reduction of dinitrogen in industrial and biological contexts, 3, 5,6] and important recent advances in dinitrogen fixation by iron complexes, earlyand mid-transition metal complexes have shown greatest promise to date in cleaving the N N bond. 8–11] A benchmark was set by Yandulov and Schrock, who reported molybdenum triamidoamine derivatives, the first welldefined catalysts capable of selectively reducing N2 to ammonia. Late-metal complexes tend to be limited by the lower energy of their d orbitals (which impedes back-donation into the high-energy N N antibonding orbitals), 14] and high N2 lability. The latter has been identified as a key barrier to the development of late-metal catalysts for N2 activation. [2a] Herein we present an experimental and computational study that addresses this barrier. Our interest in the broad catalytic utility of hydridoruthenium complexes of N-heterocyclic carbene (NHC) ligands led us to a report from Morris and co-workers describing synthesis of the activated IMes complex 2 (Scheme 1a; IMes = N,N’-bis(mesityl)imidazol-2-ylidene) through the thermolysis of 1 with excess IMes under argon. We observed a very different reaction chemistry under an atmosphere of dinitrogen: P{H} NMR analysis indicated the formation of less than 10 % of 2 (59.35, 58.72 ppm; ABq, JPP = 13 Hz, THF), but considerable free PPh3 (Scheme 1b). The absence of any phosphine ligands in the major product 3 is evident from its null P{H} NMR spectrum, and from the singlet multiplicity of its hydride signal. This species could be obtained free of 2 by carrying out the reaction at room temperature, and was isolated as an orange powder in 75% yield by precipitation from hexanes. Single-crystal X-ray analysis of 3 indicated a mononuclear structure containing two mutually trans, unactivated IMes ligands (cf. the activated IMes group present in 2). While disorder impeded the initial assignment of the remaining ligands, we identified 3 as [RuHCl(IMes)2(N2)] by detailed NMR, IR, and MALDI-TOF mass spectrometric analysis. Refinement of the X-ray data with an appropriate disorder model yields a satisfactory solution. For both complexes in the unit cell, the N2 and Cl sites are disordered over two positions (as found for other structures containing Cl trans to N2); [18] in one, the hydride is also disordered over two positions. The excellent agreement between the model and the observed data provides unambiguous confirmation of connectivity, although the presence of the disorder limits the discussion of the metrical parameters. The upfield location of the H NMR singlet for the hydride ligand in 3 ( 28.03 ppm; C6D6) is clear evidence for a square pyramidal complex with apical hydride. Integration confirms the presence of two IMes ligands. Rotation of Ru CNHC and N Mes bonds is rapid on the NMR timescale at 22 8C, as deduced from the equivalence of the mesityl orthoCH3 groups (these resolve into four singlets at 0 8C). The retention of chloride is confirmed by charge-transfer MALDI-TOF mass spectrometry, which shows an excellent match between the simulated and observed isotope patterns for both [RuHCl(IMes)2(N2)+H] + (minor signal) and [RuCl(IMes)2 H]C (major signal). We initially ruled out the possibility that an N2 ligand occupied the fifth coordination site on the basis of reactions with CO described below, but revised this conclusion in light of the quantitative formation Scheme 1. Reaction of 1 with IMes under (a) Ar (12 h, THF, reflux); (b) N2 (20 h, reflux or RT). The ORTEP diagram for 3 [35] shows nonhydrogen atoms as Gaussian ellipsoids set at the 50% probability level.

Chelate-Assisted Ring-Closing Metathesis: A Strategy for Accelerating Macrocyclization at Ambient Temperatures

Ring-closing metathesis (RCM) offers versatile catalytic routes to macrocycles, with applications ranging from perfumery to production of antiviral drugs. Unwanted oligomerization, however, is a long-standing challenge. Oligomers can be converted into the cyclic targets by catalysts that are sufficiently reactive to promote backbiting (e.g., Ru complexes of N-heterocyclic carbenes; NHCs), but catalyst decomposition limits yields and selectivity. Incorporation of a hemilabile o-dianiline (ODA) chelate into new catalysts of the form RuCl2(NHC)(ODA)(=CHPh) accelerates macrocyclization, particularly for dienes bearing polar sites capable of H-bonding: it may also inhibit catalyst decomposition during metathesis. Significant improvements relative to prior Ru-NHC catalysts result, with fast macrocyclization of conformationally flexible dienes at room temperature.