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Cationic Lewis acids (LAs) are gaining interest as targets for frustrated Lewis pair (FLP)-mediated catalysis. Unlike neutral boranes, which are the most prevalent LAs for FLP hydrogenations, the Lewis acidity of cations can be tuned through modulation of the counteranion; however, detailed studies on such anion effects are currently lacking in the literature. Herein, we present experimental and computational studies which probe the mechanism of H 2 activation using i Pr 3 SnOTf ( 1 -OTf) in conjunction with a coordinating (quinuclidine; qui) and noncoordinating (2,4,6-collidine; col) base and compare its reactivity with { i Pr 3 Sn·base}{Al[OC(CF 3 ) 3 ] 4 } (base = qui/col) systems which lack a coordinating anion to investigate the active species responsible for H 2 activation and hence resolve any mechanistic roles for OTf - in the i Pr 3 SnOTf-mediated pathway., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

We herein explore whether tris(aryl)borane Lewis acids are capable of cleaving H 2 outside of the usual Lewis acid/base chemistry described by the concept of frustrated Lewis pairs (FLPs). Instead of a Lewis base we use a chemical reductant to generate stable radical anions of two highly hindered boranes: tris(3,5-dinitromesityl)borane and tris(mesityl)borane. NMR spectroscopic characterization reveals that the corresponding borane radical anions activate (cleave) dihydrogen, whilst EPR spectroscopic characterization, supported by computational analysis, reveals the intermediates along the hydrogen activation pathway. This radical-based, redox pathway involves the homolytic cleavage of H 2 , in contrast to conventional models of FLP chemistry, which invoke a heterolytic cleavage pathway. This represents a new mode of chemical reactivity for hydrogen activation by borane Lewis acids., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Enantioselective reduction of ketimines was demonstrated using chiral N-heterocyclic carbene (NHC)-stabilised borenium ions in frustrated Lewis pair catalysis. High levels of enantioselectivity were achieved for substrates featuring secondary N-alkyl substituents. Comparative reactivity and mechanistic studies identify key determinants required to achieve useful enantioselectivity and represent a step forward in the further development of enantioselective FLP methodologies.

A range of amines catalyse the oxidative addition (OA) of H 2 to [(Me 3 Si) 2 CH] 2 Sn ( 1 ), forming [(Me 3 Si) 2 CH] 2 SnH 2 ( 2 ). Experimental and computational studies point to 'frustrated Lewis pair' mechanisms in which 1 acts as a Lewis acid and involve unusual late transition states; this is supported by the observation of a kinetic isotope effect for Et 3 N. When DBU is used the energetics of H 2 activation are altered, allowing an equilibrium between 1 , 2 and adduct [ 1 ·DBU] to be established, thus demonstrating reversible oxidative addition/reductive elimination (RE) of H 2 at a single main group centre.

The catalytic conversion of N 2 to N(SiMe 3 ) 3 by homogeneous transition metal compounds is a rapidly developing field, yet few mechanistic details have been experimentally elucidated for 3 d element catalysts. Herein we show that Fe(PP) 2 (N 2 ) (PP = R 2 PCH 2 CH 2 PR 2 ; R = Me, 1 Me ; R = Et, 1 Et ) are highly effective for the catalytic production of N(SiMe 3 ) 3 from N 2 (using KC 8 /Me 3 SiCl), with the yields being the highest reported to date for Fe-based catalysts. We propose that N 2 fixation proceeds via electrophilic N β silylation and 1e - reduction to form unstable Fe I (NN-SiMe 3 ) intermediates, which disproportionate to 1 Me/Et and hydrazido Fe II [N-N(SiMe 3 ) 2 ] species (3 Me/Et ); the latter act as resting states on the catalytic cycle. Subsequent 2e - reduction of 3 Me/Et leads to N-N scission and formation of [N(SiMe 3 ) 2 ] - and putative anionic Fe imido products. These mechanistic results are supported by both experiment and DFT calculations.

The synthesis and characterisation of the S = 1/2 Fe(i) complex [Fe(depe) 2 ] + [BArF4] - ([ 1 ] + [BArF4] - ), and the facile reversible binding of N 2 and H 2 in both solution and the solid state to form the adducts [ 1 ·N 2 ] + and [ 1 ·H 2 ] + , are reported. Coordination of N 2 in THF is thermodynamically favourable under ambient conditions (1 atm; Δ G 298 = -4.9(1) kcal mol -1 ), while heterogenous binding is more favourable for H 2 than N 2 by a factor of ∼300. [ 1 ·H 2 ] + [BArF4] - represents a rare example of a well-defined, open-shell, non-classical dihydrogen complex, as corroborated by ESR spectroscopy. The rapid exchange between N 2 and H 2 coordination under ambient conditions is unique for a paramagnetic Fe complex.

Despite the ever-broadening applications of main-group 'frustrated Lewis pair' (FLP) chemistry to both new and established reactions, their typical intolerance of water, especially at elevated temperatures (>100 °C), represents a key barrier to their mainstream adoption. Herein we report that FLPs based on the Lewis acid i Pr 3 SnOTf are moisture tolerant in the presence of moderately strong nitrogenous bases, even under high temperature regimes, allowing them to operate as simple and effective catalysts for the reductive amination of organic carbonyls, including for challenging bulky amine and carbonyl substrate partners.

The past decade has seen the subject of transition metal-free catalytic hydrogenation develop incredibly rapidly, transforming from a largely hypothetical possibility to a well-established field that can be applied to the reduction of a diverse variety of functional groups under mild conditions. This remarkable change is principally attributable to the development of so-called 'frustrated Lewis pairs': unquenched combinations of bulky Lewis acids and bases whose dual reactivity can be exploited for the facile activation of otherwise inert chemical bonds. While a number of comprehensive reviews into frustrated Lewis pair chemistry have been published in recent years, this tutorial review aims to provide a focused guide to the development of efficient FLP hydrogenation catalysts, through identification and consideration of the key factors that govern their effectiveness. Following discussion of these factors, their importance will be illustrated using a case study from our own research, namely the development of FLP protocols for successful hydrogenation of aldehydes and ketones, and for related moisture-tolerant hydrogenation.

Over the last decade there has been an explosion in the reactivity and applications of frustrated Lewis pair (FLP) chemistry. Despite this, the Lewis acids (LAs) in these transformations are often boranes, with heavier p -block elements receiving surprisingly little attention. The novel LA Bn 3 SnOTf ( 1 ) has been synthesized from simple, inexpensive starting materials and has been spectroscopically and structurally characterized. Subtle modulation of the electronics at the tin centre has led to an increase in its Lewis acidity in comparison with previously reported R 3 SnOTf LAs, and has facilitated low temperature hydrogen activation and imine hydrogenation. Deactivation pathways of the R 3 Sn + LA core have also been investigated.This article is part of the themed issue 'Frustrated Lewis pair chemistry'., (© 2017 The Authors.)

The first cationic Fe silyldiazenido complexes, [Fe(PP) 2 (NN-SiMe 3 )] + [BAr F 4 ] - (PP = dmpe/depe), have been synthesised and thoroughly characterised. Computational studies show the compounds to be useful structural and electronic surrogates for the more elusive [Fe(PP) 2 (NN-H)] + , which are postulated intermediates in the H + /e - mediated fixation of N 2 by Fe(PP) 2 (N 2 ) species.

Despite the rapid development of frustrated Lewis pair (FLP) chemistry over the last ten years, its application in catalytic hydrogenations remains dependent on a narrow family of structurally similar early main-group Lewis acids (LAs), inevitably placing limitations on reactivity, sensitivity and substrate scope. Herein we describe the FLP-mediated H 2 activation and catalytic hydrogenation activity of the alternative LA iPr 3 SnOTf, which acts as a surrogate for the trialkylstannylium ion iPr 3 Sn + , and is rapidly and easily prepared from simple, inexpensive starting materials. This highly thermally robust LA is found to be competent in the hydrogenation of a number of different unsaturated functional groups (which is unique to date for main-group FLP LAs not based on boron), and also displays a remarkable tolerance to moisture., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The catalytic fixation of N 2 by molecular Fe compounds is a rapidly developing field, yet thus far few complexes can effect this transformation, and none are selective for N 2 H 4 production. Herein we report that the simple Fe(0) complex Fe(Et 2 PCH 2 CH 2 PEt 2 ) 2 (N 2 ) (1) is an efficient catalyst for the selective conversion of N 2 (>25 molecules N 2 fixed) into N 2 H 4 , attendant with the production of ca. one molecule of NH 3 . Notably, the reductant (CoCp* 2 ) and acid (Ph 2 NH 2 OTf) used are considerably weaker than conventional chemical H + and e - sources used in previous demonstrations of N 2 turnover by synthetic Fe compounds. These results show that the direct catalytic conversion of N 2 to the hydrazine oxidation state on molecular Fe complexes is viable and that the mechanism of NH 3 formation by such systems may proceed via Fe-N 2 H 4 intermediates.

The Fe(0) species Fe(N2)(dmpe)2 exists in equilibrium with the previously unreported dimer, [Fe(dmpe2)2(μ-N2)]. For the first time these complexes, alongside Fe(N2)(depe)2, are shown unambiguously to produce N2H4 and/or NH3 upon addition of triflic acid; for Fe(N2)(depe)2 this represents one of the highest electron conversion efficiencies for Fe complexes to date.

Three structural isomers of tris{bis(trifluoromethyl)phenyl}borane have been studied as the acidic component of frustrated Lewis pairs. While the 3,5-substituted isomer is already known to heterolytically cleave H2 to generate a bridging-hydride; ortho-substituents in the 2,4- and 2,5-isomers quench such reactivity through electron donation into the vacant boron pz orbital and steric blocking of the boron centre; as shown by electrochemical, structural and computational studies. Electrochemical studies of the corresponding borohydrides identify that the two-electron oxidation of terminal-hydrides occurs at more positive potentials than observed for [HB(C6F5)3](-), while the bridging-hydride oxidizes at a higher potential still, comparable to that of free H2.

We describe the synthesis, structure and bonding of the first iridium and rhodium permethylpentalene complexes, syn-[M(CO)2]2(μ:η(5):η(5)-Pn*) (M = Rh, Ir). In fact, [Ir(CO)2]2(μ:η(5):η(5)-Pn*) is the first iridium pentalene complex. An interesting preference for the isolation of the sterically more demanding syn-isomer is observed and substantiated by DFT analysis. Upon photolysis, the rhodium analogue yields an unusual tetrameric species Rh4(CO)6(μ:η(3):η(5)-Pn*)2 with bridging carbonyls and Rh-Rh bonds, which has been characterised by single crystal X-ray diffraction and by solution NMR spectroscopy.

Despite rapid advances in the field of metal-free, "frustrated Lewis pair" (FLP)-catalyzed hydrogenation, the need for strictly anhydrous reaction conditions has hampered wide-scale uptake of this methodology. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solutions of B(C 6 F 5 ) 3 actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in commercially available nonanhydrous solvents without subsequent drying or use of internal desiccants.

The novel 14 electron species η(8)-Pn*TiR2 (Pn* = C8Me6; R = Me, CH2Ph) have been synthesised and spectroscopically and structurally characterised. Subsequent reaction with CO2 leads to the activation and double insertion of CO2 into both Ti-alkyl bonds to form the electronically saturated η(8)-Pn*Ti(κ(2)-O2CR)2 (R = Me, CH2Ph) complexes.

The electron-deficient and sterically bulky trialkylborane derivative tris[bis(pentafluorophenyl)methyl]borane [1, B(CH(C6F5)2)3], has been synthesised and comprehensively characterised; detailed (1)H and (19)F NMR studies reveal two dynamic bond rotational processes in the solution phase. Despite conventional probes (Gutmann-Beckett and Childs methods) implying that the compound has a very limited Lewis acidity, it was used to generate frustrated Lewis pairs capable of heterolytically activating H2 in ethereal solutions, which suggests that the hydridophilicity of 1 is comparable to the potent Lewis acid B(C6F5)3.

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Herein, we extend our "combined electrochemical-frustrated Lewis pair" approach to include Pt electrode surfaces for the first time. We found that the voltammetric response of an electrochemical-frustrated Lewis pair (FLP) system involving the B(C6 F5 )3 /[HB(C6 F5 )3 ](-) redox couple exhibits a strong surface electrocatalytic effect at Pt electrodes. Using a combination of kinetic competition studies in the presence of a H atom scavenger, 6-bromohexene, and by changing the steric bulk of the Lewis acid borane catalyst from B(C6 F5 )3 to B(C6 Cl5 )3 , the mechanism of electrochemical-FLP reactions on Pt surfaces was shown to be dominated by hydrogen-atom transfer (HAT) between Pt, [PtH] adatoms and transient [HB(C6 F5 )3 ](⋅) electrooxidation intermediates. These findings provide further insight into this new area of combining electrochemical and FLP reactions, and proffers additional avenues for exploration beyond energy generation, such as in electrosynthesis., (© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Solutions of the Lewis acid B(C6F5)3 in 1,4-dioxane are found to effectively catalyze the hydrogenation of a variety of ketones and aldehydes. These reactions, the first to allow entirely metal-free catalytic hydrogenation of carbonyl groups under relatively mild reaction conditions, are found to proceed via a "frustrated Lewis pair" mechanism in which the solvent, a weak Brønsted base yet moderately strong donor, plays a pivotal role.

The thermally robust silylium complex [iPr3Si-PtBu3](+)[B(C6F5)4](-) (1) activates H2/D2 at 90 °C (PhCl); no evidence for dissociation into the separated Lewis pair is found. DFT calculations show H2 cleavage proceeds via Si-P bond elongation to form an encounter complex directly from the adduct, thus avoiding the non-isolable iPr3Si(+)-PtBu3 FLP.

In recent years 'frustrated Lewis pairs' (FLPs) have been shown to be effective metal-free catalysts for the hydrogenation of many unsaturated substrates. Even so, limited functional-group tolerance restricts the range of solvents in which FLP-mediated reactions can be performed, with all FLP-mediated hydrogenations reported to date carried out in non-donor hydrocarbon or chlorinated solvents. Herein we report that the bulky Lewis acids B(C6Cl5)x(C6F5)(3-x) (x=0-3) are capable of heterolytic H2 activation in the strong-donor solvent THF, in the absence of any additional Lewis base. This allows metal-free catalytic hydrogenations to be performed in donor solvent media under mild conditions; these systems are particularly effective for the hydrogenation of weakly basic substrates, including the first examples of metal-free catalytic hydrogenation of furan heterocycles. The air-stability of the most effective borane, B(C6Cl5)(C6F5)2, makes this a practically simple reaction method., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In order to use H2 as a clean source of electricity, prohibitively rare and expensive precious metal electrocatalysts, such as Pt, are often used to overcome the large oxidative voltage required to convert H2 into 2 H(+) and 2 e(-). Herein, we report a metal-free approach to catalyze the oxidation of H2 by combining the ability of frustrated Lewis pairs (FLPs) to heterolytically cleave H2 with the in situ electrochemical oxidation of the resulting borohydride. The use of the NHC-stabilized borenium cation [(IiPr2)(BC8H14)](+) (IiPr2=C3H2(NiPr)2, NHC=N-heterocyclic carbene) as the Lewis acidic component of the FLP is shown to decrease the voltage required for H2 oxidation by 910 mV at inexpensive carbon electrodes, a significant energy saving equivalent to 175.6 kJ mol(-1). The NHC-borenium Lewis acid also offers improved catalyst recyclability and chemical stability compared to B(C6F5)3, the paradigm Lewis acid originally used to pioneer our combined electrochemical/frustrated Lewis pair approach., (© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Frustrated Lewis pairs have found many applications in the heterolytic activation of H2 and subsequent hydrogenation of small molecules through delivery of the resulting proton and hydride equivalents. Herein, we describe how H2 can be preactivated using classical frustrated Lewis pair chemistry and combined with in situ nonaqueous electrochemical oxidation of the resulting borohydride. Our approach allows hydrogen to be cleanly converted into two protons and two electrons in situ, and reduces the potential (the required energetic driving force) for nonaqueous H2 oxidation by 610 mV (117.7 kJ mol(-1)). This significant energy reduction opens routes to the development of nonaqueous hydrogen energy technology.

1,2-Bis(dialkylphosphino)ethanes are readily prepared from the parent phosphine oxides, via a novel sodium aluminium hydride/sodium hydride reduction protocol of intermediate chlorophosphonium chlorides. This approach is amenable to multi-gram syntheses, utilises readily available and inexpensive reagents, and benefits from a facile non-aqueous work-up in the final reductive step.

The product of the intermolecular 'frustrated Lewis pair' (FLP) B(C6F5)2(C6Cl5)/2,2,6,6-tetramethylpiperidine and H2 has been studied by single-crystal neutron diffraction. This is the first structurally characterised example of a geometrically unconstrained dihydrogen (H···H) bond within a hydrogenated FLP system.

We report a kinetic and mechanistic study into the one-electron reduction of the archetypal Lewis acid tris(pentafluorophenyl)borane, B(C(6)F(5))(3), in dichloromethane and 1,2-difluorobenzene. Electrochemical experiments, combined with digital simulations, DFT computational studies and multinuclear NMR analysis allow us to obtain thermodynamic, kinetic and mechanistic information relating to the redox activity of B(C(6)F(5))(3). We show that tris(pentafluorophenyl)borane undergoes a quasi-reversible one-electron reduction followed by rapid chemical decomposition of the B(C(6)F(5))(3)˙(-) radical anion intermediate via a solvolytic radical pathway. The reaction products form various four-coordinate borates of which [B(C(6)F(5))(4)](-) is a very minor product. The rate of the follow-up chemical step has a pseudo-first order rate constant of the order of 6 s(-1). This value is three orders of magnitude larger than that found in previous studies performed in the donor solvent, tetrahydrofuran. The standard reduction potential of B(C(6)F(5))(3) is reported for the first time as -1.79 ± 0.1 V and -1.65 ± 0.1 V vs. ferrocene/ferrocenium in dichloromethane and 1,2-difluorobenzene respectively.

This chapter reviews the published work to date on the interaction of CO2 and CO with frustrated Lewis pairs (FLPs). The ability of FLP-derived systems reversibly to bind and release CO2 is a dramatic and exciting development, offering new routes to sequester this environmentally important molecule. Furthermore, in combination with FLPs' documented ability to cleave H2 heterolytically, new CO2 hydrogenation chemistry has been uncovered. Novel tandem catalytic processes involving FLPs are beginning to be developed which allow the chemical functionalisation of CO2. Structure-function relationships which affect the thermal stability of FLP-CO2 adducts are highlighted, alongside an insight towards the future design of successful FLP-mediated CO2 hydrogenation catalysts.

Tris[3,5-bis(trifluoromethyl)phenyl]borane (1, BArF(18)), has been synthesised on a practical scale for the first time. According to the Gutmann-Beckett method it is a more powerful Lewis acid than B(C(6)F(5))(3). It forms a 'frustrated Lewis pair' with 2,2,6,6-tetramethylpiperidine which cleaves H(2) to form a salt containing the novel anion [μ-H(BArF(18))(2)](-).

A new family of electron-deficient tris(aryl)boranes, B(C(6)F(5))(3-n)(C(6)Cl(5))(n) (n = 1-3), has been synthesized, permitting an investigation into the steric and electronic effects resulting from the gradual replacement of C(6)F(5) with C(6)Cl(5) ligands. B(C(6)F(5))(2)(C(6)Cl(5)) (3) is accessed via C(6)Cl(5)BBr(2), itself prepared from donor-free Zn(C(6)Cl(5))(2) and BBr(3). Reaction of C(6)Cl(5)Li with BCl(3) in a Et(2)O/hexane slurry selectively produced B(C(6)Cl(5))(2)Cl, which undergoes B-Cl exchange with CuC(6)F(5) to afford B(C(6)F(5))(C(6)Cl(5))(2) (5). While 3 forms a complex with H(2)O, which can be rapidly removed under vacuum or in the presence of molecular sieves, B(C(6)Cl(5))(3) (6) is completely stable to refluxing toluene/H(2)O for several days. Compounds 3, 5, and 6 have been structurally characterized using single crystal X-ray diffraction and represent the first structure determinations for compounds featuring B-C(6)Cl(5) bonds; each exhibits a trigonal planar geometry about B, despite having different ligand sets. The spectroscopic characterization using (11)B, (19)F, and (13)C NMR indicates that the boron center becomes more electron-deficient as n increases. Optimized structures of B(C(6)F(5))(3-n)(C(6)Cl(5))(n) (n = 0-3) using density functional theory (B3LYP/TZVP) are all fully consistent with the experimental structural data. Computed (11)B shielding constants also replicate the experimental trend almost quantitatively, and the computed natural charges on the boron center increase in the order n = 0 (0.81) < n = 1 (0.89) < n = 2 (1.02) < n = 3 (1.16), supporting the hypothesis that electrophilicity increases concomitantly with substitution of C(6)F(5) for C(6)Cl(5). The direct solution cyclic voltammetry of B(C(6)F(5))(3) has been obtained for the first time and electrochemical measurements upon the entire series B(C(6)F(5))(3-n)(C(6)Cl(5))(n) (n = 0-3) corroborate the spectroscopic data, revealing C(6)Cl(5) to be a more electron-withdrawing group than C(6)F(5), with a ca. +200 mV shift observed in the reduction potential per C(6)F(5) group replaced. Conversely, use of the Guttmann-Beckett and Childs' methods to determine Lewis acidity on B(C(6)F(5))(3), 3, and 5 showed this property to diminish with increasing C(6)Cl(5) content, which is attributed to the steric effects of the bulky C(6)Cl(5) substituents. This conflict is ascribed to the minimal structural reorganization in the radical anions upon reduction during cyclic voltammetric experiments. Reduction of 6 using Na((s)) in THF results in a vivid blue paramagnetic solution of Na(+) [6](•-); the EPR signal of Na(+)[6](•-) is centered at g = 2.002 with a((11)B) 10G. Measurements of the exponential decay of the EPR signal (298 K) reveal [6](•-) to be considerably more stable than its perfluoro analogue.

The synthesis of the bimetallic permethylpentalene complexes Pn*2M2 (M = V, Cr, Mn, Co, Ni; Pn* = C8Me6) has been accomplished, and all of the complexes have been structurally characterized in the solid state by single-crystal X-ray diffraction. Pn*2V2 (1) and Pn*2Mn2 (3) show very short intermetallic distances that are consistent with metal-metal bonding, while the cobalt centers in Pn*2Co2 (4) exhibit differential bonding to each side of the Pn* ligand that is consistent with an eta(5):eta(3) formulation. The Pn* ligands in Pn*2Ni2 (5) are best described as eta(3):eta(3)-bonded to the metal centers. (1)H NMR studies indicate that all of the Pn*2M2 species exhibit D(2h) molecular symmetry in the solution phase; the temperature variation of the chemical shifts for the resonances of Pn*2Cr2 (2) indicates that the molecule has an S = 0 ground state and a thermally populated S = 1 excited state and can be successfully modeled using a Boltzmann distribution (DeltaH(o) = 14.9 kJ mol(-1) and DeltaS(o) = 26.5 J K(-1) mol(-1)). The solid-state molar magnetic susceptibility of 3 obeys the Curie-Weiss law with mu(eff) = 2.78 muB and theta = -1.0 K; the complex is best described as having an S = 1 electronic ground state over the temperature range 4-300 K. Paradoxically, attempts to isolate the "double ferrocene" equivalent, Pn*2Fe2, led only to the isolation of the permethylpentalene dimer Pn*2 (6). Solution electrochemical studies were performed on all of the organometallic compounds; 2-5 exhibit multiple quasi-reversible redox processes. Density functional theory calculations were performed on this series of complexes in order to rationalize the observed structural and spectroscopic data and provide estimates of the M-M bond orders.

Novel permethylated pentalenide anions are reported which offer exciting new opportunities for the future development of organometallic pentalene chemistry.

We applied sib-pair and association methods to a GAW data set of nuclear families with quantitative traits. Our approaches included 1) preliminary statistical studies including correlations and linear regressions, 2) sib-pair methods, and 3) association studies. We used a single data set to screen for linkage and association and, subsequently, additional data sets to confirm the preliminary results. Using this sequential approach, sib-pair analysis provided evidence for the genes influencing Q1, Q2, and Q4. We correctly predicted MG1 for Q1, MG2 for Q2, and MG4 for Q4. We did not find any false positives using this approach. Association studies identified chromosomes 8 and 9 to be associated with Q4; however these are assumed to be false positives as no associations were modeled into the data.

To better define the nature of FMR1 CGG-repeat expansions, changes in allele sizes for 191 families with fragile X and for 33 families with gray-zone repeats (40-60) were analyzed. Expansion of the fragile X chromosome to the full mutation was seen in 13.4% of offspring from premutation mothers with 56-59 repeats, 20.6% of those with 60-69 repeats, 57.8% of those with 70-79 repeats, 72.9% of those with 80-89 repeats, and 97.3% of those with 90-199 repeats. For premutation fathers, the majority (62%) of their daughters had a larger repeat number, while a few had either a smaller (22%) or the same (16%) repeat number, compared with their fathers' sizes. However, daughters with a smaller repeat number were observed only if their fathers had > or = 80 repeats. Fifteen (39.5%) of 38 such daughters carried a smaller repeat than did their fathers. We observed that a similar repeat number was inherited more often than expected by chance, among the members of a sibship segregating fragile X. This familial clustering, observed in the offspring of both males and females with a premutation, implies there may be an additional factor, independent of parental repeat size, that influences CGG-repeat instability. Instability in gray-zone allele transmissions was observed in 25% of alleles with 50-60 CGGs but in <8% of those with 40-49 CGGs. Examination of gray-zone allele organization revealed that long tracts of pure CGGs (>34) are not always unstably transmitted. These results raise new questions regarding the familial factors that may determine transmission expansions.

The Collaborative Prospective Fragile X Study was established to collect information on the pregnancy outcome of women known to be carriers of the fragile X syndrome. The prospective design of this study allows collection of ascertainment-free data and, thereby, avoids biases caused by sampling problems encountered in retrospective family studies. The results of 337 submitted cases are summarized. These data show that the segregation of the fragile X mutation is normal and the sex ratio of conceptuses is as expected for a prenatal sample. There is no excess of dizygotic twinning among the pre- or full mutation carrier females. Data are limited at this time but provide a suggestion that the risk of expansion to the full mutation may be correlated with maternal age and to the parental origin of premutation of carrier women. More data are needed to confirm these suggested trends. The prospective data base provides a valuable resource to continue to examine factors in an unbiased fashion.

To begin to understand the population dynamics of the fragile X (FRAXA) mutation and to learn more about the fragile X E (FRAXE) syndrome, we have initiated a surve of children in special needs education programs in the public school system. With respect to the FRAXA syndrome, we found approximately 1/1,000 full mutations among males. No large alleles at the FRAXE locus were observed among 462 individuals. The allele distributions at the two loci among Caucasians and among African Americans were examined as well as the level of heterozygosity. We found a significant difference in the FRAXA allele distribution among the two ethnic groups; the major difference was due to the lack of smaller alleles among the African Americans. No difference was found for the FRAXE allele distribution among the two groups. The level of heterozygosity was less than predicted by the allele distribution at both loci. This is probably due to unidentified large alleles among females with a test result of a single band. Alternatively, this excess may indicate that the population is not at equilibrium.

A model to explain the mutational process and population dynamics of the fragile X syndrome is presented. The mutational mechanism was assumed to be a multipathway, multistep process. Expansion of CGG repeats was based on an underlying biological process and was assumed to occur at two time points: meiosis and early embryonic development (mitosis). Meiotic expansion was assumed to occur equally in oogenesis and spermatogenesis, while mitotic expansion was restricted to somatic, or constitutional, alleles of maternal origin. Testable hypotheses were predicted by this meiotic/mitotic model. First, parental origin of mutation is predicted to be associated with the risk of a woman to have a full mutation child. Second, "contractions" seen in premutation male transmissions are predicted not to be true contractions in repeat size, but a consequence of the lack of mitotic expansion in paternally derived alleles. Third, a portion of full-mutation males should have full-mutation alleles in their sperm, due to the lack of complete selection against the full-mutation female. Fourth, a specific premutation-allele frequency distribution is predicted and differs from that based on models assuming only meiotic expansion. Last, it is predicted that approximately 65 generations are required to achieve equilibrium, but this depends greatly on the expansion probabilities.