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Non-disjoined chromosomes 15 from 115 cases of uniparental disomy (ascertained through Prader-Willi syndrome) and 13 cases of trisomy of maternal origin were densely typed for microsatellite loci spanning chromosome 15q. Of these 128 cases a total of 97 meiosis I (MI) errors, 19 meiosis II (MII) errors and 12 mitotic errors were identified. The genetic length of a map created from the MI errors was 101 cM, as compared with a maternal length of 137 cM based on CEPH controls. No significant differences were detected in the distribution of recombination events along the chromosome arm and a reduction was seen for most of the chromosome 15 intervals examined. It was estimated that 21% of tetrads leading to MI non-disjunction were achiasmate, which may account for most or all of the reduction in recombination noted. The mean age of mothers of cases involving MI errors which showed no transitions from heterodisomy to isodisomy was significantly lower (32.7) than cases showing one or more observable transitions (36.3) (P < 0.003, t -test). However, even among chiasmate pairs the highest mean maternal age was seen for multiple exchange tetrads. Chromosome-specific differences in maternal age effects may be related to the normal distribution of exchanges (and their individual susceptibilities) for each chromosome. However, they may also reflect the presence of multiple factors which act to ensure normal segregation, each affected by maternal age in a different way and varying in importance for each chromosome.

— One hundred consecutive patients were studied because of stress incontinence between 1990 and 1993. All the patients agreed to follow an out-patients combined therapeutic rehabilitation protocol: physiotherapy, biofeedback and FES. The short and medium-term results were correlated with all the studied parameters (personal, obstetric, anamnestic, clinical, instrumental). In this unselected population of patients affected by stress incontinence, the full recovery and/or improvement rates of the short-term rehabilitation therapy amounted to 26 and 73%. Such rates are significantly changed by some parameters: severity and the physiopathologic mechanism of the stress incontinence, high parity rate and/or patients’ age. A more careful selection of patients may help us achieve much better results. However, pelvic floor rehabilitation is an efficacious and conservative therapeutic procedure in the treatment of female urinary stress incontinence.

Maternal uniparental disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for uniparental disomy 7. Four of 35 patients were found to have maternal disomy, including three with isodisomy and one with heterodisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardation.

Publisher Summary This chapter describes the developments regarding the principle of nonperfect synchronization (PNS). The foundations of the PNS rest mainly on a relation between two fundamental concepts of physical organic chemistry: the concept of intrinsic barriers and the concept of transition state imbalances. The benefit of determining intrinsic barriers or intrinsic rate constants as the measures of chemical reactivity is that they can be used to describe the reactivity of an entire reaction family, irrespective of the thermodynamic driving force of a particular member of that family, and to make comparisons between different families. Because the observed trends in the intrinsic barriers can plausibly be explained by assuming that charge delocalization lags behind proton transfer, this may be taken as evidence for the existence of imbalance. The higher intrinsic rate constant for 1,1-dinitroethane compared to that for CH3NO2 is open to two interpretations, but both are related to the steric hindrance of the coplanarity of the two nitro groups in the anion. Even though the intrinsic barriers of the gas-phase reactions depend on the same factors as solution-phase proton transfers—such as resonance, polar, and polarizability effects—the electrostatic effects involving the proton-in-flight constitute an important additional factor.

Reactions of anions with acrylonitrile, acrolein, methyl vinyl ketone, and methyl acrylate at room temperature under SIFT conditions are described. Stabilized carbanions such as benzyl anion, cyanomethyl anion, cyclohexadienide, acetone enolate, and nitromethyl anion add to activated carbon-carbon double bonds in a process that is competitive with other modes of reaction. With acrylonitrile and methyl acrylate, addition is in a 1,4 or Michael fashion, while with acrolein and methyl vinyl ketone, 1,2 addition completes with 1,4 addition. Hydroxide, methoxide, fluoride, and cyanide do not add to activated olefins by either mode. A mechanism is proposed for hydride transfer from cyclohexadienide to activated olefins

Fischer carbene complexes have over the last 25 years become a major focus of many synthetic groups. On the other hand, until recently there have been only a few kinetic and/or thermodynamic studies of even the simplest reactions of these complexes. A number of such studies have now been carried out in my laboratory. This review summarizes the results obtained thus far and focuses on three areas: (1) thermodynamic and kinetic acidities of carbene complexes that contain an ionizable proton on the carbon adjacent to the carbene carbon; (2) mechanism and structure-reactivity relationships in the reactions of carbene complexes with nucleophiles; (3) mechanism of hydrolysis of carbene complexes with and without ionizable protons.

A kinetic study of the reaction of benzylidene Meldrum's acid, PhCHC(COO)2C(CH3)2 (5-H), with a series of thiolate and alkoxide ions in 50% DMSO−50% water (v/v) at 20 °C is reported. The reactions ...

Nucleophilic vinylic substitution (SNV), in which a leaving group such as halogen is replaced by a carbon, oxygen, nitrogen, sulfur, or other nucleophile, is an important synthetic tool. It generat...

The question as to what extent aromaticity in a reactant or product is expressed in the transition state of a reaction has only recently received serious attention. Inasmuch as aro- maticity is related to resonance, one might expect that, in a reaction that leads to aromatic products, its development at the transition state should lag behind bond changes as is invari- ably the case for the development of resonance in reactions that lead to delocalized products. However, recent experimental and computational studies on proton transfers from carbon acids suggest the opposite behavior, i.e., the development of aromaticity at the transition state is more advanced than the proton transfer. The evidence for this claim is based on the deter- mination of intrinsic barriers that show a decrease with increasing aromaticity. According to the Principle of Nonperfect Synchronization (PNS), this decrease in the intrinsic barrier im- plies a disproportionately large amount of aromatic stabilization of the transition state. Additional evidence for the high degree of transition state aromaticity comes from the cal- culation of aromaticity indices such as HOMA, NICS, and the Bird Index. Possible reasons why the degree to which aromaticity and resonance are expressed at the transition state is dif- ferent are discussed.

Nucleophilic vinylic substitution (S(N)V), in which a leaving group such as halogen is replaced by a carbon, oxygen, nitrogen, sulfur, or other nucleophile, is an important synthetic tool. It generates compounds with a carbon- or heteroatom-substituted carbon-carbon double bond, such as vinyl ethers, enamines, a variety of heterocyclic systems, and intermediates to pharmaceutically important compounds. The S(N)V reaction has many mechanistic variants, which depend on the substituents, nucleophile, leaving group, and solvent, among other factors. Among these mechanisms, the "addition-elimination" S(N)V route is the most important to synthetic chemists. S(N)V reactions are involved in several biological processes, notably (i) in the inactivation of proteases, (ii) in intermediates of herbicide metabolism, and (iii) in the formation of mutagenic intermediates by reaction of glutathione with the environmental pollutant trichloroethylene. A variant involving a tetrahedral intermediate was found in the enzymatic transfer of an enolpyruvyl group of phosphoenolpyruvate. The main S(N)V mechanism was previously analyzed in terms of a variable transition state with perpendicular nucleophilic attack. Electron-withdrawing groups Y and Y' in the beta position adjacent to the C(alpha) reaction site increase the nucleophilic attack rate; the retention of stereochemistry was mostly ascribed to formation of carbanionic intermediate 1, in which internal rotation is slower than nucleofuge expulsion (k2). As predicted, poor nucleofuges and high activation led to partial or complete stereoconvergence, and an intramolecular element effect in polyhaloethylenes gave competition ratios, kF/kBr1. Evidence for a zwitterionic intermediate comes from amine-catalyzed substitutions with amines. The mechanistic spectrum investigated is wide in terms of rate constants, electron-withdrawing groups, nucleophiles, leaving groups, and solvents. However, the two extremes, that is, the very slightly activated systems where in-plane invertive substitution is feasible and conversely the highly activated systems carrying poor nucleofuges where the intermediate may be observable and kinetics examined, remained almost unexplored for a long time. In this Account, we describe the progress during the last two decades in these areas. Computations on low-reactivity systems showed that the in-plane invertive single-step nucleophilic sigma attack can have a lower barrier than the pi-perpendicular retentive attack. A kBr/kCl1 could be deduced for the H2C=CHX (X = Cl, Br) system. Several inverted substitution-cyclizations or inverted ring openings were observed. Alkenyl iodonium salts with superb nucleofuges, showed in-plane substitutions by various nucleophiles. In parallel, we demonstrated that several highly activated systems carrying poor nucleofuges enabled a direct detection of the intermediate 1 when attacked by strong nucleophiles. Poor correlation between the equilibrium constants K1(RS) for RS- attack and pKa(CH2YY') indicates large nucleofuge steric effects (SPrSMeOMeH). Rate and equilibrium constants for RS- attack as a function of YY' also correlate poorly owing to differences in intrinsic barriers caused by different resonance effects of YY'. The expulsion of either the nucleofuge (k2) or the nucleophile (k(-1)) from 1 was analyzed with respect to several factors. Challenges still remain, including acquiring experimental data for unactivated systems and observing an intermediate carrying a good nucleofuge.

Publisher Summary This chapter deals with the chemistry of the Fischer-type complexes. The key to the rich chemistry of the Fischer carbene complexes is that they can undergo reactions at several sites; they include modification of the carbene fragment, reaction on the side chain or the metal, and insertion of unsaturated organic molecules into the metal–carbon bond. After such elaborations of the carbene complex, removal of the metal to complete the synthesis of the target organic molecule is usually a simple task. The most prominent systems studied so far are the Fischer carbene complexes of the Group 6 metals. The chapter discusses nucleophilic substitution process, for example, the replacement of the MeO group by a group with a different heteroatom, such as an amino or thioalkyl group. This reaction proceeds via a tetrahedral intermediate and is similar to nucleophilic substitutions on carboxylic esters. Another common reaction based on the acidity of the α-carbon proton—that is, the carbon attached to the carbene carbon—has also been discussed in detail. The carbanion that results from the deprotonation of the α-carbon can act as a nucleophile and react with a variety of electrophiles, especially in the presence of Lewis acid catalysis, to form many different products.