And internal return

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleo diilic substitution reactions. They are primary and do not form caibocation intermediates, but the /-butyl substituent efiTectively hinders back-side attack. The rate of reaction of neopent>i bromide with iodide ion is 470 times slower than that of n-butyl bromide. Usually, tiie ner rentyl system reacts with rearrangement to the /-pentyl system, aldiough use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. The primary beiuyl system in entry 3 exhibits high, but not complete, inversiotL This is attributed to racemization of the reactant by ionization and internal return. 

The product ratios were identical within experimental error from pure 179a and 179b. The products were shown to be stable under the reaction conditions. A small amount of cis tram reactant isomerization, 179a =5 179b, presumably via ion pairs and internal return, was observed this factor, however, was ruled... 

Element effects for the hydrogen and deuterium compounds can also be used to distinguish between a concerted E2 mechanism and one with two steps and internal return. Scheme 18.2. Data in Table 18.2 can be used to calculate element effects comparing p-CF3QH4C HClCH2Cl and p-CF3C5H4C HClCH2F where a... 

The authors speculate that the stereochemical divergence may be related to the ability of the electrophile to coordinate with the lithium, coupled with the presence or absence of a low-lying LUMO. Curiously, protonation by methanol proceeds with retention whereas protonation with either acetic acid or triphenyl methane proceeds with inversion. The authors speculate that, in acetic acid, protonation of the TMEDA nitrogen and internal return (c/. Schemes 3.2 and 3.24) may occur instead of direct protonation [184]. Presumably, direct protonation is the only mechanistic course with weak acids such as methanol and triphenylmethane and steric effects dictate inversion for the latter. Hoppe also noted that the enantiomeric purity of the products also depended on the solvent. In THF, the products were nearly racemic, and the enantiomeric purity of several of the other alkylation products was variable in solvents such as ether and pentane. This variability is due, at least in part, to the degree of covalency of the C-Li bond. In donor solvents such as THF, racemization is more facile. 

Entry 2 exhibits high, but not complete, inversion for acetolysis, which is attributed to competing racemization of the reactant by ionization and internal return. Entry 3 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs with complete inversion. The results cited in Entry 4 serve to illustrate the importance of solvation of ion pair intermediates in reactions of secondary tosylates. The data show that partial racemization occurs in aqueous dioxane but that an added nucleophile (azide ion) results in complete inversion in the products resulting from reaction with both azide ion and water. The alcohol of retained configuration is attributed to an intermediate oxonium ion resulting from reaction of the ion pair... 

On the other hand, the primary benzyl system in entry 3 exhibits high, but not complete, inversion. This is attributed to racemization of the reactant by ionization and internal return. Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs with complete inversion. 

In summary, the results discussed above reveal that an ether oxygen in a medium or a bicyclic ring system may offer significant anchimeric assistance in reactions in solvolytic displacement reactions. Because of inductive effects, steric effects, field effects, and internal return, anchimeric assistance, when present, is often difficult to demonstrate kinetically. Products formed from bicyclic and tricyclic oxonium ions probably more often result from participation after carbocation formation. Participation by oxygen apparently occurs to the exclusion of transannular hydride shifts in medium ring systems, but other types of participation such as homoallylic or formation of cyclopropyl carbinyl cations will most likely occur to the exclusion of ether oxygen participation. 

The unsaturated brosylate (127) reacts with exclusive 1,3-hydrogen shift both in formation of acetate products and internal return to brosylates corresponding to the acetate products 200). The production of delta-cyclene (128) via apparent 1,3-hydrogen elimination is analogous to the biogenetic formation of cyclopropanes discussed above (see also section B.l). 

AU processed material is screened to return the coarse fraction for a second pass through the system. Process feed rates are matched to operating variables such as rpm speed and internal clearances, thus minimizing the level of excess fines (—200 mesh (<0.075 mm mm)). At one installation (3) the foUowing product size gradation of total smaller than mesh size (cumulative minus) was obtained ... 

The internal return rate (IRR), a fixed point on the diagram, caimot be viewed as a measure of profitabihty, which should vary with the cost of capital (discount rate). Because the curvature of the total return curve caimot be predicted from the single IRR point, there is no way that the IRR can be correlated with profitabihty at meaningful discount rates. Even both end points, ie, the IRR and the total return at zero discount rate, are not enough to predict the curvature of the total return curve. 

Temperature limits of flight engine alloys have been steadily inereasing about 20 °F (11 °C) per year sinee 1945. Transpiration and internally eooled metal blades have resulted in higher temperatures and more effieient operation. But the direet eorrelation between effieieney and fabrieation eost has resulted in a situation of diminishing returns for the superalloys. As more and more eooling air is needed for the superalloy eomponents, the effieieney of the engine drops to a point where turbine inlet temperatures around 2300 °F (1260 °C) are the optimum and, at that point, they are uneeonomie for automotive use. 

Studies of the stereochemical course of rmcleophilic substitution reactions are a powerful tool for investigation of the mechanisms of these reactions. Bimolecular direct displacement reactions by the limSj.j2 meohanism are expected to result in 100% inversion of configuration. The stereochemical outcome of the lirnSj l ionization mechanism is less predictable because it depends on whether reaction occurs via one of the ion-pair intermediates or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of internal return. It is important to dissect the overall stereochemical outcome into the various steps of such reactions. 

The kinetic method of determining relative acidity suffers from one serious complication, however. This complication has to do with the fate of the ion pair that is formed immediately on removal of the proton. If the ion pair separates and difiuses into the solution rapidly, so that each deprotonation results in exchange, the exchange rate is an accurate measure of the rate of deprotonation. Under many conditions of solvent and base, however, an ion pair may return to reactants at a rate exceeding protonation of the carbanion by the solvent. This phenomenon is called internal return ... 

This process is referred to as internal return, i.e., the base returns the proton to the carbanion faster than exchange of the protonated base with other solvent molecules occurs. If internal return is important under a given set of conditions, how would the correlation between kinetics of exchange and equilibrium acidity be affected How could the occurrence of internal return be detected experimentally ... 

The differences in rate for the two positions of naphthalene show clearly that an additional-elimination mechanism may be ruled out. On the other hand, the magnitude of the above isotope effect is smaller than would be expected for a reaction involving rate-determining abstraction of hydrogen, so a mechanism involving significant internal return had been proposed, equilibria (239) and (240), p. 266. In this base-catalysed (B-SE2) reaction both k and k 2 must be fast in view of the reaction path symmetry. If diffusion away of the labelled solvent molecule BH is not rapid compared with the return reaction kLt a considerable fraction of ArLi reacts with BH rather than BH, the former possibility leading to no nett isotope effect. Since the diffusion process is unlikely to have an isotope effect then the overall observed effect will be less than that for the step k. ... 

The lack of a substrate isotope effect suggests very extensive internal return and is readily explained in terms of the fact that conversion of the hydrocarbon to the anion would require very little structural reorganisation. Since koba = k 1k 2/(kLl+k 2) and k 2 is deduced as > k2, then kobs = Kk 2, the product of the equilibrium constant and the rate of diffusion away of a solvent molecule, neither of the steps having an appreciable isotope effect. If the diffusion rates are the same for reactions of each compound then the derived logarithms of partial rate factors (above) become pAT differences between benzene and fluorobenzene hydrogens in methanol. However, since the logarithms of the partial rate factors were similar to those obtained with lithium cyclohexylamide, a Bronsted cor-... 

The activation entropies were considerably different from the large negative values expected for a second-order reaction and this was attributed to the effect of the internal return mechanism. 

This system assures overall compliance with cGMPs and internal procedures and specifications. The system includes the quality control unit and all of its review and approval duties (e.g. change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.). It includes all product defect evaluations and evaluation of returned and salvaged drug products. 

---