Mechanistic hypothesis

Correlations of nucleation rates with crystallizer variables have been developed for a variety of systems. Although the correlations are empirical, a mechanistic hypothesis regarding nucleation can be helpful in selecting operating variables for inclusion in the model. Two examples are (/) the effect of slurry circulation rate on nucleation has been used to develop a correlation for nucleation rate based on the tip speed of the impeller (16) and (2) the scaleup of nucleation kinetics for sodium chloride crystalliza tion provided an analysis of the role of mixing and mixer characteristics in contact nucleation (17). Pubhshed kinetic correlations have been reviewed through about 1979 (18). In a later section on population balances, simple power-law expressions are used to correlate nucleation rate data and describe the effect of nucleation on crystal size distribution. 

This mechanistic hypothesis which agrees with the last results obtained by Dominique Nobel (ref. 56) would certainly need much more investigations to be corroborated. 

Scheme 24 Mechanistic hypothesis for the transesterification (act = activating group) [70]...

Scheme 29 Mechanistic hypothesis of Ritter s 1,4-addition to 1,3-dienes 108 [92]...

As a mechanistic hypothesis, the authors assumed a reduction of the Fe(+2) by magnesium and subsequent coordination of the substrates, followed by oxidative coupling to form alkyl allyl complex 112a. A ti—c rearrangement, followed by a syn p-hydride elimination and reductive elimination, yields the linear product 114 with the 1,2-disubstituted ( )-double bond (Scheme 29). This hypothesis has been supported by deuterium labeling experiments, whereas the influence of the ligand on the regioselectivity still remains unclear. 

Apart from this mechanistic hypothesis, another scenario, with a ferrate complex as intermediate, may be possible. In 1928, Hieber discovered that Fe(CO)5 78 underwent a disproportionation in the presence of ethylenediamine 122 [97-101]. Depending on the reaction temperature, different ferrate complexes were formed that incorporated a [Fe(en)3] cation (en = ethylenediamine) and mono-, di- or trinuclear ferrate anions (Scheme 32) [102-107]. As the reaction discussed above is also performed with amines at high temperatures, these ferrates may well be involved in the catalytic cycle of the carbonylation discussed above. 

Nickel(O) reacts with the olefin to form a nickel(0)-olefin complex, which can also coordinate the alkyl aluminum compound via a multicenter bond between the nickel, the aluminum and the a carbon atom of the trialkylaluminum. In a concerted reaction the aluminum and the hydride are transferred to the olefin. In this mechanistic hypothesis the nickel thus mostly serves as a template to bring the olefin and the aluminum compound into close proximity. No free Al-H or Ni-H species is ever formed in the course of the reaction. The adduct of an amine-stabihzed dimethylaluminum hydride and (cyclododecatriene)nickel, whose structure was determined by X-ray crystallography, was considered to serve as a model for this type of mechanism since it shows the hydride bridging the aluminum and alkene-coordinated nickel center [31]. 

Potter, G. A. McCague, R. Jarman, M. A mechanistic hypothesis for DNA adduct formation hy tamoxifen following hepatic oxidative metaholism. Carcinogenesis 1994,5, 439 142. 

Silane reduces the palladium acetate in 119 to the palladium hydride 120, which undergoes reductive elimination to provide the organic product and the catalytic Pd(II) species. This mechanistic hypothesis was supported by the use of EtsSiD as the reductant product was formed with D incorporation at only the methyl group [70]. This reaction is best performed with a Pd(0) precatalyst in the presence of acetic acid and 10 eq. of silane, which suppresses the competitive cycloisomerization reaction [70]. 

Olsen S, Lamothe K, MartiAAnez TJ (2010) Protonic gating of excited-state twisting and charge localization in GFP chromophores a mechanistic hypothesis for reversible photoswitching. J Am Chem Soc 132 1192-1193... 

Allenamide ( )-13 was prepared by trapping the corresponding lithioallene with carbon dioxide, followed by conversion of the carboxylate to the amide. Chromatographic resolution of the enantiomers of 13 was easily accomplished on a 10x250mm Chiralcel OD HPLC column. Addition of vinyllithium 14 to (+)-13, followed by quenching the reaction with aqueous NaH2P04, led to cyclopentenone (—)-15 in 64% yield with >95% chirality transfer (Eq. 13.4). The absolute stereochemistry of (-)-5 is consistent with the mechanistic hypothesis put forth in Eq. 13.3 [8]. 

It is of interest that the mechanism shown in Fig. 8.5 should be applicable to all catechol monoesters, but this is only seen when hydrolysis is comparatively slow. More studies are needed to examine the mechanistic hypothesis presented in Fig. 8.5 and the pharmacokinetic consequences of intramolecular acyl migration in monoesters of catechols. 

Qualitative analysis has the main objective of confirming a given mechanistic hypothesis by rejection of conflicting alternatives. This may be applied to single elementary steps, the intermediates, or how the steps are linked together. 

Quantitative analysis relies on a highly probable mechanistic hypothesis and determines as many as possible kinetic, thermodynamic, and/or transport parameters for the various steps. This is often a complex problem, since the values of the parameters are usually correlated, their relation to experimental data is nonlinear, and the data contain artifacts and statistical errors [40, 41]. 

The mechanistic hypothesis was tested with experiments involving a pair of substrates differing only in olefin geometry abont the a,[3-unsatnrated ester. If the assumption that proton transfer occnrs faster than the bond rotation of converting C to D is valid then the ( )- and (Z)-isomers are expected to prodnce opposite diastereomers. In the event, ( )-99 provides 42 1 dr while (Z)-99 provides 1 6 dr favoring the opposite diastereomer (Scheme 14). 

A thorough study of the cycloaddition reactions of S4N4 with electron deficient alkynes has appeared <87JCS(P1)1579>. A clear mechanistic hypothesis is proposed along with the report of a high yielding synthesis of the versatile 3,4-diformyl-l,2,5-thiadiazole (73) (Scheme 15). 

Numerous antidepressants were synthesized, developed and marketed on the basis of the serotonin hypothesis. The selective serotonin reuptake inhibitors (SSRIs) are similarly effective as the older tricyclic antidepressants, but have the advantage of being less toxic and not inducing anticholinergically mediated side effects (Chapter 1). From the scientific point of view1 they represent an example of mechanistic, hypothesis-driven research and development in psychopharmacology (Chapter 2). 

Figure 5. Mechanistic hypothesis for the photodegradation of high molecular weight polysilane derivatives.

Our design of bimetallic catalysts based on crown-complexed alkaline-earth metal ions, for use in reactions of ester and activated amides endowed with a distal carboxylate anchoring group, is based on the mechanistic hypothesis outlined in Scheme 5.3. Such hypothesis critically rests on the finding that in EtOH solution... 

SCHEME 1 Mechanistic hypothesis for the oxidative coupling of toluene by the "HNOj-clay" system. 

The most probable mechanistic hypothesis is summarized in equations 5 to 9. Preliminary studies in situ by IR spectroscopy are confirming that scheme. 

Ironoxetane intermediates are also supported by experiments with reconstituted P450LM2 and ( )-l-D, -propene 108 which unexpectedly afforded a mixture of 98% methyloxirane 109 and 2% trarcs-2-Di-l-methyloxirane 110 [76], This remarkable stereospecific H/D-exchange at the active site was confirmed in a control experiment by incubation of unlabelled propene in D20 (80% D) which gave a mixture consisting of 80% 110 and 20% 109. In agreement with these results is a mechanistic hypothesis (Fig. 17) involving the oxetane... 

The interpretation of kinetic data begins with a hypothetical sequence of ele mentary reaction steps, each characterized by two microscopic rate constants, one for the forward and one for the reverse reaction. From this proposed mechanism a rate equation is derived, predicting the dependence of the observed reaction rate on concentrations and on microscopic rate constants, and its form is tested against the observations. If the form of the rate equation meets the test of experiment, it may be possible to derive from the data numerical values for the microscopic rate constants of the proposed elementary reaction steps. While inconsistency is clear grounds for modifying or rejecting a mechanistic hypothesis, agreement does not prove the proposed mechanism correct. 

Erlenmeyer was first to consider ends as hypothetical primary intermediates in a paper published in 1880 on the dehydration of glycols.1 Ketones are inert towards electrophilic reagents, in contrast to their highly reactive end tautomers. However, the equilibrium concentrations of simple ends are generally quite low. That of 2-propenol, for example, amounts to only a few parts per billion in aqueous solutions of acetone. Nevertheless, many important reactions of ketones proceed via the more reactive ends, and enolization is then generally rate-determining. Such a mechanism was put forth in 1905 by Lapworth,2 who showed that the bromination rate of acetone in aqueous acid was independent of bromine concentration and concluded that the reaction is initiated by acid-catalyzed enolization, followed by fast trapping of the end by bromine (Scheme 1). This was the first time that a mechanistic hypothesis was put forth on the basis of an observed rate law. More recent work... 

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