Factor 1—The Substrate

PROBLEM 10.4 Explain why the number l is used in the El mechanism. You will find that the reason is the same as the reason given for the l in S l. 

Notice that the El mechanism goes through a carbocation intermediate. The formation of this intermediate will help explain how each of the factors plays a role. There are four factors to consider, just like in substitution reactions. And the four factors are directly analogous to the factors we have already seen. We will explore those factors in the upcoming sections. 

Just as in substitution reactions, the first factor is the substrate. Go through your class notes and your textbook to determine what to expect for primary, secondary, and tertiary substrates. For each type of substrate, you need to find out if E2 is favored, if El is favored, or if they are both favored. Use the mechanisms to help you understand why. Then use the charts below to record the trends for El and E2 (just like the charts we used to compare the trends for Sn2 and S j l in Section 9.2 of the previous chapter)  

PROBLEM 10.5 Fill in the trends for El and E2 reactions, comparing relative rates for primary, secondary, and tertiary substrates. 

Keep in mind when filling in the E2 chart, that you don t have the same steric concerns in tertiary substrates that you had in SN2 reactions. The base does not need to get in and attack the carbon. It only has to pull off a proton. Sterics is no longer an effect in this case, and you can have E2 reactions on tertiary substrates  

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The copolymer-silica adhesives also follow a similar trend but fail much earlier than the terpolymer-based adhesives. This is because of two factors (1) the increase in the inherent strength of the adhesive due to more favorable terpolymer rubber-silica interaction and (2) chemisorption in much higher magnitude between the polar substrates and the nanocomposites. 

When bis-adducts are formed, both syn- and an/i-isomers (from the cyclic dienes) and meso and racemic mixtures (from the acyclic dienes) are detected [e.g. 4, 57, 127, 142], the ratio depending to a large extent on steric factors within the substrate. 1,2-Divinylbenzene reacts with two equivalents of dibromocarbene to give a mixture of the d,l and racemic adducts [106, 124],... 

The conformation of a vapor deposited film is influenced by several factors (1) the nature of the substrate (2) the temperature of the substrate during the... 

The total activity of a particular enzyme in vivo is determined primarily by three factors (1) the inherent catalytic competence of the enzyme (turnover number moles of substrate transformed per mole of enzyme per unit time) (2) the level of that enzyme which is expressed in relevant tissues (3) the possible presence of agents that inhibit enzyme activity by competitive or non-competitive actions on the enzyme protein. 

Simultaneous administration of a mixture of substrates of CYP enzymes in one study (i.e., a cocktail approach ) in human volunteers is another way to valuate a drug s inhibition or induction potential (35), provided that the study is designed properly and the following factors are present (1) the substrates are specific for individual CYP enzymes, (2) there are no interactions among these substrates, and (3) the study is conducted in a sufficient number of subjects. Negative results from a cocktail study can eliminate the need for further evaluation of particular CYP enzymes. However, positive results can indicate the need for further in vivo evaluation to provide quantitative exposure changes (such as AUC and Cmax), if the initial evaluation only assessed the changes in the urinary parent to metabolite ratios. 

Factors which affect the rate and extent of enzymatic hydrolysis of proteins include (1) the substrate specificity of the enzymes, (2) modification of the amino acid side chains of the substrate proteins, and (3) the three-dimensional structure of the substrate proteins. It is essential that the active center of the enzymes be able to bind with specific amino acid residues of the substrate protein. The native soybean protein molecules are completely folded and therefore the specific amino acid residues required by the enzymes may not be available. This is why native... 

We will shortly discuss the most important structure-reactivity features of the E2, El, and Elcb mechanisms. The variable transition state theory allows discussion of reactions proceeding through transition states of intermediate character in terms of the extreme mechanistic types. The most important structural features to be considered in such a discussion are (1) the nature of the leaving group, (2) the nature of the base, (3) steric factors in the substrate, and (4) solvent effects. 

The mono(ADP-ribosyl)ation, the transfer of the ADP-ribose moiety of NAD to a macromolecule, was discovered by Hayaishi et al. in 1968 as the mechanism of the cytotoxic effect of diphtheria toxin [1], The substrate of this toxin-catalyzed ADP-ribosylation is elongation factor-2. The same reaction is catal)Azed by Pseudomonas toxin. The second bacterial toxin involved in mono(ADP-ribosyl)ation of mammalian cell proteins is cholera toxin, the substrate of which was identified as the guanine nucleotide-binding regulatory component of membrane adenylate cyclase in 1978 [2].E. coli heat-labile enterotoxin is similar to cholera toxin in many respects. 

Four factors have an impact on whether a particular reaction will occur via an S],j2 or an S],jl mechanism (1) the substrate, (2) the leaving group, (3) the nucleophile, and (4) the solvent (Figure 7.25). We must learn to look at aU four factors, one by one, and to determine whether the factors favor Sjsjl or Si,j2. 

There are four factors that impact the competition between the n2 mechanism and Sfgl (1) the substrate, (2) the nucleophile, (3) the leaving group, and (4) the solvent. 

L. P. Candeias, L. K. Folkes, P. Wardman, Factors Controlhng the Substrate Specificity of Peroxidases Kinetics and Thermodynamics of the Reaction of Horseradish Peroxidase Compound 1 with Phenols and lndole-3-acetic Acids. Biochemistry, 36 (1997) 7081-7085. 

Unfortimately. the interpretation of the spectral changes may be obscured by a number of other factors. (1) The magnitude and even the apparent type of spectral change may be affected by the presence of endogenous substances which are displaced by drug substrate in microsomes from animals pretreated with 3-methylcholanthrene. the spectral changes caused by type I substances may be diminished or appear to be atypical type II presumably because the type I sites are occupied by a metabolite of 3-methylcholanthiene. (2) A substance may be bound to a number of different sites not all of which are enzymatically active in fact, liver microsomes contain considerable amounts of a cytochrome P-450 species which is reduced very slowly by NADPH. (3) A substance may be bound to a number of different forms of cytochrome P-450. but these forms may catalyse different reactions or proceed at markedly different rates. In any event, studies based solely on spectral changes must be interpreted with caution. 

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