Activators directing effects

Figure A3.8.3 Quantum activation free energy curves calculated for the model A-H-A proton transfer reaction described 45. The frill line is for the classical limit of the proton transfer solute in isolation, while the other curves are for different fully quantized cases. The rigid curves were calculated by keeping the A-A distance fixed. An important feature here is the direct effect of the solvent activation process on both the solvated rigid and flexible solute curves. Another feature is the effect of a fluctuating A-A distance which both lowers the activation free energy and reduces the influence of the solvent. The latter feature enliances the rate by a factor of 20 over the rigid case.

The presence of activating substituent on the carbocyclic ring can, of course, affect the position of substitution. For example, Entries 4 and 5 in Table 14.1 reflect such orientational effects. Entry 6 involves using the ipso-directing effect of a trimethylsilyl substituent to achieve 4-acetylation. 

Because we have come to associate activating substituents with ortho para directing effects and deactivating substituents with meta the properties of the halogen substituents appear on initial inspection to be unusual... 

Section 12 15 When two or more substituents are present on a nng the regioselectiv ity of electrophilic aromatic substitution is generally controlled by the directing effect of the more powerful activating substituent... 

In normal human subjects, ANP infusion for one hour causes increased absolute and fractional sodium excretion, urine flow, GFR, and water clearance (53—55). As shown in many in vitro and in vivo animal studies, ANP achieves this by direct effect on the sodium reabsorption in the inner medullary collecting duct, ie, by reducing vasopressin-dependent free-water and sodium reabsorption leading to diuresis and by indirect effect through increased hemodynamic force upon the kidney. ANP inhibits the release of renin and aldosterone resulting in the decreased plasma renin activity and aldosterone concentration (56,57). 

As shown in Chap. 7, shock compression introduces large numbers of defects which in turn cause substantial increases in solid state reactivity. Such shock activation is obviously critical to the process. One of the most direct effects of the mechanical deformation is the removal of oxides or other surface films from the surfaces of the powders. It is well recognized that such surface films can greatly inhibit chemical reaction. The very large mechanical deformation would be expected to substantially damage, if not completely remove, such films. Other manifestations of shock activation are shown in the next chapter. Effects have been shown that represent many orders of magnitude of change in solid state reactivity. 

The second point is somewhat less obvious but is readily illustrated by the synthesis of 1,3,5-tribromobenzene. This particular- substitution pattern cannot be obtained by direct brornination of benzene because bromine is an ortho, para director. Instead, advantage is taken of the powerful activating and ortho, para-directing effects of the fflnino group in aniline. Brornination of aniline yields 2,4,6-tribromoaniline in quantitative yield. Diazotization of the resulting 2,4,6-tribromoaniline and reduction of the diazonium salt gives the desired 1,3,5-tribromobenzene. 

The serine residue of isocitrate dehydrogenase that is phos-phorylated by protein kinase lies within the active site of the enzyme. This situation contrasts with most other examples of covalent modification by protein phosphorylation, where the phosphorylation occurs at a site remote from the active site. What direct effect do you think such active-site phosphorylation might have on the catalytic activity of isocitrate dehydrogenase (See Barford, D., 1991. Molecular mechanisms for the control of enzymic activity by protein phosphorylation. Bioehimiea et Biophysiea Acta 1133 55-62.)... 

The Pomeranz-Fritsch-Bobbitt cyclisation of activated amino-acetal 38 yielded the desired 4-hydroxyquinoline 39 in acceptable yield. The non-obvious regioselectivity of the cyclisation can be attributed to the overriding para-directing effect of alkoxy groups. ... 

We present below an interpretation of azine substitutions based on the principle that reactivity is greatest para to the activating nitrogen (26-29) unless specific orfAo-directing effects intervene. This principle applies also to the greater... 

The theory of radiation-induced grafting has received extensive treatment. The direct effect of ionizing radiation in material is to produce active radical sites. A material s sensitivity to radiation ionization is reflected in its G value, which represents the number of radicals in a specific type (e.g., peroxy or allyl) produced in the material per 100 eV of energy absorbed. For example, the G value of poly(vinyl chloride) is 10-15, of PE is 6-8, and of polystyrene is 1.5-3. Regarding monomers, the G value of methyl methacrylate is 11.5, of acrylonitrile is 5.6, and of styrene is >0.69. 

Inductive and resonance effects account for the directing effects of substituents as well as for their activating or deactivating effects. Take alkyl groups, for instance, which have an electron-donating inductive effect and are ortho and para directors. The results of toluene nitration are shown in Figure 16.13. 

A Summary of Substituent Effects in Aromatic Substitution A summary of the activating and directing effects of substituents in electrophilic aromatic substitution is shown in Table 16.2. 

If t he directing effects of the two groups oppose each other, the more powerful activating group has the dominant influence, but mixtures of products often result. For example, bromination of p-methylphenol yields primarily 2-bromo-4-methylphenol because —OH is a more powerful activator than -CH3. 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Another example of where the setpoint of the physiological system can change the observed behavior of drugs is the absence of direct effects of inverse agonists in nonconstitutively active receptor systems. 

Natriuretic peptides are a family of peptide hormones. All of them contain a 17-amino acid long ring that is closed by a disulfide bond between two cysteine residues. ANP (atrial natriuretic peptide) is mainly expressed in the atria of the heart, whereas BNP (B-type natriuretic peptide) is synthesized in the ventricular myocardium. CNP occurs mainly in the endothelium and is thought to have a paracrine function. ANF and BNF lower blood pressure by a direct effect on smooth muscle and on the salt retention in the kidney. Natriuretic peptides bind and activate particulate guanylyl cyclases. 

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