H-bond donor

H-Bond Donor (HBD) Inorganic acids Active H chlorides Active H fluorides Active H iodides Active H bromides ... 

H-bond acceptor = H-bond donor = hydrogen atom = methyl group... 

We consider first the Sn2 type of process. (In some important Sn2 reactions the solvent may function as the nucleophile. We will treat solvent nucleophilicity as a separate topic in Chapter 8.) Basicity toward the proton, that is, the pKa of the conjugate acid of the nucleophile, has been found to be less successful as a model property for reactions at saturated carbon than for nucleophilic acyl transfers, although basicity must have some relationship to nucleophilicity. Bordwell et al. have demonstrated very satisfactory Brjinsted-type plots for nucleophilic displacements at saturated carbon when the basicities and reactivities are measured in polar aprotic solvents like dimethylsulfoxide. The problem of establishing such simple correlations in hydroxylic solvents lies in the varying solvation stabilization within a reaction series in H-bond donor solvents. 

H-bond donor/acceptors water, alcohols, carboxylic acids, amines, amides. 

Figure 8-2. Plot of etx (from Table 8-2) against a (from Reference 46). a measure of H-bond donor ability. The numbers identify solvents in Table 8-2.

The basic premise of Kamlet and Taft is that attractive solute—solvent interactions can be represented as a linear combination of a nonspecific dipolarity/polarizability effect and a specific H-bond formation effect, this latter being divisible into solute H-bond donor (HBD)-solvent H-bond acceptor (HB A) interactions and the converse possibility. To establish the dipolarity/polarizability scale, a solvent set was chosen with neither HBD nor HBA properties, and the spectral shifts of numerous solvatochromic dyes in these solvents were measured. These shifts, Av, were related to a dipolarity/polarizability parameter ir by Av = stt. The quantity ir was... 

Hydrogen bonds 12-30 0.3 Relative strength is proportional to the polarity of the H bond donor and H bond acceptor. More polar atoms form stronger H bonds. 

FIGURE 1.14 Some of the biologically important H bonds and functional groups that serve as H bond donors and acceptors. 

Hydrogen bonding in water is cooperative. That is, an H-bonded water molecule serving as an acceptor is a better H-bond donor than an unbonded molecule (and an HgO molecule serving as an H-bond donor becomes a better H-bond acceptor). Thus, participation in H bonding by HgO molecules is a phenomenon of mutual reinforcement. The H bonds between neighboring molecules are weak (23 kj/mol each) relative to the H—O covalent bonds (420 kj/mol). As a consequence, the hydrogen atoms are situated asymmetrically... 

However, an evaluation of the observed (overall) rate constants as a function of the water concentration (5 to 25 % in acetonitrile) does not yield constant values for ki and k2/k i. This result can be tentatively explained as due to changes in the water structure. Arnett et al. (1977) have found that bulk water has an H-bond acceptor capacity towards pyridinium ions about twice that of monomeric water and twice as strong an H-bond donor property towards pyridines. In the present case this should lead to an increase in the N — H stretching frequency in the o-complex (H-acceptor effect) and possibly to increased stabilization of the incipient triazene compound (H-donor effect). Water reduces the ion pairing of the diazonium salt and therefore increases its reactivity (Penton and Zollinger, 1971 Hashida et al., 1974 Juri and Bartsch, 1980), resulting in an increase in the rate of formation of the o-complex (ik ). 

Later, Taft and his coworkers examined the H-bonding donor ability of the amino protons in 4-nitroaniline and 4-nitrophenol as the hydrogen bond donors. They also tried... 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

H-bond donor enthalpy and free energy factors thermodynamic Ed, Q 27... 

Phenol and hexamethylphoshoramide (HMPA) were selected, respectively, as the standard H-bond donor and H-bond acceptor with their values fixed on free energy and enthalpy H-bond scales for phenol, -2.50 for the H-bond donor enthalpy factor (TJ and also for the H-bond donor free energy factor (Ca) for HMPA, 2.50 for the H-bond acceptor enthalpy factor ( J and 4.00 for the H-bond acceptor free energy factor (CJ. 

From 163 calculated H-bond donor and 195 calculated H-bond acceptor factors, one can get enthalpy and free energy values for 31785 reactions using Eqs. (3) and (4). Later, the number of H-bond factor values was significantly increased. A special program for calculating factor values was created and included in the HYBOT (Hydrogen Bond Thermodynamics) program [28, 29]. The current version, HYBOT-2006, has about 20000 values of H-bond acceptor factors and about 5000... 

Table 6.2 demonstrates large intervals of enthalpy and free energy H-bond donor and acceptor factor values as result of a different nature of H-bonding atoms as well as an infiuence of substituents at those atoms on its H-bond capability. 

The satisfactory correlations between Kamlet-Abraham s acidity parameters and H-bond donor free energy factors, and between Kamlet-Abraham s basicity parameters and H-bond acceptor free energy factors for many sets of compounds [26] deserve particular mentioning ... 

Tab. 6.2 Enthalpy and free energy H-bond donor and acceptor factor values for a few chemicals [28].

Surface area around a molecule where optimum enthalpy of interactions of acceptor atoms with H-bond donor probe is realized [38, 39]... 

Edipiobe) = enthalpy factor of the probe H-bond donor 1/3... 

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