Substituent interactions

The relation between p values and Aq values is determined by the extent of substituent interaction with the charge developed in the transition state and thus is related to the pattern of charge distribution within the ring itself (386). 

One underlying physical basis for the failure of Hammett reaction series is that substituent interactions are some mixture of resonance, field, and inductive effects. When direct resonance interaction is possible, the extent of the resonance increases, and the substituent constants appropriate to the normal mix of resonance and field effects then fail. There have been many attempts to develop sets of a values that take into account extra resonance interactions. 

In general, the dissection of substituertt effects need not be limited to resonance and polar components, vdiich are of special prominence in reactions of aromatic compounds.. ny type of substituent interaction with a reaction center could be characterized by a substituent constant characteristic of the particular type of interaction and a reaction parameter indicating the sensitivity of the reaction series to that particular type of interactioa For example, it has been suggested that electronegativity and polarizability can be treated as substituent effects separate from polar and resonance effects. This gives rise to the equation... 

When a positively charged substituent such as the trimethylam-monio group is anywhere on the ring, but most effectively when it is ortho to the leaving group, it can favorably affect the entropy of activation with anionic nucleophiles and accelerate reaction. A recent example of reagent-substituent interaction is the electrophilic substitution of 2-carboxybiphenyl, nitration (non-polar solvent) of which occurs only at the 2 -position and not the 4 -position and has been postulated to be due to the interaction of the nitronium ion with the carboxyl group. 

The major difference, when compared with simple diastereoselection in aldol-type additions, is the E- and Z-geometrical isomers of the Michael acceptor. Model transition state G shows one of the orientations of the enantiofaces of an (A)-enolate with a (Z)-enone. These additions, again, result in the same. vyn/an/i-adducts, as in the case of an (A)-enone, but the substituent interactions will be different. 

We infer from the results of our statistical analysis that the four scales of Table V are definitive and characteristic of the substituent interacting within a given pi framework. The pi interaction frameworks suggested are as follows... 

The exact enthalpy of polymerization for a particular monomer will depend on the steric and electronic effects imposed by the substituents attached to the E=E double bond. For olefins, resonance stabihzation of the double bond and increased strain in the polymer due to substituent interactions are the most important factors governing AHp For example, propylene has a calculated AH of -94.0 kJ moT, whereas the polymerization of the bulkier 2-methylpropene is less exothermic (-78.2 kJ moT ) [63]. Due to resonance effects, the experimentally determined AH of styrene (-72.8 kJ mol ) is less exothermic than that for propylene, while that for bulkier a-methylstyrene is even less favorable (-33.5 kJ moT ) [63]. In general, bulky 1,2-disubstituted olefins (i.e., PhHC= CHPh) are either very difficult or impossible to polymerize. 

Entry 2 involves the use of a sterically biased enol boronate with an a-substituted aldehyde. The reaction, which gives 40 1 facial selectivity, was used in the synthesis of 6-deoxyerythronolide B and was one of the early demonstrations of the power of double diastereoselection in synthesis. In Entry 3, the syn selectivity is the result of a chelated TS, in which the (3-p-methoxybenzyl substituent interacts with the tin ion.120... 

Synthesis from pyrido[7,2-a/pyrimidines. Reaction of the disubstituted pyridopyrimidinone 416 with hydrazine gives the aminopyrazole-fused product 417 (Equation 153) <1996FA781, 2003JIC311, 2004IJB1561>. Similarly, substituent interaction in the pyridopyrimidine 418 with amines in toluene at reflux gives, in various proportions, diastereomeric mixtures of the pyrrolopyridopyrimidines 419 and 420 (Equation 154) <2003T4581>. 

In addition to the possible C2,C2 -substituent interactions with a hydrophobic pocket in the regulatory domain site, the much higher affinity of calphostin A (Chart 7.1 4a, R1 = R2 = COPh, IC50 = 0.25 pM) compared to calphostin D (4d, R1 = R2 = H, IC50 = 6.4 pM) also points to interaction of the C7,C7 -portion with the binding site [51]. The C2,C2 - and C7,C7 -analogs would be invaluable in understanding the relative importance of each of these interactions. To determine... 

Finally, as shown in Table 13, p for an aromatic ring is also strongly dependent on the other substituents at the double bond it varies from —1.6 to — 5.5 on going from a-methoxystyrenes to stilbenes. This variation, which is related to the well-known non-additivity of multiple substituent effects, and contrasts with what is observed for alkene bromination, is discussed in the next paragraph, devoted to substituent interaction and selectivity relationships in bromination. 

In this scheme, a highly puckered metallocycle was envisioned, possessing pseudoaxial and equatorial substituents, and reaction pathways were said to be favored which minimized the following effects (a) 1,3-diaxial interactions of substituents on the two a-carbons (b) axial substituent interactions with juxtaposed ring carbons and (c) 1,2-diequatorial interactions. This scheme predicts relatively nonstereospecific metathesis of rra/j.v-olefins but highly stereospecific metathesis of ra-olefins. For example, the following pathways for reactions of m-olefins were proposed ... 

In this equation the —225.7 1.3 kJ mol 1 is the hydrogenation enthalpy of 1,3-butadiene to n-butane. This last expression speaks to substituent/diene interactions and to substituent-substituent interactions. Both electronic and steric effects contribute. Again, this allows calibration of a substituted diene with 1,3-butadiene itself. A positive sign can be interpreted as the substituted species being more stabilized than the archetype. 

It has not yet been clarified whether the ring substituents interact directly with the binding site or affect the molecular characteristics of the DHP molecules in common. A recently used atomistic pseudoreceptor model for a series of DHP indicated a putative charge-transfer interaction was stabilizing the DHP-binding site complex [19]. To prove this hypothesis qualitative and quantitative analysis of the molecular orbitals of nine DHP derivatives (Fig. 9.11) was performed [18]. Charge-transfer (or electron-donor-acceptor) interactions are indicative of electronic... 

Retention volumes of monosubstituted benzenes, benzoic acid, phenols, and anilines have been measured in RPLC [76]. Buffered acetonitrile/water and tetrahydrofuran/water eluents were used with an octadecylsilica adsorbent. From the net retention volumes, a substituent interaction effect was calculated and described with the linear free energy relationship developed by Taft. The data was interpreted in terms of hydrogen bonding between the solutes and the eluent. 

In their study of the conformations of oligosilanes with methyl and ethyl substituents,9 Michl and co-workers pinpointed the specific substituent-substituent interactions in tetrasilanes responsible for inducing C, Z), and A conformations, allowing a prediction of backbone dihedral angle and direction of twist, given a specific arrangement of ethyl groups. 

This approach is admissible because SCSs are well known to be additive unless (i) the conformational equilibrium of the molecule is altered by progressive substitution, and/or (ii) there is no intramolecular substituent interaction whatsoever. Thus, if application of eq. [18] to a rigid molecular system affords ICS values other than zero, such an interaction must exist. In earlier publications (216,221) the abbreviation NAE (nonadditivity effect)—a merely descriptive term—was employed. 

NMR spectroscopy has been used to study flavonoids only in a few cases. Natural abundance NMR spectra have been recorded for 11 methoxyflavones, and NMR data for some 3-arylidenechromanones and flavanones have recently been discussed in terms ofmesomeric and steric substituent interactions. NMR spectroscopy has also been used to study the effect of sugar on anthocyanin degradation and water mobility in a roselle anthocyanin model system. ... 

The observation of natural ORD or CD requires lack of symmetry in the molecule, but any molecule may exhibit magnetic circular dichroism (MCD). It constitutes a molecular analogy for the Zeeman effect in atomic spectra. Measurements in this area may well reveal substituent interactions which are masked in normal UV spectra. Extensive definitive papers of great interest which well illustrate this have appeared on MCD of pyridine derivatives, measured in cyclohexane, acetonitrile, and alcohol or aqueous acidic solutions for protonated... 

H and 13C chemical shifts have been reported for many 1,2-disubstituted oxiranes432 436-439. Similar to cyclopropanes, oxirane ring carbon chemical shifts are smaller in the cis- than in the frans-isomers, and an increment rule using pairwise substituent interaction cross-terms has also been developed439. 

The variation in activity is governed mainly by the steric effect of substituents within the compounds examined in both series. However, the mode of interactions seems to be different, as revealed by the different steric parameters incorporated. The significance of the Arw in Eq. 52 may be that the meso-substituents interact in such a manner that they come into contact with the receptor surface of walls, whereas that of the AVW in Eq. 53 may indicate the importance or fitting into a cavity or pocket on the receptor surface in the region where the (//-substituents direct. The AVW value for C1(0.0) is nearest to the optimum steric condition (AVW 2 —0.24) calculated from Eq. 53. Thus, (//-Cl substituents in lindane are thought to be those which best fit the receptor cavity among the (//-substituents. 

Figure 3.19. Group orbitals for a tetracoordinated atom as a substituent interacting through a bonds. A methylene group is illustrated.

In many cases, the simple approach of using or meta and o para values is applied with reasonable success. One should be aware, however, that good correlations are not always obtained, simply implying that in those cases one has not incorporated all of the molecular interactions into the LFER that play a role in that particular system. This is usually encountered when substituents exhibit a more complex interaction with the reaction center or when substituents interact with one another. 

In one interpretation a perpendicular olefin to carbene approach and a highly puckered metallacyclobutane intermediate were assumed. The favored pathway leads to conformations with the fewest 1,2 and 1,3 metal/ligand-substituent interactions ... 

It seems that substituent interactions on adjacent carbons in the metallacyclobutane dominate the stereochemistry of the transformation in this case. 

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