Steric Series

It now became clear that the (-H-tartaric acid produced by oxidation of n-saccharic (n-glucaric) acid is formed from its first four carbon atoms, and that racemic tartaric acid (31 + 32) is produced in the same manner, from mucic (galactaric) acid (19). The choice of formula (31) for (+)- 

Fischer s statement, cited above, that aspartic acid bears a simple relationship to the a-hydroxy acids and, consequently, to the sugars, was made with the explicit reservation that no Walden inversion may occur on deamination with nitrous acid (1896). This condition could not be retained. Furthermore, his conclusion that acetobromoglucose belongs to the /3-d series because it forms /3-D-glucosides is also inadmissible. It is amazing that these two cases seem to be the only ones in which he was misled by the then partially unknown, sometimes unfathomable phenomena of inversion. 

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For the first time, an alkaloid of this type was isolated that lacked the ethyl chain. Compound 185 might biogentically arise from 19-hydroxyibophyllidine (180) through a Polonovski fragmentation process (Scheme 12). The strong positive optical rotation of all of these ibophyllidine-related alkaloids suggests that they belong to the same steric series as ibophyllidine (178). 

Mercaptoketones (83) and (84) can be prepared in a simple manner by adding H2S to pulegone [carbonyl derivative of (49)] which was also found to be a component of Buchu leaf oil (311). Hydroxyketones (91) and (93), which belong to different steric series, are both formed by photooxygenation of the corresponding pulegones (552). Furthermore, 3-hydroxy-6-menthen-2-one (94) in the form of its angelate was initially detected in the root oil of a Pluchea species (48). 

The indices d- and / - in this case are not connected with the sign of the optical rotation but determine only the steric series to which the compounds belong. 

By convention, D-glyceraldehyde, in whose projection formula the OH group points to the right, is taken as the basis of the entire D-series. This convention is very important for the carbohydrates. Assignment to a steric series is independent of the direction of rotation of light (cf. Chapt. 1-3, II-l). 

Attack on the electrophilic C-2 may occur as in the 2-aminothiazoles series, which probably explains the rearrangements observed in acidic medium (121, 711, 712, 723, 724), in aqueous medium with NaOAc (725), or with aqueous NaHCOj (725) (Scheme 232). That the initial attack probably involves the C-2 atom is substantiated by the fact that this rearrangement occurs under extremely mild conditions for 2-iinino-3-substituted-5-nitro-4-thiazolines (725). As the whole mechanism proposed (see p. 92) is reversible, when imino derivatives are submitted to such rearrangement conditions the rearrangement is expected to occur faster if steric interaction between 3- and 4-substituents exists in the 2-imino isomer. Another reaction may occur in acidic medium phenylimino-2-bipheny]-3,4-4-thiazoline hydrolyzed with hydrochloric acid gives the corresponding 4-thiazoline-2-one and aniline (717). 

Quantum chemistry methods allow the prediction of the ultraviolet transitions in good agreement with the experimental values in the case of thiazole and its three methyl derivatives (Table 1-18). A very weak absorption has been indicated at 269.5 nm that could correspond to an n- TT transition given by calculation at 281.5 nm (133). Ultraviolet absorption spectroscopy has been investigated in connection with steric interactions in the A-4-thiazoline-2-thione (74) series (181). It was earlier demonstrated by NMR technique that 4-alkyl-3 isopropyl-A-4-thiazoline-2-thiones exist in solution as equilibrium mixtures of two conformers (75 and 76), the relative populations of which vary with the size of R4 (182) for R4 = rBu the population of rotamer A is 100%, whereas for R4 = Me it is only 28%. Starting from the observed absorption wavelength for... 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

The quatemization reaction of the thiazole nitrogen has been used to evaluate the steric effect of substituents in heterocyclic compounds since thiazole and its alkyl derivatives are good models for such study. In fact, substituents in the 2- and 4-positions of the ring only interact through their steric effects (inductive and resonance effects were constant in the studied series). The thiazole ring is planar, and the geometries of the ground and transition states are identical. Finally, the 2- and 4-positions have been shown to be different (259. 260). 

This particular sequence of conformations-trans bonds that advance the helix along the axis, alternating with gauche bonds which provide the twist-takes the chain through a series of relatively low potential energy states and generates a structure with minimum steric hindrance between substituents. If the polymer series is extended to include bulkier substituents, for example. 

Numerous studies have probed how novolac microstmcture influences resist hthographic properties. In one example, a series of resists were formulated from novolacs prepared with varying feed ratios ofpara-jmeta-cmso. These researchers found that the dissolution rate decreased, and the resist contrast increased, as thepara-jmeta-cmso feed ratio increased (33). Condensation can only occur at the ortho position ofpara-cmso but can occur at both the ortho- and i ra-positions of meta-cmso. It is beheved that increased steric factors and chain rigidity that accompany increasedpara-cmso content modify the polymer solubihty. 

Absorption, metaboHsm, and biological activities of organic compounds are influenced by molecular interactions with asymmetric biomolecules. These interactions, which involve hydrophobic, electrostatic, inductive, dipole—dipole, hydrogen bonding, van der Waals forces, steric hindrance, and inclusion complex formation give rise to enantioselective differentiation (1,2). Within a series of similar stmctures, substantial differences in biological effects, molecular mechanism of action, distribution, or metaboHc events may be observed. Eor example, (R)-carvone [6485-40-1] (1) has the odor of spearrnint whereas (5)-carvone [2244-16-8] (2) has the odor of caraway (3,4). 

Alkyl substituents. The steric effect of 1-alkyl substituents in the pyrrole series has been demonstrated in, for example, Vilsmeier formylation reactions. Thus as the bulk of the alkyl substituent on nitrogen is increased e.g. from Me to Bu ) so does the proportion of /3 substitution (70JCS(C)2573). A similar trend has been observed in a series of experiments on the trifiuoroacetylation of A-alkylpyrroles with trifluoroacetic anhydride (80JCR(S)42). 

Satisfactory Brpnsted correlations for a-substituted azoles offer further evidence of the lesser importance of steric effects in the azole series (78AHC(22)7l). 

The phototransposition reaction in the isoindazole series (187) to give benzimidazoles (188) has been carefully investigated when R = Me, Et, Pr , Bu, Bz and Ph (67HCA2244). The reaction is sensitive to steric effects thus for r = Bu and R = Me, the l-t-butyl-7-methylbenzimidazole is not formed. 

An example of the application of molecular mechanics in the investigation of chemical reactions is a study of the correlation between steric strain in a molecule and the ease of rupture of carbon-carbon bonds. For a series of hexasubstituted ethanes, it was found that there is a good correlation between the strain calculated by the molecular mechanics method and the rate of thermolysis. Some of the data are shown in Table 3.3. 

Steric effects play a major role in determining the ortho para ratio in Friedel-Crafts alkylations. The amount of ortho substitution of toluene decreases as the size of the entering alkyl group increases along the series methyl, ethyl, /-propyl. No ortho product is found when the entering group is /-butyl. ... 

Steric fectors clearly enter into determining the ortho para ratio. The hindered 2,4,6-trimethylbenzoyl group is introduced with a 50 1 preference for the para position. Similarly, in the benzoylation of alkylbenzenes by benzoyl chloride-aluminum chloride, the amount of ortho product decreases (10.3%, 6.0%, 3.1%, 0.6%, respectively) as the branching of the alkyl group is increased along the series methyl, ethyl, i-propyl, t-butyl. ... 

Aryl migrations are promoted by steric crowding in the initial radical site. This trend is illustrated by data from the thermal decomposition of a series of diacyl peroxides. The amount of product derived from rearrangement increases with the size and number of substituents ... 

The direct formation of a dimethyl ketal by reaction of the ketone with methanol is particularly sensitive to steric effects. Only cyclohexanones react under these conditions.In the steroid series only saturated 3-ketones form dimethyl ketals with methanol and acid although partial reaction of a 2-ketone has been observed in the presence of homogenous rhodium catalyst. ... 

A decisive solvent effect is also observed with other a,/ -epoxy ketones. Specifically, 3jS-hydroxy-16a,17a-epoxypregn-5-en-20-one and its acetate do not react with thiocyanic acid in ether or chloroform. However, the corresponding thiocyanatohydrins are formed by heating an acetic acid solution of the epoxide and potassium thiocyanate. As expected, the ring opening reaction is subject to steric hindrance. For example, 3j6-acetoxy-14f ,15f5-epoxy-5) -card-20(22)-enoIide is inert to thiocyanic acid in chloroform, whereas the 14a,15a-epoxide reacts readily under these conditions.Reactions of 14a,15a-epoxides in the cardenolide series yields isothiocyanatohydrins, e.g., (135), in addition to the normal thiocyanatohydrin, e.g., (134). 

Ethynylation of 3j -hydroxy-16a-methyl-5a-androstan-17-one in a mixture of diethylene glycol dimethyl ether and diethylene glycol monoethyl ether in the presence of potassium hydroxide produces two isomeric 17-ethynyl derivatives. This result is not unexpected since molecular models suggest that the steric influence of the 13/ -methyl group is nearly offset by the 16a-methyl group. The presence of a 16a-acetoxy group in the estrone series also leads to the formation of epimeric 17-ethynyl compounds (61) and (62) on reaction with acetylenedimagnesium bromide. 

Taft began the LFER attack on steric effects as part of his separation of electronic and steric effects in aliphatic compounds, which is discussed in Section 7.3. For our present purposes we abstract from that treatment the portion relevant to aromatic substrates. Hammett p values for alkaline ester hydrolysis are in the range +2.2 to +2.8, whereas for acid ester hydrolysis p is close to zero (see Table 7-2). Taft, therefore, concluded that electronic effects of substituents are much greater in the alkaline than in the acid series and. in fact, that they are negligible in the acid series. This left the steric effect alone controlling relative reactivity in the acid series. A steric substituent constant was defined [by analogy with the definition of cr in Eq. (7-22)] by Eq. (7-43), where k is the rate constant for acid-catalyzed hydrolysis of an orr/to-substituted benzoate ester and k is the corresponding rate constant for the on/to-methyl ester note that CH3, not H, is the reference substituent. ... 

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