P-substitution

A point in case is provided by the bromination of various monosubstituted benzene derivatives it was realized that substituents with atoms carrying free electron pairs bonded directly to the benzene ring (OH, NH2, etc) gave 0- and p-substituted benzene derivatives. Furthermore, in all cases except of the halogen atoms the reaction rates were higher than with unsubstituted benzene. On the other hand, substituents with double bonds in conjugation with the benzene ring (NO2, CHO, etc.) decreased reaction rates and provided m-substituted benzene derivatives. 

The p-substituted amino ketones can be reduced readily to the more stable P-dialkylamino alcohols, many of which are useful local anaesthetics. Thus the local anaesthetic Tutocaine is made from the Mannich base derived from formaldehyde, methyl ethyl ketone and dimethylamine, followed by reduction and conversion into the p-aminobenzoate ... 

Wheland intermediate (see below) as its model for the transition state. In this form it is illustrated by the case mentioned above, that of nitration of the phenyltrimethylammonium ion. For this case the transition state for -nitration is represented by (v) and that for p-substitution by (vi). It is argued that electrostatic repulsions in the former are smaller than in the latter, so that m-nitration is favoured, though it is associated rvith deactivation. Similar descriptions can be given for the gross effects of other substituents upon orientation. 

The best-known equation of the type mentioned is, of course, Hammett s equation. It correlates, with considerable precision, rate and equilibrium constants for a large number of reactions occurring in the side chains of m- and p-substituted aromatic compounds, but fails badly for electrophilic substitution into the aromatic ring (except at wi-positions) and for certain reactions in side chains in which there is considerable mesomeric interaction between the side chain and the ring during the course of reaction. This failure arises because Hammett s original model reaction (the ionization of substituted benzoic acids) does not take account of the direct resonance interactions between a substituent and the site of reaction. This sort of interaction in the electrophilic substitutions of anisole is depicted in the following resonance structures, which show the transition state to be stabilized by direct resonance with the substituent ... 

The general phenomenon of o p-substitution into the ring other than... 

N,N -Diacetylethylenediamine-N,N -dithioacetamide (42) reacts with oj-bromoacetophenone and its p-substituted derivatives to give the expected N,N -diacetyl-N,N -bis(4-phenyl-2-thiazolylmethylethylene diamine) (43) (Scheme 21) with R = H, Me, Cl, Br, MeO, yields ranged from 65 to 80% (482). 

Various 4-, 5-, or 4,5-disubstituted 2-aryIamino thiazoles (124), R, = QH4R with R = 0-, m-, or p-Me, HO C, Cl, Br, H N, NHAc, NR2, OH, OR, or OjN, were obtained by condensing the corresponding N-arylthiourea with chloroacetone (81, 86, 423), dichloroacetone (510, 618), phenacyichloride or its p-substituted methyl, f-butyl, n-dodecyl or undecyl (653), or 2-chlorocyclohexanone (653) (Method A) or with 2-butanone (423), acetophenone or its p-substituted derivatives (399, 439), ethyl acetate (400), ethyl acetyl propionate (621), a- or 3-unsaturated ketones (691), benzylidene acetone, furfurylidene acetone, and mesityl oxide in the presence of Btj or Ij as condensing agent (Method B) (Table 11-17). 

Dimethyl derivatives of benzene are called xylenes There are three xylene isomers the ortho (o) meta (m) and para (p) substituted derivatives... 

Michael condensations are catalyzed by alkaU alkoxides, tertiary amines, and quaternary bases and salts. Active methylene compounds and aUphatic nitro compounds add to form P-substituted propionates. These addition reactions are frequendy reversible at high temperatures. Exceptions are the tertiary nitro adducts which are converted to olefins at elevated temperatures (24). 

Hydroxybenzaldehydes readily react with compounds containing methyl or methylene groups bonded to one or two carboxyl, carbonyl, nitro, or similar strong electron-withdrawing groups. The products are usually P-substituted styrenes. 4-Hydroxybenzaldehyde, for example, reacts with 2-methylquinazolines (where R = H, Cl) to give compounds which have anti-inflammatory activity (59). 

A significant advance in the synthesis of monoorganotin trihaHdes was the preparation of P-substituted ethyl tin trihaHdes in good yield from the reaction of stannous chloride, hydrogen haHdes, and a,P-unsaturated carbonyl compounds, eg, acryHc esters, in common solvents at room temperature and atmospheric pressure (153,154). The reaction is beHeved to proceed through a solvated trichlorostannane intermediate (155) ... 

Anthraquinone dyes are derived from several key compounds called dye intermediates, and the methods for preparing these key intermediates can be divided into two types (/) introduction of substituent(s) onto the anthraquinone nucleus, and (2) synthesis of an anthraquinone nucleus having the desired substituents, starting from benzene or naphthalene derivatives (nucleus synthesis). The principal reactions ate nitration and sulfonation, which are very important ia preparing a-substituted anthraquiaones by electrophilic substitution. Nucleus synthesis is important for the production of P-substituted anthraquiaones such as 2-methylanthraquiQone and 2-chloroanthraquiaone. Friedel-Crafts acylation usiag aluminum chloride is appHed for this purpose. Synthesis of quinizatia (1,4-dihydroxyanthraquiQone) is also important. 

Pteridin-4-one, 7-(p-substituted phenyl)-hydroxylation, 3, 287 Pteridin-6-one, 7-amino-synthesis, 3, 314... 

Tetrazolate, 5-(3-chlorobenzyldimethylammonium)-structures, 5, 796 Tetrazolate, 5-cyclopropyl-rearrangement, 5, 810 Tetrazolate, 5-(p-substituted)phenyl-alkylation, 5, 818 Tetrazolates anions... 

Tetrazole, l-(p-substituted phenyl)-antimicrobial activity, 5, 835 Tetrazole, 5-thio-rearrangements, 5, 823 Tetrazole, 2-thioacyl-reactions, 5, 109 Tetrazole, 5-(o-tolyl)-tautomerism, 5, 804 Tetrazole, 5-(p-tolyl)-dipole moments, 5, 795 tautomerism, 5, 804 Tetrazole, 5-(trimethylsilylamino)-synthesis, 5, 832 Tefrazolecarbaldehydes reactions, 5, 820 Tetrazole-5-carbaldehydes reactions, 5, 820 Tetrazolecarbonitriles reactions, 5, 820 Tetrazole carbonyl compounds reactions, 5, 820 Tetrazolecarboxylic acid, 5-aryl-acidity, 5, 816... 

Studies of the solvolysis of 1-phenylethyl chloride and its p-substituted derivatives in aqueous trifluorethanol containing azide anion as a potential nucleophile provide details relative to the mechanism of nucleophilic substitution in this system. 

Treatment of a- or P hydroxyacids with sulfur tetrafluoride leads to conver Sion of the carboxylic group into the tiifluoromethyl group, but the hydroxyl group undergoes either fluorination, fluorosulfination, esterification, or dehydration to form esters, ethers, or alkenes The ratio of the products depends on P substitution [209, 210] (equations 103 and 104)... 

A Hammett plot of the pK values of p-substituted phenols against the Op values shows serious deviations for the members of the series at the extremes of the o scale, that is, for substituents that are strongly electron donating or electron withdrawing. It was recognized very early that such deviations could be rectified by choosing an appropriate o value for such substituents in effect, this means a different model reaction was adopted. The chemical basis of the procedure can be illustrated with the p-nitro substituent. The p-nitrophenolate ion is stabilized by through resonance as shown in 2. 

Indolization of the p-substituted phenylhydrazone 45 provides only one regioisomer as expected, the 5-substituted indole 46. It is the most useful example of Fischer indole chemistry. An electron donating substituent on the phenyl ring in 45 enhances the rate of the indolization, whereas electron-withdrawing groups decrease the rate of cyclization. 

Cyclization of an o-substituted arylhydrazone provides one isomer in many cases. However, the cyclization is more sluggish than the m- or p-substituted analogs. Sometimes the cyclization gives low yields of the desired indole products along with side products. Cyclization of the 2-substituted arylhydrazone can occur either to the unsubstituted side to provide the normal indole product (50), or to the substituted side, where other reactions take place (53 and 56). 

It seems reasonable to assume that in regard to their formation and decomposition the derivatives of phenylpentazole correspond roughly to the unsubstituted compound (see Table V). The rate data for m-and p-substituted phenylpentazoles conform to the Hammett equation with p= -f-1.01. Finally, the high rate of decomposition and... 

Similarly, for 2-(p-substituted-anilino)benzothiazoles (180 181), the relative proportions of the isomeric A -methyl derivatives produced on reaction with methyl iodide in neutral solution has been related to... 

Reaction of the diphosphine ligand R2P(CH2)2PR2 (R = benzothiazolyl) (L) with [RhCl(PPh3)3] gives the exclusively P-coordinated product [RhCl(PPh3)(L)] (88JOM(338)C31, 92JCS(D)241), which is perhaps a common feature of the P-substituted derivatives of oxazole and thiazole. 

Nishioka and Fujita 78> have determined the Kd values for a- and P-cyclodextrin complexes with m- and p-substituted phenols at pH 7.0. Taking into account the directionality in inclusion of a guest molecule, they assumed three and two probable orientational isomers for the cyclodextrin complexes with m- and p-substituted phenols respectively (Fig. 6). Then the observed Kd values were divided into two or three terms corresponding to the dissociation of the orientational isomers involved (Eqs. 16, 17) ... 

Fig. 6. Probable orientational isomers for cyclodextrin complexes with m- and p-substituted phenols...

Upon formulating these relationships, phenols with branched alkyl substituents were not included in the data of a-cyclodextrin systems, though they were included in (3-cyclodextrin systems. In all the above equations, the n term was statistically significant at the 99.5 % level of confidence, indicating that the hydrophobic interaction plays a decisive role in the complexation of cyclodextrin with phenols. The Ibrnch term was statistically significant at the 99.5% level of confidence for (3-cyclo-dextrin complexes with m- and p-substituted phenols. The stability of the complexes increases with an increasing number of branches in substituents. This was ascribed to the attractive van der Waals interaction due to the close fitness of the branched substituents to the (3-cyclodextrin cavity. The steric effect of substituents was also observed for a-cyclodextrin complexes with p-substituted phenols (Eq. 22). In this case, the B parameter was used in place of Ibmch, since no phenol with a branched... 

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