Cyanuric chloride, nucleophilic substitution

The reactivity of cyanuric chloride (2,4,6-trichloro-s-triazine) as an indication of s-triazine activation is misleadingly high because of mutual activation of the chlorines meta activation > ortho or para activation) and its symmetry (cf. Section III,A, 1), However, the greatest variety of nucleophilic substitutions have been investigated with this substrate. 

Even polyalkoxy-s-triazines are quite prone to nucleophilic substitution. For example, 2,4,6-trimethoxy-s-triazine (320) is rapidly hydrolyzed (20°, dilute aqueous alkali) to the anion of 4,6-dimethoxy-s-triazin-2(l )-one (331). This reaction is undoubtedly an /S jvr-4r2 reaction and not an aliphatic dealkylation. The latter type occurs with anilines at much higher temperatures (150-200°) and with chloride ion in the reaction of non-basified alcohols with cyanuric chloride at reflux temperatures. The reported dealkylation with methoxide has been shown to be hydrolysis by traces of water present. Several analogous dealkylations by alkoxide ion, reported without evidence for the formation of the dialkyl ether, are all associated with the high reactivity of the alkoxy compounds which ai e, in fact, hydrolyzed by usually tolerable traces of water. Brown ... 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

The 1,3,5-triazines are all synthesized by nucleophilic substitution of cyanuric chloride, which in turn is made by trimerization of cyanogen chloride. As each chlorine is replaced, the reactivity of the remaining ones diminishes. Thus the first displacement takes place at room temperature or below, the second requires moderate heat and the third needs strong heating (Scheme 1). The chemistry of the triazine herbicides has been reviewed (B-75MI10700, B-60MI10700). 

Nucleophilic substitution of R. Cyanuric chloride activated gel is divided into n aliquots, where n is the number of different amines used to synthesize the combinatorial library. A twofold molar excess (relative to the amount of amination of the gel) of each amine is dissolved in the appropriate solvent (1 mL/g gel) (see Note 8). The n aliquots are suspended in the previous mixture, and incubated at 30°C in a rotary shaker (200 rpm) for 24 h. After this period, each R,-substituted gel is thoroughly washed on a sintered funnel with the appropriate buffer for each amine. The resulting gel is stored in 20% v/v ethanol at 0-4°C or used immediately for R2 substitution (Fig. 3). 

Cyanuric chloride (2,4,6-trichloro-l,3,5-triazine) resembles the nitrogen analog of an acid chloride (imidoyl chloride). The chlorine atoms can be replaced sequentially using different reaction conditions. The rate of reaction for such processes which involve cyanuric chloride or other chlorotriazines is dependent on solubility, temperature, actual ring substitution, the catalyst used and the nature of the nucleophile. Several reviews on the chemistry of cyanuric chloride reactions are reported.54 66... 

Sulfur-containing nucleophiles react with cyanuric chloride to form sulfanyl-substituted 1,3,5-triazines.42,96,97 In the presence of sodium hydroxide, sodium sulfide and cyanuric chloride give the trisodium salt of 1,3,5-triazine-2,4,6-trithiol (13), which is used as a scavenger of heavy metals.98,99... 

Cyanuric chloride can be considered as a trimeric imide chloride, the chlorine atoms of which can easily be substituted by nucleophilic reactants, such as e.g. alcohols, phenols, mercaptans, thiophenols and amines. 

Nucleophilic displacement of chlorine, in a stepwise manner, from cyanuric chloride leads to triazines with heteroatom substituents (see Section 6.12.5.2.4) in symmetrical or unsymmetrical substitution patterns. New reactions for introduction of carbon nucleophiles are useful for the preparation of unsymmetrical 2,4,6-trisubstituted 1,3,5-triazines. The reaction of silyl enol ethers with cyanuric chloride replaces only one of the chlorine atoms and the remaining chlorines can be subjected to further nucleophilic substitution, but the ketone produced from the silyl enol ether reaction may need protection or transformation first. Palladium-catalyzed cross-coupling of 2-substituted 4,6-dichloro-l,3,5-triazine with phenylboronic acid gives 2,4-diaryl-6-substituted 1,3,5-triazines <93S33>. Cyanuric fluoride can be used in a similar manner to cyanuric chloride but has the added advantage of the reactions with aromatic amines, which react as carbon nucleophiles. New 2,4,6-trisubstituted 1,3,5-triazines are therefore available with aryl or heteroaryl and fluoro substituents (see Section 6.12.5.2.4). 

Doubly and triply bridged polyoxapolyazaheterophanes developed from cyanuric chloride are available which can complex alkali cations and therefore act as catalysts in nucleophilic aliphatic substitutions under phase-transfer conditions <84JOC4i97>. 

Small hydrogen isotope effects have been found in a nucleophilic substitution of an aromatic heterocycle, the reaction of cyanuric chloride with aniline-N,N-d2 in benzene solution (Zollinger, 1961a). As the effects are small (5%), it is difficult to draw definite mechanistic conclusions. The reactions of cyanuric chloride and other halogenated triazine derivatives are subject to bifunctional catalysis (e.g. by carboxylic acids and by a -pyridone) and to catalysis by monofunctional bases like pyridine (Bitter and Zollinger, 1961). Reinheimer et al. (1962) measured the solvent isotope effect in the hydrolysis of 2-chloro-5-nitro-pyridine (A h,o/ d.o = 2 36). The result makes it probable, but... 

Another special feature connected with the 1,3,5-triazine moiety is spontaneous formation of a long-lived glassy state, by bisarylamino-1,3,5-triazines. A wide series of differently substituted derivatives 49 was synthesized by nucleophilic substitution of chlorine atoms in cyanuric chloride 20 with methylamine in the first step and then two equivalents of substituted aniline in the second step (13NJC3881). 

It is worth noting that 2,4,6-trifluoro-l,3,5-triazine 55 is less active than cyanuric chloride in the reaction of with aniline (Scheme 49) [84]. N,N-Dimethylaniline and l,8-bis(dimethylamino)naphthalene react with cyanuric fluoride 55 as C-nucleophiles to give 2,4-difluoro-6-(4-dimethylaminophenyl)-l,3,5-triazine 119 and l,8-bis(dimethylamino)-4,5-(2,4-difluoro-l,3,5-triazinyl-6)naphthalene 123 (Scheme 49) [8], Contrary to it, N,N-diethylaniline, and ortho- or para-substituted N,N-dimethylanilines react with trifluoro-l,3,5-triazine 55 as N-nucleophiles. These reactions are accompanied by elimination of N-alkyl group and the formation of 2,4-difluoro-6-arylamino-l,3,5-triazines 120-122 (Scheme 49). 

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