Chlorination electrophilic substitution

Chlorination. Electrophilic chlorination of quinoline (66) in neutral medium showed a positional selectivity order of 3 > 6 > 8. The 5- and 8-positions should be sterically hindered to some extent. Hammett cr+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. Treatment with chlorine at 160-190°C converted quinoline into a mixture of 3-chloro-, 3,4-dichloro-, 3,4,6- and 3,4,8-trichloro-, 3,4,6,8-tetrachloro-, and 3,4,6,7,8-pentachloro-quinolines. At lower temperatures ( 100°C) the major product was 3-chloroquinoline, albeit in low yield. The 4-substituted species may have arisen from an addition-elimination or radical process (70JHC171). 

Substitutions may be electrophilic or nucleophilic according to the reagent used. Electrophilic chlorination or bromination usually takes place at position 3 and /or 5 where a relatively high 7t-electron density is located in all pyran-like heterocycles. In a second process, electrophilic attack occurs only after deprotonation of a starting substrate with a strong base substitution in the 2-, 4-, or 6-positions is typical. Nucleophilic substitution usually takes place if a pyran or thiopyran has in the 2-, 4-, or 6-position a chlorine, methoxy, or an amine leaving group. 

Electrophilic chlorination of quinoline under neutral conditions occurs in the orientation order 3 > 6 > 8. Hammett ct+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. The reactivity order can be affected by substitution of an electron-withdrawing group in the benzene ring, which directs the chlorination to the pyridine ring. Thus, NCS in acetic acid or sulfuryl chloride in o-dichlorobenzene converts 8-nitroquinoline into 3-chloro-8-nitroquinoline in high yield (91M935). 

Chromium activation allows a strategy for aryl ether synthesis in four stages (i) electrophilic chlorination (ii) chromium coordination (iii) alkoxide substitution for chloride and (iv) oxidative decomplexa-tion.33 The process is effective for the synthesis of 6-methoxytetrahydroquinolines and 5-methoxydihydroindole derivatives, for example. Chlorination of iV-acetyltetrahydroquinoline with SO2CI2 followed by deacetylation provides 6-chlorotetrahydroisoquinoline in 77% yield (equation 11).33 Complexation with [Cr(CO)6] in diglyme-cyclohexane at 125 °C for 53 h using the Strohmeier apparatus gave the chromium complex (13) in 85% yield, based on 40% recovery of starting material. The unre-... 

Scheme 1.17 Electrophilic addition of CHCI3 to SWCNTs (i), followed by substitution of chlorine (ii) and esterification (iii) (i) CHCI3, AICI3 (ii) OH", MeOH (iii) C2H5COCI.

Reactions of chloramine include radical, nucleophilic, and electrophilic substitution of chlorine, electrophilic substitution of hydrogen, and oxidative additions, for example ... 

Nucleophiles Nu attack the N-Cl bond ((371) and (378)), formally an electrophilic or nucleophilic substitution of chlorine. In the reaction of electrophiles E+ with chloramine NH2CI, a nitrogen bound proton is substituted. This results in the transfer of the NHCC to E+. 

Benzyloxy(cyano)carbene would be expected to be electrophilic by virtue of the calculated selectivity index, Wp -HjOccN 111- This has not yet been experimentally proved as 3-bcnzyloxy-3-cyano-3//-diazirine is rather labile and cannot be isolated if it is synthesized by the substitution of chlorine by a cyano group in 3-benzyloxy-3-chloro-3if-diazirine consequently, this substitution reaction is carried out in the presence of an alkene, hence, preparing 1-benzyloxy-cyclopropane-l-carbonitrile derivatives. However, the cyanide ion present in the system induces the polymerization of electrophilic alkenes, such as acrylonitrile or methyl acrylate. 

Several innovations have significantly extended the scope and synthetic utility of the classical Darzens reaction. For example, a useful supplement has been described to convert diethyl alkylphosphonates into diethyl 1-substituted 1,2-epoxyalky Iphosphonates by a one-pot process. Thus, metallation of diethyl alkylphosphonates with n-BuLi (2 eq) at low temperature in THF followed by electrophilic chlorination using benzenesulfonyl chloride yields diethyl 1-lithio-l-chloroalky 1-phosphonates, which can be converted in moderate to good overall yields (30-80%) into diethyl 1-substituted 1,2-epoxyalky Iphosphonates by reaction with carbonyl compounds (Scheme 4.2). ... 

Aromatic difluoromethyl ethers are conveniently synthesized by reaction of phenolates with CHClFj [4]. Although this is superficially similar to simple nucleophilic substitution of chlorine by the phenolate, the conversion in fact proceeds via difluorocarbene as the reactive, electrophilic species [5] (Scheme 2.167). Analogous difluoromethylation products are also obtained from other nucleophiles [6]. 

This reaction could be of interest for substituting chlorine for bromine or for iodine in certain aromatic compounds. Indeed, in the halogenation by aromatic electrophilic substitution, the chlorinated reagents are more effective [2] and cheaper than brominated and iodinated reagents. However, bromo or iodo compounds are generally more interesting if the haloaromatic compounds are intended to be used in subsequent reactions because they are generally more reactive [2],... 

Reaction of 2-substituted-1,3-dithianes with sulfuryl chloride in strictly anhydrous conditions gives 1,3-dithienium hydrogen dichlorides, which are extremely hygroscopic and hydrolysable <83CB1739>. Chlorination of 1,3-dithianes at the C-2 position occurs with common sources of electrophilic chlorine such as sulfuryl chloride or NCS, presumably through initial chlorination at sulfur and Pummerer-type rearrangement (Scheme 25a) <94JOCl672>. 

The cationic intermediates also can be captured by solvent. Halogenation with solvent capture is a synthetically important reaction, especially for the preparation of chlorohydrins and bromohydrins. Chlorohydrins can be prepared using various sources of electrophilic chlorine. Chloroamine T is a convenient reagent for chloro-hydrin formation. Bromohydrins are prepared using NBS and an aqueous solvent mixture with acetone or THF. DMSO has also been recommended as a solvent. These reactions are regioselective, with the nucleophile water introduced at the more-substituted position. 

Until a few years ago, no quantitative comparison of overall reactivities in electrophilic substitution of the fundamental five-membered rings was available. Only the reactivity of thiophene relative to benzene had been measured quantitatively in several electrophilic substitutions bromination, chlorination, nitration,hydrogen exchange,protodesilylation, and mercura-tion. ... 

Substituted -1,2-epoxyalkyIphosphonates are obtained via metallation of dialkyl phosphonates with BuLi in THF followed by electrophilic chlorination with benzenesul-fonyl chloride [ 262],... 

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