Poor leaving groups

This reactivity pattern underlies a group of important synthetic methods in which an a-substituent is displaced by a nucleophile by an elimination-addition mechanism. Even substituents which are normally poor leaving groups, such as alkoxy and dialkylamino, are readily displaced in the indole series. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

A poor leaving group can be made more reactive by coordination to an electrophilic species. Hydroxide is a very poor leaving group. Normally, alcohols therefore do not undergo direct nucleophilic substitution. It has been estimated that the reaction... 

The acetal might undergo ionization with formation of an alkoxide ion and a carbocation. In a second step, the alkoxide would be protonated. This mechanism is extremely rare, if not impossible, because an alkoxide ion is a poor leaving group. 

The pH of the solution is of overwhelming importance in determining the course of these hydrolyses. In basic solution, oxygen elimination is dominant. This is because the unprotonated nitrogen substituent is a very poor leaving group and is also more effective at facilitating the alkoxide elimination by electron donation ... 

When position 4 of perfluoropyridine is blocked with a poor leaving group, ammonia replaces the fluonne in position 2 in good yield. Oxidation of the products obtained with hypochlorite, followed by lodme-catalyzed rearrangement, yields interesting fluorodienes [78] (equation 41) Ultraviolet irradiation can be used to assist reactions m which substitution is difficult [79]... 

Cyclohexyl bromide, for exfflnple, is converted to cyclohexene by sodium ethoxide in ethanol over 60 times faster than cyclohexyl chloride. Iodide is the best leaving group in a dehydrohalogenation reaction, fluoride the poorest. Fluoride is such a poor leaving group that alkyl fluorides are rarely used as starting materials in the preparation of alkenes. 

Inspection of the citrate structure shows a total of four chemically equivalent hydrogens, but only one of these—the pro-/J H atom of the pro-i arm of citrate—is abstracted by aeonitase, which is quite stereospecific. Formation of the double bond of aconitate following proton abstraction requires departure of hydroxide ion from the C-3 position. Hydroxide is a relatively poor leaving group, and its departure is facilitated in the aeonitase reaction by coordination with an iron atom in an iron-sulfur cluster. 

Neutral alcohols, ROH, and ethers, ROR, do not undergo either substitution or elimination reactions, presumably because OH (OR ) is a poor leaving group. Acids can activate OH (OR) by converting it into a better leaving group. 

The activation in cinnolines is sufficient to enable nucleophilic substitution of poor leaving groups such as amino and phenoxy... 

Unlike other ethers, epoxide rings con be cleaved by base as well as by acid. Although an ether oxygen is normally a poor leaving group in an reaction (Section 11.3), the strain of the three-membered ring causes epoxides to react with hydroxide ion at elevated temperatures. 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

Dithiocarbamatc 16 has been used to prepare low dispersity PMAA ( Mw 1 Mn-1.2).52 Photopolymerization of S in the presence of dithiocarbamate 16 also displays some living characteristics (molecular weights that increase with conversion, ability to make block copolymer). However, 17 appears to behave as a conventional initiator in S polymerization.53 The difference in behavior was attributed to the relatively poor leaving group ability of the 2-carboxyprop-2-yI radical. This hypothesis is supported by MO calculations. Dithiocarbamatc 17 was used to control polymerizations of MMA,54 HEMA54 and NIPAM.5... 

As would be expected in a substrate with a poor leaving group the predominant elimination process is of the Hofmann type. However, the authors did find some unexpected reactions. For example, the p-nitrophenyl sulphone was completely consumed within six hours of heating with the glycolate system, yet alkenes formed only a minor part of the products, the major part not being clearly identified. The p-dimethylaminophenyl sulphone was three to six times more reactive than the other sulphones, but it also underwent elimination at a significant rate with either solvent, even in the absence of alkoxides. The reasons for this are obscure. 

H2O departs about 10 times as fast as CN . A good attacking group is a poor leaving group with very few exceptions. OH is notable, for it is a very poor nucleophile for Pt(II) but is only very slowly replaced. In the main, lability also corresponds to thermodynamic instability, for example in the series... 

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