Secondary alkyl halides example

The 8n2 mechanism is believed to describe most substitutions m which simple pri mary and secondary alkyl halides react with anionic nucleophiles All the examples cited in Table 8 1 proceed by the 8 2 mechanism (or a mechanism very much like 8 2— remember mechanisms can never be established with certainty but represent only our best present explanations of experimental observations) We 11 examine the 8 2 mecha nism particularly the structure of the transition state in more detail in 8ection 8 5 after hrst looking at some stereochemical studies carried out by Hughes and Ingold... 

Figure 8.19 Concentration profiles for a concurrent reaction, e.g. of a secondary alkyl halide + OH- -> alcohol reaction (2) is twice as fast as reaction (1) in this example...

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

The primary advantage in the first step of the method described here (using 1-chlorobutane diluted in MeCN) is that it eliminates long reaction periods and allows the use of secondary alkyl halides without competitive elimination reactions. For example, the reaction of sec-butyl bromide with N-methylimidazole using the classical method (in neat alkyl halide) produces, along with the desired product, 20-30% of butenes and 1-methylimidazole hydrobromide. In the second step, the use of water as solvent allows the anion metathesis reaction to be quantitative in a very short time and allows the easy purification of the ionic liquids. Moreover, employing the potassium salt avoids the use of corrosive and difficult to handle hexafluorophosphoric add and the expensive silver tetrafluoroborate. ... 

Still another method for the conversion of halides to acid derivatives makes use of Na2Fe(CO)4. As described in 0-102, primary and secondary alkyl halides and tosylates react with this reagent to give the ion RFe(CO)4 (141) or, if CO is present, the ion RCOFe(CO)4 (142). Treatment of 141 or 142 with oxygen or sodium hypochlorite gives, after hydrolysis, a carboxylic acid.1613 Alternatively, 141 or 142 reacts with a halogen (for example, I2) in the... 

Further application of the in-situ generation of chiral quaternary ammonium fluorides from the corresponding hydrogen sulfates has also been shown in the facile preparation of optically active esters via the alkylative kinetic resolution of secondary alkyl halides. For example, simple stirring of the mixture of 3-phenylpropionic acid, l-(l-bromoethyl)naphthalene, (S,S)-6b (X = HS04 2 mol%) and KF-2H20 (5 equiv.)... 

Non-deprotonated amides are weak nucleophiles and are only alkylated by trialkyl -oxonium salts or dimethyl sulfate at oxygen or by some carbocations at nitrogen [16, 83]. Alkylation with primary or secondary alkyl halides under basic reaction conditions is usually rather difficult, because of the low nucleophilicity and high basicity of deprotonated amides. Non-cyclic amides are extremely difficult to N-alkylate, and few examples of such reactions (mainly methylations, benzylations, or allyla-tions) have been reported (Scheme 6.21). 4-Halobutyramides, on the other hand, can often be cyclized to pyrrolidinones in high yield by treatment with bases (see Scheme 1.8) [84—86]. 

Under these conditions, the order of reactivity to nucleophilic substitution changes dramatically from that observed in the Sn2 reaction, such that tertiary alkyl halides are more reactive then secondary alkyl halides, with primary alkyl halides not reacting at all. Thus a different mechanism must be involved. For example, consider the reaction of 2-iodo-2-methylpropane with water. (Following fig.). In it, the rate of reaction depends on the concentration of the alkyl halide alone and the concentration of the attacking nucleophile has no effect. Thus, the nucleophile must present if the reaction is to occur, but it does not matter whether there is one equivalent of the nucleophile or an excess. Since the reaction rate depends only on the alkyl halide, the mechanism is called the SN1 reaction, where SN stands for substitution nucleophilic and the 1 shows that the reaction is first order or unimolecular, i.e. only one of the reactants affects the reaction rate. 

The examples in Table 3 demonstrate that many SN2-active alkyl halides can be employed as electrophiles with good success 68 Secondary alkyl halides like 2-propyl iodide, however, are not reactive enough in the low temperature ranges required for obtaining clean addition without decomposition of the enolate. 

Yields are also acceptable for reactions of hydroxide ion with secondary alkyl halides if the compound is especially favorable for SN2 reactions (halides that are allylic, ben-zylic, or adjacent to a carbonyl group), as shown in the following example ... 

For example, hydrolysis of a secondary alkyl halide 2-iodo-3-methylbutane (2.3) gives rearranged tertiary alcohol 2-methyl-2-butanol (2.4) (Scheme 2.6). 

These points may be illustrated by two examples acid-catalyzed dehydration of tertiary alcohols (Scheme 3), and solvolytic dehydrohalogenation of secondary alkyl halides (Scheme 4). ... 

Delocalization of charge decreases basicity a lot and nucleophilicity somewhat. For example, EtO (pAq, = 17) reacts with s-BuBr at lower temperatures than AcO- (pAq, = 4.7), but EtO- acts mostly as a base to give 2-butene by an E2 elimination (Chapter 2), whereas AcO- acts mostly as a nucleophile to give, v-BuOAc by Sn2 substitution. AcO- is both less basic and less nucleophilic than EtO, so it requires higher temperatures to react at all, but when it does react, the proportion of substitution product is greater, because AcO- is much less basic and only somewhat less nucleophilic than EtO-. Likewise, simple ester eno-lates (pAfb = 25) react with secondary alkyl halides such as -PrBr at lower tern-... 

While exploring the use of secondary alkyl halides as partners for ortho-alkylation, Lautens reported some very interesting examples where a secondary alkyl halide and Heck acceptor are tethered to an oxygen or nitrogen heteroatom to make several tricyclic molecules in one step (Scheme 24) [32, 44], This work was instrumental in proving the stereochemical requirements of the oxidative addition of an enantioenriched alkyl halide to the intermediate palladacycle. 

A secondary alkyl halide can form both substitution and elimination products under Sn2/E2 conditions. The relative amounts of the two products depend on the base strength and the bulk of the nucleophile/base. The stronger and bulkier the base, the greater the percentage of the elimination product. For example, acetic acid is a stronger acid = 4.76) than ethanol (pA a = 15.9), which means that acetate ion is a weaker base than ethoxide ion. The elimination product is the main product formed from the reaction of 2-chloropropane with the strongly basic ethoxide ion, whereas no elimination product is formed with the weakly basic acetate ion. The percentage of elimination product produced would be increased further if the bulky ferf-butoxide ion were used instead of ethoxide ion (Section 10.3). 

In principle, reaction 22 may be extended to the preparation of the products 394 with n having any value >1, and conventional reactions have thus been carried out with 3-halo-propanoic " 4-halobutanoic, 5-chloropentanoic and 6-bromohexanoic acid derivatives. Triethyl 3-pho honopropanoate has also been obtained from triethyl phosphite and j5-propiolactone although a normal Michaelis-Arbuzov reaction occurs between trialkyl phosphites and a-bromobutyrolactones (3-bromotetrahydrofuran-2-ones) from which the anhydrides 396 (R = H or Me) have been obtained Difficulties may be encountered should the carbon chain of the acid derivative be branched for example, whereas Michaelis-Arbuzov reactions proceed satisfactorily with primary alkyl halides, and generally also with secondary alkyl halides , the use of tertiary alkyl halides is rarely, if ever, satisfactory. Compounds branched on the a-carbon atom may also be prepared, in principle, by the alkylation of trialkyl phosphonoacetates. 

The secondary alkyl halides can be prepared from the alcohols by the action of the halogen acids or the phosphorus halides. In certain cases they can be made by adding the halogen hydride to unsaturated hydrocarbons. Addition takes place most readily with hydriodic acid. Secondary butyl iodide, for example, can be prepared in this way from butylene and a strong aqueous solution of hydriodic acid —... 

S 2 reaction, such that tertiary alkyl halides are more reactive then secondary alkyl halides, with primary alkyl halides not reacting at all. Thus a different mechanism must be involved. For example, consider the reaction of 2-iodo-2-methylpropane... 

Quatemization involves the reaction of a tertiary amine with an alkylating agent. Typically, primary and some secondary alkyl halides are used for this purpose, although alkyl sulfates have also been used. Tertiary hahdes are not useful because they undergo elimination rather than substitution. The reaction, which is an example of an Sn2 process, proceeds readily to give crystalline, stable, and still-aromatic quaternary salts (Scheme 6.6). These have been used for many years to characterize amines. Acyl halides also react in a similar manner with pyridine, but the resulting salts are unstable and generally not isolated. 

The synthesis of secondary nitriles by the reaction of secondary alkyl halides with cyanide ion is a process which normally gives poor results. Two methods have been introduced to circumvent this difficulty, in each case a ketone is the starting material. The first method consists of converting a ketone to its tosyl hydrazone which adds HCN to give (48) in excellent yield. The decomposition of this product was attempted with basic reagents but the yield was poor (20-30%) however, good results were obtained by adding (48) to a bath of decalin maintained at 180°. Decomposition was complete in two hours and for the two examples quoted (cyclohexanone and heptan-4-one) yields of 60% were obtained [122],... 

Tertiary amines react with primary or secondary alkyl halides by an 8 2 mechanism (eq. 11.6). The products are quaternary ammonium salts, in which all four hydrogens of the ammonium ion are replaced by organic groups. For example,... 

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