Nucleophilic Aliphatic Substitution Reactions

Problem 11.25 Compare addition-elimination aromatic nucleophilic and electrophilic substitution reactions with aliphatic 5 2 reactions in terms of (a) number of steps and transition states, (b) character of intermediates. 

Most reactions in two-phase systems occur in a liquid phase following the transfer of a reactant across an interface these are commonly known as extractive reactions. If the transfer is facilitated by a catalyst, it is known as phase-transfer catalysis [2]. Unusually, reactions may actually occur at an interface (interfacial reactions) examples include solvolysis and nucleophilic substitution reactions of aliphatic acid chlorides [3 ] and the extraction of cupric ion from aqueous solution using oxime ligands insoluble in water [4], see Section 5.2.1.3(ii). 

That is, the act of shifting the single electron from Y to X may occur either with or without free-radical formation. Usually, the concerted non-radicaloid process is energetically favoured. For a more detailed discussion of the various mechanisms of nucleophilic substitution reactions in aliphatic compounds and their solvent dependence, see references [14, 483, 782-785]. 

Silver(I) compounds are often used as promoters for substitution reactions of aliphatic halides with carbon nucleophiles. A cyclic (8-bromo ether 29 can be reacted with allyltrimethylsilane (30) imder the influence of AgBp4, yielding a mixture of ally-lated products 31 and 32 (Sch. 7) [15]. Product 31 is formed by direct substitution of the bromine atom in ether 29 by an allyl group and isomeric ether 32 arises from the carboxonium ion which is generated by debromination and subsequent [l,2]-hydrogen shift. A synthesis of optically active 4-allylazetidinone 33 (Ft = phthalimido) has also been achieved by employing the silver-promoted substitution reaction of 4-chloro-azetidinone 34 with allylsilane 30 [16]... 

Nucleophilic substitution of aromatic halides with amines is generally more difficult than the substitution reaction of aliphatic halides, and under ordinary pressure is limited to the reactions of some halides that have strong electron-attracting substituents, with amines of strong nucleophilicity. 

Substitution reactions on aliphatic compounds are some of the most prevalent reactions known. Nature needs to perform these reactions, too, but at a rate appropriate for metabolism. Hence, enzymes are involved for many such reactions. As one example, the enzyme haloalkane dehydrogenase from the bacteria Xanthobacter autotrophicus catalyzes the detoxification of 1,2-dichloroethane. Many of the methods of catalysis noted in Chapter 9 are operative with this enzyme, such as proximity of the nucleophile and stabilization of the transition state. 

A considerable number of ring-fluorinated diazines undergoes various nucleophilic aromatic substitution reactions. Nucleophilic aromatic substitution reactions follow the well-established two-step addition-elimination mechanism via a Meisenheimer intermediate. The destabilization of sp -C bound fluorine by p-Jt repulsion activates fluorinated aromatic compounds toward nucleophilic attack and subsequent substitution. The susceptibility of the carbon center toward nucleophiles is also enhanced by the negative inductive (-la) effect of fluorine. Therefore the ease of nucleophilic halogen replacement - F>Cl>Br>I - is in the opposite order to that for aliphatic... 

A more detailed classification of chemical reactions will give specifications on the mechanism of a reaction electrophilic aromatic substitution, nucleophilic aliphatic substitution, etc. Details on this mechanism can be included to various degrees thus, nucleophilic aliphatic substitutions can further be classified into Sf l and reactions. However, as reaction conditions such as a change in solvent can shift a mechanism from one type to another, such details are of interest in the discussion of reaction mechanism but less so in reaction classification. 

The attack by a reagent of a molecule might be hampered by the presence of other atoms near the reaction site. The larger these atoms and the more are there, the higher is the geometric restriction, the steric hindrance, on reactivity. Figure 3-6e illustrates this for the attack of a nucleophile on the substrate in a nucleophilic aliphatic substitution reaction. 

Thus, to name just a few examples, a nucleophilic aliphatic substitution such as the reaction of the bromide 3.5 with sodium iodide (Figure 3-21a) can lead to a range of stereochemical products, from a l l mbrture of 3.6 and 3.7 (racemization) to only 3.7 (inversion) depending on the groups a, b, and c that are bonded to the central carbon atom. The ring closure of the 1,3-butadiene, 3.8, to cyclobutene... 

Figure 3-22 shows a nucleophilic aliphatic substitution with cyanide ion as a nucleophile, i his reaction is assumed to proceed according to the S f2 mechanism with an inversion in the stereochemistry at the carbon atom of the reaction center. We have to assign a stereochemical mechanistic factor to this reaction, and, clearly, it is desirable to assign a mechanistic factor of (-i-1) to a reaction with retention of configuration and (-1) to a reaction with inversion of configuration. Thus, we want to calculate the parity of the product, of 3 reaction from the parity of the... 

Nucleophilic aliphatic substitution (Chapter 8) Reaction m which a nucleophile replaces a leaving group usually a halide ion from sp hybridized carbon Nucleophilic aliphatic substitution may proceed by either an S l or an Sfj2 mechanism... 

The thenyl chlorides appear to be more reactive in nucleophilic aliphatic substitution than the benzyl analogs. Thus, 2-thenyh chloride gives, in the reaction with sodium cyanide in ethanol, a mixture of ethyl 2-thenyl ether (25% yield) and 2-thenyl cyanide (32% yield), whereas benzyl chloride gives a high 3deld of benzyl cyanide uncontaminated with benzyl ether. When 2-thenyl chloride and benzyl chloride were allowed to compete for a deficiency of sodium amyloxide, 2-thenyl chloride reacted three times faster. In acetone solution 2-thenyl cyanide is obtained smoothl. ... 

Compound 40 has not yet been synthesized. However, there is a large body of synthetic data for nucleophilic substitution reactions with derivatives of 41 [synthesized from aliphatic and aromatic aldehydes, pyridine, and trimethylsilyl triflate (92S577)]. All of these experimental results reveal that the exclusive preference of pathway b is the most important feature of 41 (and also presumably of 40). 

Several distinct mechanisms are possible for aliphatic nucleophilic substitution reactions, depending on the substrate, nucleophile, leaving group, and reaction conditions. In all of them, however, the attacking reagent carries the electron pair with it, so that the similarities are greater than the differences. Mechanisms that occur at a saturated carbon atom are considered first. By far the most common are the SnI and Sn2 mechanisms. 

In any heterolytic reaction in which a new carbon-carbon bond is formed one carbon atoms attacks as a nucleophile and the other as an electrophile. The classification of a given reaction as nucleophilic or electrophilic is a matter of convention and is usually based on analogy. Although not discussed in this chapter, 11-12-11-28 and 12-14-12-19 are nucleophilic substitutions with respect to one reactant, though, following convention, we classify them with respect to the other. Similarly, all the reactions in this section (10-93-10-123) would be called electrophilic substitution (aromatic or aliphatic) if we were to consider the reagent as the substrate. 

Because the Sn2 nucleophilic substitution of uncharged amines with uncharged aliphatic organic halides involves a transition state that is more polar than that of the starting materials, such substitution reactions... 

In a faster, selective and cleaner applications of the microwave-accelerated reactions, Stone-Elander et al. have synthesized a variety of radiolabeled (with 3H, 11C, and 19F) organic compounds via the nucleophilic aromatic and aliphatic substitution reactions, esterifications, condensations, hydrolysis and complexation reactions using monomodal MW cavities on microscale [121]. A substantially reduced level of radioactive waste is generated in these procedures that are discussed, at length, in Chapt. 13 [122]. 

A heterobimetallic BINOL-Ga/Li complex 53 has been developed for the enantioselective ARO of meso-cpoxides (BINOL = l,T-bi(2-naphthol)).278 Using />-methoxyphenol as the nucleophile, this etherification reaction was observed to take place with a high level of asymmetric induction. An improved catalyst 54 has also been reported that exhibits greater stability under the reaction conditions and delivers higher yields and ee s (Equation (78)).279 A simple catalyst derived from Sc(OTf)3 and the chiral bipyridine ligand 52 has been shown to be effective for the ARO of aryl-substituted /// -epoxides with aliphatic alcohols to give high ee s (Equation (79)).280... 

Many theories have been put forward to explain the mechanism of inversion. According to the accepted Hugles, Ingold theory aliphatic nucleophilic substitution reactions occur eigher by SN2 or SN1 mechanism. In the SN2 mechanism the backside attack reduces electrostatic repulsion in the transition state to a minimum when the leaving meleophile leaves the asymmetric carbon, naturally an inversion of configuration occurs at the central carbon atom. 

The polymers used in this study were prepared by a nucleophilic activated aromatic substitution reaction of a bisphenate and dihalo diphenyl sulfone ( ). The reaction was carried out in an aprotic dipolar solvent (NMP) at 170°C in the presence of potassium carbonate (Scheme 1) (5,6). The polymers were purified by repeated precipitation into methanol/water, followed by drying to constant weight. The bisphenols used were bisphenol-A (Bis-A), hydroquinone (Hq) and biphenol (Bp). Thus, the aliphatic character of Bis-A could be removed while retaining a similar aromatic content and structure. The use of biphenol allows an investigation of the possible effect of extended conjugation on the radiation degradation. 

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]. 

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