Examples of Nucleophilic Substitutions

Let us look at a typical nucleophilic substitution reaction. Ethyl bromide (bromo-ethane) reacts with hydroxide ion to give ethyl alcohol and bromide ion.  

Hydroxide ion is the nucleophile (Sec. 3.9). It reacts with the substrate (ethyl bromide) and displaces bromide ion. The bromide ion is called the leaving group. 

In reactions of this type, one covalent bond is broken, and a new covalent bond is formed. In this example, the carbon-bromine bond is broken and the carbon-oxygen bond is formed. The leaving group (bromide) takes with it both of the electrons from the carbon-bromine bond, and the nucleophile (hydroxide ion) supplies both electrons for the new carbon-oxygen bond. 

These ideas are generalized in the following equations for a nucleophilic substitution reaction  

If the nucleophile and substrate are neutral (eq. 6.2), the product will be positively charged. If the nucleophile is a negative ion and the substrate is neutral (eq. 6.3), the product will be neutral. In either case, an unshared electron pair on the nucleophile supplies the electrons for the new covalent bond. 

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Many examples of nucleophilic substitutions of the phosphonitrilic hahdes are known and the first physical-organic papers on the... 

Y is a strongly pi electron donor group. As previously noted in the results section, examples of Y from Table VI include centers of high pi electron charge density at carbon, sulfur, nitrogen, and oxygen. Also included in Table VI are examples of nucleophilic substitution transition states (cf. reactions 21 and 22) of the type... 

The most frequently encountered reactions in organic sulfur chemistry are nucleophilic displacement reactions. The mechanism and steric course of reactions have been the main points of interest of research groups all over the world, in particular, Andersen, Cram, Johnson, and Mislow in the United States Kobayashi and Oae in Japan Kjaer in Denmark and Fava and Montanari in Italy. The results of these investigators have been discussed exhaustively in many reviews on sulfur stereochemistry. In a recent report on nucleophilic substitution at tricoordinate sulfur, the literature was covered by Tillett (10) to the end of 1975. Therefore only some representative examples of nucleophilic substitution reactions at chiral sulfur are discussed here. However, recent results obtained in the authors laboratory are included. 

There are no examples of nucleophilic substitution of hydrogen on thianthrene. Methylmagnesium iodide, in the presence of [1,3-bis (diphenylphosphino)-propyl]nickel dichloride caused ring opening, probably initially via 48 o-xylene, from a second organometallic attack, and, by... 

The only carbon susceptible to a nucleophilic attack is the imine-type 3-carbon in 2i/-l,4-oxazines. This compound type only exists in the 3-substituted form as it would otherwise be too reactive. There are three interesting examples of nucleophilic substitution at the 3-carbon and they are shown in Schemes 5 and 6. The methylthio compound 128 can be converted by nucleophiles to 129 <1988M1439>, 130, and 131 <1989JHC205>. In a more deep-seated transformation, 132 and 133 can be reacted with diamines to give compounds of the type 134 and with a triamine to give 135 and 136 (Scheme 6) <2003MI47>. 

No example of nucleophilic substitution of hydrogen has been reported, but chloro and ethoxy groups are labile when conjugated with the azome-thine moiety. 

The base hydrolyses of PtCl(NH3) + and c/s-PtCl2(NH3)4+ are possibly examples of nucleophilic substitution reactions 204 these remain the only cases which have not been proven otherwise. These reactions follow a rate law which is first order in the platinum(IV) complex, and a hydroxide ion dependence which is intermediate between zero and first order. The reaction is not catalyzed by Pt(NH3)2+. 

One remarkable example of nucleophilic substitution at a 1,3-dioxane in which the isomer with an axial (and thus weaker) bond to the leaving group reacts more rapidly than the equatorial epimer is shown in Scheme 2.17 [57]. Because the product is formed with retention of configuration, the reaction must proceed by an SNl-like... 

Scheme4.49. Examples of nucleophilic substitutions with neighboring-group participation [201,203-208].

Be familiar with the examples of nucleophilic substitution reactions listed in Table 6.1. 

The use of acetylides as nucleophiles is a particularly important example of nucleophilic substitution because it results in a new carbon-carbon bond. Thus, larger organic molecules can be assembled from smaller ones using this method. The same is true for cyanide ion as a nucleophile (part b). 

Once the alkynide is formed, it can be treated with an alkyl halide to form more complex alkynes. This reaction is called an alkylation and is an example of nucleophilic substitution. 

Reactive acid derivatives (i.e. acid chlorides and acid anhydrides) get hydrolysed by water to give the constituent carboxylic acids (Following fig.). The reaction is an example of nucleophilic substitution where water acts as the nucleophile. Hydrochloric acid is a by-product from the hydrolysis of an acid chloride, so pyridine is generally added to the reaction mixture to mop it up (Fig.J). 

Other examples of nucleophilic substitutions on epoxides are given in the following... 

Fig. 2. Examples of nucleophilic substitution reactions performed in microemulsions. Scheme 1 synthesis of decyl sulfonate from decyl bromide and hydrogen sulfite. Scheme 2 synthesis of 2-hydroxyoctyl sulfonate from 1,2-epoxyoctane and hydrogen sulfite. Scheme 3 reaction of 4-nitrobenzylpyridine (NBP) with an alkyl halide (RX) followed by alkaline hydrolysis of the N-alkyl derivative (NBP-R+) formed. Scheme 4 a reaction involving displacement of the trinitrophenoxide ion by bromide...

A few examples of nucleophilic substitution of halogen from the 3-position of an isoxazolium salt have been reported.182... 

The above mentioned gas phase and solution studies are examples of nucleophilic substitution reactions, and will be the topic in the next section. 

Apart from these examples of nucleophilic substitution reactions, there are many more applications of reactions which are enhanced by the addition of macro(poly)cyclic ligands examples can be found in some excellent reviews [346-348, 362, 643, 645-648]. 

The only example of nucleophilic substitution in the pyrrole ring is the treatment of the chloropyrroloquinoline (75) with methyl magnesium iodide or tin and hydrochloric acid (nucleophilic substitution by hydride). However, the structures of these three compounds have never been rigorously proved. 

Fluorinated dienes, like fluoroalkenes, are very susceptible to nucleophilic attack [90, 91] some examples of nucleophilic substitution processes are given in Table 7.17. Examples of rearrangements and other reactions are also listed. An early demonstration that... 

Reduction of these C X a bonds is another example of nucleophilic substitution, in which LiAlHi serves as a source of a hydride nucleophile (H ). Because H" is a strong nucleophile, the reaction follows an Sn2 mechanism, illustrated for the one-step reduction of an alkyl halide in Mechanism 12.3. 

Some examples of nucleophilic substitution of Grignard reagents with group XIII species are shown in Table 7. 

Some selected examples of nucleophilic substitution for the transition metals are listed in Tables 11-14. 

Ether formation by dehydration is an example of nucleophilic substitution with the protonated alcohol as substrate and a second molecule of alcohol as nucleophile. 

It is in this class of compounds that the practice of semi-synthesis particularly in the industrial sphere of single or two-step operations is pre-eminent and traditional. The preparation of soap, monoglycerides, or their sulphates, the fatty alcohols, amides and numerous other functional compounds many of which are examples of nucleophilic substitution almost entirely devolve on the reactions of glycerides many of which are examples of nucleophilic substitution. The range of these tranformations particularly with reference to recent developments in surfactant chemistry has been summarised (ref. 100) and discussed with regard to edible applications (ref.101). 

An example of nucleophilic substitution combined with a partial reduction of the nitro group was given by Davis and co-workers (74 -76 J. They examined the action of phenylacetonitryl anion on nitrobenzene and found that it formed a substitution compound with a p-quinoid ring according to scheme (14) ... 

Cine-nucleophilic substitution is an interesting example of nucleophilic substitution with the loss of a nitro group. This was reviewed (77) and a few new examples were given by Barnett. Dickens and West (78) and by Markwell (79). The tatter work gives an example of such substitution (IS) ... 

Examples of nucleophilic substitution with tin alkynides are also known. Thus, treatment of a masked a-bromo amino acid with tin alkynides in the presence of zinc chloride has been shown to lead to the corresponding ethynyl derivative (Scheme 11). ... 

An abundance of examples of nucleophilic substitution reactions are available which occur with inversion. Examples for phosphorus and silicon are found in Charts XI and XII respectively. A fine illustration of what are probably aa inversion mechanisms at sulfur that involve electronegative entering and leaving groups is found in Chart XXI2Sa e). 

Yet another example of nucleophilic substitution in the pyrimidine fragment of thienopyrimidines is the replacement of the 1,2,4-triazolyl substituent with a nucleophile (1992EUP452002). 

Some examples of nucleophilic substitution on aromatic compounds and electron-deficient alkenes have also been reported. 

An example of nucleophilic substitution involving a quaternary ammonium salt such as [A-(l,3-benzodithiol-2-ylidene)]-A-methylbenzaminium iodide 321 and 5-aminopyr-azol-3-one 51 was described by Sprague and Heikes (79S297) (Scheme 88). The reaction required heating in dry DMF at 120 °C with anhydrous sodium carbonate but iminobenzothiadiazolepyrazol-3-one 322 was obtained in only 34% yield. 

Complexes of the type (ri -arene)Cr(CO)3 are very important from the viewpoint of selective organic synthesis involving aromatic substitution reactions since the tricar-bonylchromium moiety attached to the arene ring can modify its reactivity. Interesting stereo- and regioselective organic syntheses have been developed based on the specific properties of (ri -arene)Cr(CO)3 [32]. A typical example of nucleophilic substitution on the aromatic ring by a carbanion is shown in eq (12). 

Let us now turn to an example of nucleophilic substitution involving a group of pollutants other than alkyl halides. We consider the hydrolysis of thiometon and disulfoton, two insecticides that were among the major contaminants that entered the Rhine River after the famous accident at Schweizerhalle in Switzerland in 1986 (Capel et al., 1988). This example is representative for the hydrolysis of a variety of phosphoric and thiophosphoric acid derivatives (e.g., esters, thioesters, see Fig. 1), and it illustrates that hydrolysis of a more complex molecule may be somewhat more complicated. The kinetic data, as well as the proposed mechanisms of hydrolysis of thiometon and disulfoton, are presented in Table 4 and Figure 2, respectively. In these cases, the base catalyzed reaction... 

Numerous examples of nucleophilic substitution in isoxazoles have been reported these reactions have been used for the preparation of AI (Section IV.B.2). A strong electron-donating effect of the amino group hampers the nucleophilic substitution, which is rarely observed in AI. Treatment of 5-chloro-4-AI 1 with the lithium salt of 2-aminoethanethiol gave 4-AI 2 (89MI1) (Scheme 1). 

Only a few examples of nucleophilic substitution have been reported - displacement of halogen a and y to the pyridine nitrogen can be carried out under vigorous conditions or with long reaction times. No Chichibabin substitutions have been reported. Reaction of 4-chloro-7-azaindole with a secondary amine results in normal substitution of the halogen, but reaction with primary amines gives 5-azaindole rearrangement products by the sequence shown below. ... 

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