Nucleophilic displacements

A second more subtle effect may also be operative in the metal ion control of nucleophilic reactions. When amines, thiolates or alkoxides are used as nucleophiles, they are expected to be highly reactive and hence relatively unselective. However, we saw in Chapter 2 that the proximity of the metal cation to the nucleophile reduces the charge density on the donor atom, and is thus expected to reduce the reactivity. We can use the reduced reactivity, and greater selectivity, of such co-ordinated nucleophiles to direct reaction towards the cyclic products. 

Sometimes this deactivation is so great that co-ordinated amines are non-nucleophilic. This is particularly likely when the ligand is co-ordinated to a non-labile metal centre. However, even in these cases, all is not lost. We may also use the enhanced acidity of ligands co-ordinated to a metal centre to generate reactive nucleophiles which would not otherwise be readily accessible. For example, nickel(n) complexes of deprotonated diamines may be prepared, and react with dialkylating agents to yield macrocyclic complexes (Fig. 6-10). To clarify this, consider the reaction in Fig. 6-10 in a little more detail. The amine 6.14 is reactive and unselective, and does not give the desired macrocycle upon reaction with the ditosylate. Deprotonation of the amine under mild conditions is not pos- 

Another useful anionic nucleophile is [Co(CO)4] , whose chemistry has been developed by Heck. A rather mild nucleophile, [Co(CO)4] can be synthesized by the reduction of Co2(CO)g by sodium it reacts with organic halides to generate alkyl complexes  

The alkyl complex reacts with carbon monoxide to apparently insert CO into the cobalt-alkyl bond (insertion reactions will be discussed later in this chapter) to give an acyl complex (containing a —C( = 0)R ligand)  

The acyl complex can then react with alcohols to generate esters O O 

Reaction of HCo(CO)4, a strong acid, with base can regenerate the [Co(CO)4] to make the overall process catalytic. 

Many other nucleophilic anionic organometallic complexes have been studied, and the relative nucleophilicities of various carbonyl anions have been reported. Parallels between these anions and anions of main group elements will be discussed in Chapter 15. 

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Nucleophilic substitution of benzene itself is not possible but the halogeno derivatives undergo nucleophilic displacement or elimination reactions (see arynes). Substituents located in the 1,2 positions are called ortho- 1,3 meta- and 1,4 para-. 

Methods of producing B —C bonds include hydroboration, nucleophilic displacement at a boron atom in BX., (X = halogens or B(0R>3) by e.g. a Grignard reagent, and a psewiio-Friedel-Crafts reaction with an aromatic hydrocarbon, BX3, and AICI3. 

The reaction therefore involves nucleophilic displacement on carbon passing through the transition state indicated otherwise expressed, the reaction involves nucleophUic di.splacement in the conjugate acid R—OH2 in which the displaced group is OHj" " ... 

The activation of halothiazoles toward nucleophilic displacement is discussed in Chapter V no unique conclusion can be drawn because of the various possible interactions between the halothiazole base and the electrophilic counterpart of the nucleophile. 

Next an alkyl halide (the alkylating agent) is added to the solution of sodium acetylide Acetylide ion acts as a nucleophile displacing halide from carbon and forming a new carbon-carbon bond Substitution occurs by an 8 2 mechanism... 

Higher perfluoroalkanesulfonates are slightly more reactive than triflates toward nucleophilic displacements. The rate constants for acetolysis of methyl nonafluorobutanesulfonate [6401 -03-2J, methyl trifluoromethanesulfonate [333-27-7] and methyl toluenesulfonate [80-48-8] are 1.49 x, ... 

Nucleophilic Displacement Reactions. The presence of activating groups, eg, o,p mX.1.0 groups, makes aromatic fluorine reactive in nucleophilic displacement reactions. This has been demonstrated by deterrnination of the relative fluorine—chlorine displacement ratios from the reaction of halonitroben2enes with sodium methoxide in methanol (137) F is displaced 200—300 times more readily than Cl. 

Less activated substrates such as uorohaloben2enes also undergo nucleophilic displacement and thereby permit entry to other useful compounds. Bromine is preferentially displaced in -bromofluoroben2ene [460-00-4] by hydroxyl ion under the following conditions calcium hydroxide, water, cuprous oxide catalyst, 250°C, 3.46 MPa (500 psi), to give -fluorophenol [371-41-5] in 79% yield (162,163). This product is a key precursor to sorbinil, an en2yme inhibitor (aldose reductase). 

Nucleophilic Displacement Reactions. The strong electron-withdrawing effect of a trifluoromethyl group activates ortho and para halogen toward nucleophilic attack. Such chlorine labiUty is utili2ed in the manufacture of crop control chemicals containing trifluoromethyl and nitro groups. 

DicblorobenzotnfIuoride. This compound is produced by chlorination of 4-chloroben2otrifluoride and exhibits sufficient activation to undergo nucleophilic displacement with phenols to form diaryl ether herbicides, eg, acifluorofen sodium [62476-59-9]. 

Experiments ( P nmr) using 0.8 and 2 equivalents of octyhnagnesium chloride with ethyl ben2enephosphinate indicate that the nucleophilic displacement occurs first, foHowed by proton abstraction (80). Interestingly, the order of the two steps is reversed when methyhnagnesium chloride is used (81). This reaction demonstrates the difference ia reactivity between the octyl and the methyl Grignard reagents. 

Polyetherimide synthesis has been achieved by reaction of a dianhydride containing an ether linkage with a diamine, reaction of a diamine containing an ether linkage with a dianhydride, or nucleophilic displacement of halo or nitro groups of a bisimide by bisphenol dianion (19,20). Such Pis exhibit good thermal stabiUty and melt processibiUty. 

Similarly, the reaction with bromine yields the corresponding 5-bromo derivatives, which are suitable substrates for nucleophilic displacement or dehydrohalogenation reactions. Typical nucleophiles (Nu) are H2O, NH, RNH2, and sodium barbiturates ... 

DiaLkyl peroxides also undergo nucleophilic displacements by organometaUic compounds ... 

Substitution reactions on dialkyl peroxides without concurrent peroxide cleavage have been reported, eg, the nitration of dicumyl peroxide (44), and the chlorination of di-/ fZ-butyl peroxide (77). Bromination by nucleophilic displacement on a-chloro- or a-hydroxyalkyl peroxides with hydrogen bromide produces a-bromoalkyl peroxides (78). 

Amines also react with diacyl peroxides by nucleophilic displacement on the oxygen—oxygen bond forming an ion pair iatermediate (187) ... 

Rate studies show that base-cataly2ed reactions are second order and depend on the phenolate and methylene glycol concentrations. The most likely path involves a nucleophilic displacement by the phenoxide on the methylene glycol (1), with the hydroxyl as the leaving group. In alkaline media, the methylolated quinone intermediate is readily converted to the phenoxide by hydrogen-ion abstraction (21). 

Syntheses. The presence of the ether and imide functionahties provides two general approaches for synthesis. Polyetherimides can be prepared by a nucleophilic displacement polymerkation similar to the haUde displacement inpolysulfone synthesis or by a condensation of dianhydrides and diamines that is similar to normal polyimide synthesis (see POLYIMIDES). 

I itro-DisplacementPolymerization. The facile nucleophilic displacement of a nitro group on a phthalimide by an oxyanion has been used to prepare polyetherimides by heating bisphenoxides with bisnitrophthalimides (91). For example with 4,4 -dinitro monomers, a polymer with the Ultem backbone is prepared as follows (92). Because of the high reactivity of the nitro phthalimides, the polymerkation can be carried out at temperatures below 75°C. Relative reactivities are nitro compounds over halogens, Ai-aryl imides over A/-alkyl imides, and 3-substituents over 4-substituents. Solvents are usually dipolar aprotic Hquids such as dimethyl sulfoxide, and sometimes an aromatic Hquid is used, in addition. 

The first commercial PPS process by Phillips synthesized a low molecular weight linear PPS that had modest mechanical properties. It was usehil in coatings and as a feedstock for a variety of cured injection-molding resins. The Phillips process for preparing low molecular weight linear PPS consists of a series of nucleophilic displacement reactions that have differing reactivities (26). 

In the general preparation of quinolones by forming the nitrogen aryl bond a in the ring closure, typical precursors are prepared as shown in Figure 2. The ring closure involves nucleophilic displacement of a halogen, usually a chlorine or fluorine (76) eg, (29) and (30) lead to (31) [86483-54-7] and (32) [123942-15-4] respectively. 

Alternatively, HC(OC2H )3 may be used in step 1. The appioptiate group is attached by a second nucleophilic displacement to give the desired quinolone. 

Solvent for Displacement Reactions. As the most polar of the common aprotic solvents, DMSO is a favored solvent for displacement reactions because of its high dielectric constant and because anions are less solvated in it (87). Rates for these reactions are sometimes a thousand times faster in DMSO than in alcohols. Suitable nucleophiles include acetyUde ion, alkoxide ion, hydroxide ion, azide ion, carbanions, carboxylate ions, cyanide ion, hahde ions, mercaptide ions, phenoxide ions, nitrite ions, and thiocyanate ions (31). Rates of displacement by amides or amines are also greater in DMSO than in alcohol or aqueous solutions. Dimethyl sulfoxide is used as the reaction solvent in the manufacture of high performance, polyaryl ether polymers by reaction of bis(4,4 -chlorophenyl) sulfone with the disodium salts of dihydroxyphenols, eg, bisphenol A or 4,4 -sulfonylbisphenol (88). These and related reactions are made more economical by efficient recycling of DMSO (89). Nucleophilic displacement of activated aromatic nitro groups with aryloxy anion in DMSO is a versatile and useful reaction for the synthesis of aromatic ethers and polyethers (90). 

The organic chemistry of thiocyanates is notably that of nucleophilic displacement of alkyl haHdes by thiocyanate anion to form alkyl thiocyanates ... 

Rea.ctlons, The utility of triorganotin chlorides and their appHcation as starting materials for most other triorganotin compounds results from the ease of nucleophile displacement, as indicated in Figure 1. The commercially important triorganotin compounds are most frequendy the oxides or hydroxides, the duotides, and the carboxylates. 

This reaction is useful in the preparation of anionic derivatives from the chlorides when the nucleophilic displacement route is unsatisfactory. Even weak acids, eg, phenols, mercaptans, and cycHc nitrogen compounds, can be made to undergo reaction with triorganotin hydroxides or bisoxides if the water of reaction is removed a2eotropicaHy as it forms. 

Nicotinyl alcohol (3-pyridinylcarbinol, 3-pyridinemethanol) (27) has use as an antilipemic and peripheral vasodilator. It is available from either the reductions of nicotinic acid esters or preferably, the reduction of the nitrile to the amine followed by dia2otation and nucleophilic displacement. It is frequently adininistered in the form of the tartrate (Eig. 7). Nicotinic acid is frequently used as a salt in conjunction with basic dmgs such as the peripheral vasodilator xanthinol niacinate (28). Nicotinic acid and its derivatives have widespread use as antihyperlipidemic agents and peripheral vasodilators (1). 

Extension of the Phosphorane Route. Ample evidence of the versatihty of the phosphorane synthesis strategy is provided by the proliferation of penems that followed. Nucleophilic displacement of the acetate function of the acetoxy-azetidinone (51, R = OCOCH ) [28562-53-0] (86) provided azetidinones where R = SCOCH, SCSSC2H, and SCSOC2H, which on elaboration gave the penems (52, R = CH ) (87), (52, R = SC2H ) (88), (52, R = 0C2H ) (89). Similar treatment of 3-substituted (or disubstituted) acetoxyazetidinones allowed the synthesis of a number of 2-substituted- 6-alkyl-and 6,6-dialkylpenems (90). 

The schemes depicted in Figure 7 contrast two complimentary approaches to cefotiam (50) in which the timing of the introduction of the C-3 substituent differs. In Route A the heterocycHc thiol C-3 substituent is introduced even before the removal of the aminoadipoyl acyl side chain. The acetonylacetyl C-3 substituent was introduced because it gave considerably higher yields and cleaner product in the nucleophilic displacement step than the corresponding acetoxy, and the starting material, deacetylcephalosporin C (5) was readily available from a fermentation process (190,191). 

A.mina.tlon. Amination describes the introduction of amino groups into aromatic molecules by reaction of ammonia or an amine with suitably substituted halogeno, hydroxy, or sulfonated derivatives by nucleophilic displacement. Although reaction and operational conditions vary, the process always involves the heating of the appropriate precursor with excess aqueous ammonia or amine under pressure. 

O- Alkylation is comparable to A/-alkylation, but since the sodium salts are water-soluble it is most convenient to treat the phenol or naphthol in aqueous caustic solution with dimethyl sulfate or diethyl sulfate. These are comparatively expensive reagents, and therefore, alkoxy groups are introduced at a prior stage by a nucleophilic displacement reaction whenever possible. 

The resins are made by batch processes employing Friedel-Crafts reactions or nucleophilic aromatic substitution. Udel resin and Radel R resin are produced by the nucleophilic displacement of chloride on 4,4 -dichlorodiphenyl sulfone by the potassium salts of bisphenol A and 4,4 -biphenol, respectively (97) ... 

In the case of substituted phenazine fV-oxides some activation of substituents towards nucleophilic substitution is observed. 1-Chlorophenazine is usually very resistant to nucleophilic displacements, but the 2-isomer is more reactive and the halogen may be displaced with a number of nucleophiles. 1-Chlorophenazine 5-oxide (56), however, is comparable in its reactivity with 2-chlorophenazine and the chlorine atom is readily displaced in nucleophilic substitution reactions. 2-Chlorophenazine 5,10-dioxide (57) and 2-chlorophenazine 5-oxide both show enhanced reactivity relative to 2-chlorophenazine itself. On the basis of these observations, similar activation of 5- or 6-haloquinoxaline fV-oxides should be observed but little information is available at the present time. 

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