Nucleophilic Substitution Reactions Competing Nucleophiles

Nucleophilic substitution Heating under reflux Extraction Gas chromatography NMR spectroscopy 

In this experiment, you will compare the relative nucleophilidties of chloride ions and bromide ions toward each of the following alcohols 1-butanol (n-butyl alcohol), 2-butanol (scc-butyl alcohol), and 2-methyl-2-propanol (f-butyl alcohol). The two nucleophiles will be present at the same time in each reaction, in equimolar concentrations, and they will be competing for substrate. A protic solvent is used in these reactions. 

In general, alcohols do not react readily in simple nucleophilic displacement reactions. If they are attacked by nucleophiles directly, hydroxide ion, a strong base, must be displaced. Such a displacement is not energetically favorable and cannot occur to any reasonable extent  

To avoid this problem, you must carry out nucleophilic displacement reactions on alcohols in acidic media. In a rapid initial step, the alcohol is protonated then water, a stable molecule, is displaced. This displacement is energetically favorable, and the reaction proceeds in high yield  

Once the alcohol is protonated, it reacts by either the Sj l or the Sj.j2 mechanism, depending on the structure of the alkyl group of the alcohol. For a brief review of these mechanisms, consult the chapters on nucleophilic substitution in your lecture textbook. 

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Experiment 22 Nucleophilic Substitution Reactions Competing Nucleophiles Technique 7 Reaction Methods, Section 7.2,7.4,7.5, and 7.7 Technique 12 Extractions, Separations, and Drying Agents, Sections 12.5,... 

We shall now examine some applications of these ideas. Experiments were carried out on the reaction between isopropyl bromide and ethoxide ions. This process consists of competing elimination and nucleophilic substitution reactions,19... 

Such an intermediate ean also stabilize itself by combining with a positive species. When it does, the reaction is nucleophilic addition to a C=C double bond (see Chapter 15). It is not surprising that with vinylie substrates addition and substitution often compete. For chloroquinones, where the charge is spread by resonance, tetrahedral intermediates have been isolated ... 

Effect of Solvent on Elimination versus Substitution. Increasing polarity of solvent favors Sn2 reactions at the expense of E2. In the classical example, alcoholic KOH is used to effect elimination, while the more polar aqueous KOH is used for substitution. Charge-dispersal discussions, similar to those on page 450, only partially explain this. In most solvents, SnI reactions are favored over El. The El reactions compete best in polar solvents that are poor nucleophiles, especially dipolar aprotic solvents" A study made in the gas phase, where there is no solvent, has shown that when 1-bromopropane reacts with MeO only elimination takes place no substitution even with this primary substrate." ... 

When p-ethylaminobenzoate and N,N-dimethyl-p-phenylene diamine sulfate were similarly treated with the dibromosulfone (I) for 2 h, the yield was only 32% and 15% respectively (Figure 1). A possible explanation is that the nucleophilicity of these monosubstituted anilines is weaker than that of aniline while a Na2C03 1,4-HBr elimination reaction could be competing with the substitution reaction, leading to the lower yield (18). 

For carbon-carbon bond-formation purposes, S 2 nucleophilic substitutions are frequently used. Simple S 2 nucleophilic substitution reactions are generally slower in aqueous conditions than in aprotic organic solvents. This has been attributed to the solvation of nucleophiles in water. As previously mentioned in Section 5.2, Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions (Scheme 6.1). In alkylations of phenoxide ions by benzylic chlorides, S/y2 substitutions can occur both at the phenoxide oxygen and at the ortho and para positions of the ring. In fact, carbon alkylation occurs in water but not in nonpolar organic solvents and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para). The effects of phenol substituents and of cosolvents on the rates of the competing alkylation processes... 

Nucleophileic substitution reactions and elimination reactions often compete with each other. 

Since eliminations occur best by an E2 path when carried out with a high concentration of a strong base (and thus a high concentration of a strong nucleophile), substitution reactions by an SN2 path often compete with the elimination reaction. 

Ionisation of the hydroxy groups in cellulose is essential for the nucleophilic substitution reaction to take place. At neutral pH virtually no nucleophilic ionised groups are present and dye-fibre reaction does not occur. When satisfactory exhaustion of the reactive dye has taken place, alkali is added to raise the pH to 10-11, causing adequate ionisation of the cellulose hydroxy groups. The attacking nucleophile ( X ) can be either a cellulosate anion or a hydroxide ion (Scheme 7.8), the former resulting in fixation to the fibre and the latter in hydrolysis of the reactive dye. The fact that the cellulosic substrate competes effectively with water for the reactive dye can be attributed to three features of the reactive dye/ cellulosic fibre system ... 

In a comparative study of fluorination of l,2 3,4-di-0-isopropyli-dene-6-O-p-tolylsulfonyl-a-D-galactopyranose with tetrabutylammonium fluoride in a variety of dipolar, aprotic solvents (as well as 1,2-eth-anediol, in which no reaction was observed), acetonitrile was found to give the highest proportion of substitution of the sulfonic esters relative to their elimination.106 Elimination is the major, competing reaction in these nucleophilic-substitution reactions, because of the high basicity and low nucleophilicity of the fluoride ion or, in terms of the... 

The interfacial mechanism probably competes to some extent with the extraction mechanism, particularly with the less lipophilic catalysts. The dependence of the rate of many nucleophilic substitution reactions on the stirring rate up to 250-300 rpm and the independence of the reaction rate at higher stirring rates has been taken as evidence for a change over from a predominant interfacial mechanism to an extraction process. The interfacial mechanism is also particularly relevant to base-initiated reactions. 

The interfacial mechanism provides an acceptable explanation for the effect of the more lipophilic quaternary ammonium salts, such as tetra-n-butylammonium salts, Aliquat 336 and Adogen 464, on the majority of base-initiated nucleophilic substitution reactions which require the initial deprotonation of the substrate. Subsequent to the interfacial deprotonation of the methylene system, for example the soft quaternary ammonium cation preferentially forms a stable ion-pair with the soft carbanion, rather than with the hard hydroxide anion (Scheme 1.8). Strong evidence for the competing interface mechanism comes from the observation that, even in the absence of a catalyst, phenylacetonitrile is alkylated under two-phase conditions using concentrated sodium hydroxide [51],... 

As an alternative to the oxidation of sulphides and sulphoxides (see Chapter 10), sulphones can be prepared by the nucleophilic substitution reaction of the sulphinite anion on haloalkanes. In the absence of a phase-transfer catalyst, the reaction times are generally long and the yields are low, and undesirable O-alkylation of the sulphinite anion competes with S-alkylation. The stoichiometric reaction of the preformed tetra-n-butylammonium salt of 4-toluenesulphinic acid with haloalkanes produces 4-tolyl sulphones in high yield [1], but it has been demonstrated that equally good... 

This ambiguity was removed by the results of a comprehensive investigation on the gas-phase acid-induced nucleophilic substitution on several allylic alcohols showing that the concerted 8 2 reaction competes with the classical 8 2 pathway in the absence of solvation and ion-pairing factors. " Assessment of the... 

We have examined the competing isomerization and solvolysis reactions of 1-4-(methylphenyl)ethyl pentafluorobenzoate with two goals in mind (1) We wanted to use the increased sensitivity of modern analytical methods to extend oxygen-18 scrambling studies to mostly aqueous solutions, where we have obtained extensive data for nucleophilic substitution reactions of 1-phenylethyl derivatives. (2) We were interested in comparing the first-order rate constant for internal return of a carbocation-carboxylate anion pair with the corresponding second-order rate constant for the bimolecular combination of the same carbocation with a carboxylate anion, in order to examine the effect of aqueous solvation of free carboxylate anions on their reactivity toward addition to carbocations. 

Several types of intramolecular allylic substitution reactions of carbon, nitrogen, and oxygen nucleophiles catalyzed by metalacyclic iridium phosphoramidite complexes have been reported. Intramolecular allylic substitution is much faster than the competing intermolecular process when conducted in the presence of iridium catalysts. Thus, conditions involving high dilution are not required. Intramolecular... 

As the term suggests, a substitution reaction is one in which one group is substituted for another. For nucleophilic substitution, the reagent is a suitable nucleophile and it displaces a leaving group. As we study the reactions further, we shall see that mechanistically related competing reactions, eliminations and rearrangements, also need to be considered. 

When nucleophilic substitution reactions are attempted, the expected product may often be accompanied by one or more additional products that arise from competing reactions. Since these competing reactions share features of the nucleophilic substitution mechanism, they are readily rationalized. 

Consider a proposed nucleophilic substitution reaction on the secondary alcohol shown using aqueous HBr. As a secondary alcohol, either Sn2 or SnI mechanisms are possible (see Section 6.2.3), but SnI is favoured because of the acidic environment and the large fert-butyl group hindering approach of the nucleophile. The expected SnI bromide product is formed, together with a smaller amount of the El-derived alkene in a competing reaction. 

The electrophile shown in step 2 is the proton. In almost all the reactions considered in this chapter the electrophilic attacking atom is either hydrogen or carbon. It may be noted that step 1 is exactly the same as step 1 of the tetrahedral mechanism of nucleophilic substitution at a carbonyl carbon (p. 331), and it might be expected that substitution would compete with addition. However, this is seldom the case. When A and B are H, R, or Ar, the substrate is an aldehyde or ketone and these almost never undergo substitution, owing to the extremely poor nature of H, R, and Ar as leaving groups. For carboxylic acids and their... 

Depending on the relative nucleophilicities, [Nu]50% ranges from micromolar to molar concentrations (Table 13.5). Although these values represent only order-of-magnitude estimates, they allow some important conclusions. First, in uncontaminated freshwa-ters (where bicarbonate typically occurs at about 10"3 M, chloride and sulfate occur at about 10 4 M, and hydroxide is micromolar or less, Stumm and Morgan, 1996), the concentrations of nucleophiles are usually too small to compete successfully with water in SN2 reactions involving aliphatic halides. Hence the major reaction will be the displacement of the halide by water molecules. In salty or contaminated waters, however, nucleophilic substitution reactions other than hydrolysis may occur Zafiriou (1975), for example, has demonstrated that in seawater ([CL] 0.5 M) an important sink for methyl iodide is transformation to methyl chloride ... 

We note that in Eq. 13-11 we have introduced the El (elimination, unimolecular) reaction, which commonly competes with the SN1 reaction provided that an adjacent carbon atom carries one or several hydrogen atoms that may dissociate. We also note that similar to what we have stated earlier for nucleophilic substitution reactions, elimination reactions may occur by mechanisms between the E2 and El extremes. 

Palladium-catalyzed allylic oxidations, in contrast, are synthetically useful reactions. Palladium compounds are known to give rise to carbonyl compounds or products of vinylic oxidation via nucleophilic attack on a palladium alkene complex followed by p-hydride elimination (Scheme 9.16, path a see also Section 9.2.4). Allylic oxidation, however, can be expected if C—H bond cleavage precedes nucleophilic attack 694 A poorly coordinating weak base, for instance, may remove a proton, allowing the formation of a palladium rr-allyl complex intermediate (89, path by694-696 Under such conditions, oxidative allylic substitution can compete... 

The disconnection underlying this procedure is an alkyl-oxygen fission and not the acyl-oxygen fission as in the reactions discussed above. The non-nucleophilic base used in this reaction is l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) which converts the carboxylic acid into its carboxylate ion but does not interact in a competing substitution reaction with the alkyl halide. The ester-forming reaction may therefore be regarded as an SN2 reaction between the carboxylate ion and the alkyl halide.162... 

During an elimination reaction, a bond forms by the removal of two atoms or groups from the original molecule. In most instances, the bond that forms is a n bond. Elimination reactions compete with substitution reactions when alkyl halides react with a nucleophile. 

In 1991, we reported that a nucleophilic vinylic substitution of (E)-fi-alkylvinyl-AModanes with halides (BuN4X, X = C1, Br, I) in dichloromethane, methanol, or acetonitrile at room temperature proceeds with exclusive inversion of configuration [Eq. (100)] [176,177]. This is the first clear example of a vinylic Sn2 reaction. This reaction competes with an alkyne-forming reductive syn /3-elimination. 

The allylic class of substitution reactions is gaining in popularity as catalysts become more general and the factors that govern the selectivity are better understood.76,77 Allylic systems can undergo nucleophilic substitution by either an SN2 or S.,2 reaction.78-81 The SN2 reaction can compete effectively with an S.,2 reaction. 

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