Substrates tertiary

Secondary or tertiary alkyl halides are much less reactive. For example an alkyl dichloride with a primary and a secondary chloride substituent reacts selectively by exchange of the primary chloride. The reactivity with respect to the Finkelstein reaction is thus opposite to the reactivity for the hydrolysis of alkyl chlorides. For the Finkelstein reaction on secondary and tertiary substrates Lewis acids may be used," e.g. ZnCla, FeCls or MesAl. 

Normal Fischer esterification of tertiary alcohols is unsatisfactory because the acid catalyst required causes dehydration or rearrangement of the tertiary substrate. Moreover, reactions with acid chlorides or anhydrides are also of limited value for similar reasons. However, treatment of acetic anhydride with calcium carbide (or calcium hydride) followed by addition of the dry tertiary alcohol gives the desired acetate in good yield. 

Steric hindrance raises the energy of the Sjv-2 transition state, increasing AG- and decreasing the reaction rate (Figure 11.7a). As a result, SN2 reactions are best for methyl and primary substrates. Secondary substrates react slowly, and tertiary substrates do not react by an S -2 mechanism. 

The S il reaction occurs when the substrate spontaneously dissociates to a carbocation in a slow rate-limiting step, followed by a rapid reaction with the nucleophile. As a result, SN1 reactions are kinetically first-order and take place with racemization of configuration at the carbon atom. They are most favored for tertiary substrates. Both S l and S 2 reactions occur in biological pathways, although the leaving group is typically a diphosphate ion rather than a halide. 

In the El reaction, C-X bond-breaking occurs first. The substrate dissociates to yield a carbocation in the slow rate-limiting step before losing H+ from an adjacent carbon in a second step. The reaction shows first-order kinetics and no deuterium isotope effect and occurs when a tertiary substrate reacts in polar, nonbasic solution. 

For some tertiary substrates, the rate of SnI reactions is greatly increased by the relief of B strain in the formation of the carbocation (see p. 366). Except where B strain is involved, P branching has little effect on the SnI mechanism, except that carbocations with P branching undergo rearrangements readily. Of course, isobutyl and neopentyl are primary substrates, and for this reason they react very slowly by the SnI mechanism, but not more slowly than the corresponding ethyl or propyl compounds. 

To sum up, primary and secondary substrates generally react by the Sn2 mechanism and tertiary by the SnI mechanism. However, tertiary substrates seldom undergo nucleophilic substitution at all. Elimination is always a possible side reaction of nucleophilic substitutions (wherever a P hydrogen is present), and with tertiary substrates it usually predominates. With a few exceptions, nucleophilic substitutions at a tertiary carbon have little or no preparative value. However, tertiary substrates that can react by the SET mechanism (e.g., /i-N02C6H4CMe2Cl) give very good yields of substitution products when treated with a variety of nucleophiles. ... 

Alkyl halides can be hydrolyzed to alcohols. Hydroxide ion is usually required, except that especially active substrates such as allylic or benzylic types can be hydrolyzed by water. Ordinary halides can also be hydrolyzed by water, if the solvent is HMPA or A-methyl-2-pyrrolidinone." In contrast to most nucleophilic substitutions at saturated carbons, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl a-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aqueous acetonitrile." The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols. 

As usual, tertiary substrates do not give the reaction at all but undergo preferential elimination. However, tertiary (but not primary or secondary) halides R3CCI can be converted to primary amines R3CNH2 by treatment with NCI3 and AlCl3 in a reaction related to 10-53. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Now that we have seen all four factors individually, we need to see how to put them all together. When analyzing a reaction, we need to look at all four factors and make a determination of which mechanism, SnI or Sn2, is predominating. It may not be just one mechanism in every case. Sometimes both mechanisms occur and it is difficult to predict which one predominates. Nevertheless, it is a lot more common to see situations that are obviously leaning toward one mechanism over the other. For example, it is clear that a reaction will be Sn2 if we have a primary substrate with a strong nucleophile in a polar aprotic solvent. On the flipside, a reaction will clearly be SnI if we have a tertiary substrate with a weak nucleophile and an excellent leaving group. 

Finally we learned that if we analyze the first factor (substrate), we will find two effects at play electroiucs and sterics. We saw that Sn2 reactions require primary or secondary substrates because of sterics—it is too crowded for the nucleophile to attack a tertiary substrate. On the other hand, SnI reactions did not have a problem with sterics, but electronics was a bigger issue. Tertiary was the best, because the alkyl groups were needed to stabilize the carbocation. 

Now let s consider the effect of the substrate on the rate of an E2 process. Recall from the previous chapter that Sn2 reactions generally do not occur with tertiary substrates, because of steric considerations. But E2 reactions are different than Sn2 reactions, and in fact, tertiary substrates often undergo E2 reactions quite rapidly. To explain why tertiary substrates will undergo E2 but not Sn2 reactions, we must recognize that the key difference between substitution and elimination is the role played by the reagent. In a substitution reaction, the reagent functions as a nucleophile and attacks an electrophilic position. In an elimination reaction, the reagent functions as a base and removes a proton, which is easily achieved even with a tertiary substrate. In fact, tertiary substrates react even more rapidly than primary substrates. 

As described in the previous section, there are four categories of reagents. For each category, we must explore the expected outcome with a primary, secondary, or tertiary substrate. All of the relevant information is summarized in the following flow chart. It is important to know this flow chart extremely well, but be careful not to memorize it. It is more important to understand the reasons for all of these outcomes. A proper understanding will prove to be far more useful on an exam than simply memorizing a set of rules. 

When the reageht fuhotiohs exclusively as a nucleophile (ahd hot as a base), ohiy substitutioh reactions occur (not elimination). The substrate determines which mechahism operates. 3 2 predominates for primary substrates, and 3 1 predominates for tertiary substrates. For secondary substrates, both 3 2 ahd 3 1 cah occur, although 3 2 is generally favored (especially when a polar aprotic solvent is used). 

For tertiary substrates, oniy E2 is observed, because the 3n2 pathway is too stericaiiy hindered to occur. 

In addition to electrostatic medium effects and to electrophilic assistance described by Yx, nucleophilic solvents can assist positive charge development in heterolysis of secondary, and sometimes tertiary, substrates via an SN2 (intermediate) mechanism (Bentley et al., 1981). Equation (55), involving... 

In general terms then, the Sn2 reaction is only important for primary and secondary substrates, and the rate of reaction for primary substrates is considerably greater than that for secondary substrates. Should a reaction be attempted with tertiary substrates, one does not usually get substitution, but alternative side-reactions occur (see Section 6.4). 

Accordingly, the E2 mechanism becomes relatively favourable, even with tertiary substrates, when we use a strong base or more concentrated base. We are thus more likely to get an El mechanism when we have a tertiary centre, and weak bases or bases in low concentration. Obviously, polar solvents are also going to be conducive to carbocation mechanisms (see Section 6.2.3). Just as acidic conditions help to favour SnI reactions, they also going to favour El reactions. 

The rate constant for solvolysis of the model tertiary substrate 5-Cl is independent of the concentration of added azide ion, and the reaction gives only a low yield of the azide ion adduct (e.g., 16% in the presence of 0.50 M NaNa in 50 50 (v/v) water/trifluoroethanol]." Therefore, this is a borderline reaction for which it is not possible to determine the kinetic order with respect to azide ion, because of uncertainties about specific salt effects on the reaction." ... 

The a-spirocyclopropylcycloalkyl cations have the ideal bisected geometry of the cyclopropyl group with respect to the cation center. Hence solvolysis of such substrates reveals enormous rate accelerations. Thus the solvolytic rate acceleration of 87, as compared with the analogous a,a-dimethyl system 88, is in the range of 10596. Even the tertiary substrate 89 undergoes enhanced solvolytic rates.as compared with its a,a-dimethyl analogue 90. 

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