In tertiary substrates

Keep in mind when filling in the E2 chart, that you don t have the same steric concerns in tertiary substrates that you had in SN2 reactions. The base does not need to get in and attack the carbon. It only has to pull off a proton. Sterics is no longer an effect in this case, and you can have E2 reactions on tertiary substrates ... 

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. 

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. 

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. 

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. 

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. 

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... 

Aqueous two-phase hydrogenations are dominated by platinum group metal catalysts containing water-soluble tertiary phosphine ligands. The extremely stable and versatile N-heterocyclic carbene complexes attracted only limited interest, despite the fact that such complexes were described in the literature [62-65]. Recently, it was reported that the water-soluble [RuXY(l-butyl-3-methylimi-dazol-2-ylidene) ( 76-p-cymene)]n+ (X=Ch, H20 Y = C1-, H20, pta) complexes preferentially hydrogenated cinnamaldehyde and benzylideneacetone at the C = C double bond (Scheme 38.5) with TOF values of 30 to 60 h 1 in water substrate biphasic mixtures (80 °C, lObar H2) [66]. 

That the formation of molecular complexes (especially EDA complexes) can catalyse the decomposition of the cr-adduct has been discussed in Section n.E. Another possibility is that the substrate and catalyst (nucleophile or added base) form a complex which is then attacked by a new molecule of the nucleophile in this context catalysis need no longer be associated with proton removal. Thus, Ryzhakov and collaborators183 have recently shown that the N-oxides of 4-chloropyridine and 4-chloroquinoline act as jt-donors toward tetracyanoethylene and that the reactions of these substrates with pyridine and quinoline are strongly catalysed by the jr-acceptor. Similarly, the formation of a Meisenheimer complex between 1,3,5-trinitrobenzene and l,8-diazabicyclo[5,4,0]undec-7-ene in toluene has been assumed to take place via an association complex to explain the observed second-order in tertiary amine184. 

Lipid transfer peptides and proteins occur in eukaryotic and prokaryotic cells. In vitro they possess the ability to transfer phospholipids between lipid membranes. Plant lipid transfer peptides are unspecific in their substrate selectivity. They bind phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and glycolipids. Some of these peptides have shown antifungal activity in vitro The sequences of lipid transfer proteins and peptides contain 91-95 amino acids, are basic, and have eight cysteine residues forming four disulfide bonds. They do not contain tryptophan residues. About 40% of the sequence adopts a helical structure with helices linked via disulfide bonds. The tertiary structure comprises four a-helices. The three-dimensional structure of a lipid transfer peptide from H. vulgare in complex with palmitate has been solved by NMR. In this structure the fatty acid is caged in a hydrophobic cavity formed by the helices. 

How does phosphorylation of the substrate control ubiquitination. In the case of protein such as c-jun, phosphorylation perhaps masks a signal in the substrate recognized by the E3 ligase such that the substrate is unavailable for ubiquitination. In contrast, in those substrates that become susceptible to degradation after phosphorylation such as yeast cyclins, it is probable that phosphorylation unmasks a sequence or tertiary structure in the substrate, which the E3 ligase can recognize for ubiquitination. 

In the examples above, one or both of the reaction centers are already attached to the metal center. In many cases, the reactants are free before reaction occurs. If a metal ion or complex is to promote reaction between A and B, it is obvious that at least one species must coordinate to the metal for an effect. It is far from obvious whether both A and B enter the coordination sphere of the metal in a particular instance. A number of metal-oxygen complexes can oxygenate a variety of substrates (SOj, CO, NO, NO2, phosphines) in mild conditions. Probably the substrate and O2 are present in the coordination sphere of the metal during these so-called autoxidations. In the reaction of oxygen with transition metal phosphine complexes, oxidation of metal, of phosphine or of both, may result. The initial rate of reaction of O2 with Co(Et3P)2Cl2 in tertiary butylbenzene. 

For tertiary, secondary, and primary chlorides the reduction becomes increasingly difficult due to shorter chain lengths. On the other hand, the replacement of a chlorine atom by hydrogen in polychlorinated substrates is much easier. Table 4.2 shows the rate constants for the reaction of (TMS)3Si radical with some chlorides [32]. The comparison with the analogous data of Table 4.1 shows that for benzyl and tertiary alkyl substituents the chlorine atom abstraction is 2-3 orders of magnitude slower than for the analogous bromides. 

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. 

Trifluoromethylation can be achieved with the use of imidazolylidene carbene 1 [159], Song and co-workers found this transformation is tolerant of both electron-rich and electron-poor aldehydes (Table 26). Even enolizable aldehydes undergo trifluoromethylation in 81% yield (entry 3). Selective reaction occurs with an aldehyde in the presence of a ketone in the substrate (entry 5). The use of activated ketones as acceptors leads to tertiary alcohols in good yields (entries 7 and 8). 

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." ... 

Elemental fluorine can be used to replace relatively electron rich C-H bonds by C-F. In particular, tertiary hydrogen atoms which are remote from electron withdrawing substituents can be selectively replaced by fluorine and, where there is more than one tertiary hydrogen atom in the substrate, that with the higher electron density is replaced (Fig. 44). In contrast, where there is an electron withdrawing group close to tertiary hydrogen, very little reaction with fluorine takes place and, consequently, when one fluorine atom has been introduced into a molecule further reaction is often inhibited. 

---