Tertiary carbon centers, nucleophilic reactions

First, identify the leaving group, the electrophilic carbon, and the nucleophile. Then decide whether the reaction follows the SN1 or SN2 mechanism because this determines the stereochemistry. If the leaving group is bonded to a tertiary carbon, then the reaction must occur by the SN1 mechanism. (Later we will learn other factors that control which substitution mechanism a reaction follows.) For an SNI reaction, replace the leaving group on the electrophilic carbon with the nucleophile with loss of stereochemistry at the reaction center. 

The reaction starts with the nucleophilic addition of a tertiary amine 4 to the alkene 2 bearing an electron-withdrawing group. The zwitterionic intermediate 5 thus formed, has an activated carbon center a to the carbonyl group, as represented by the resonance structure 5a. The activated a-carbon acts as a nucleophilic center in a reaction with the electrophilic carbonyl carbon of the aldehyde or ketone 1 ... 

The new reaction appears to be a simple one-step procedure, which is particularly suitable for tertiary alkyl-aryldiazenes for which alternative synthetic routes are less convenient. However, aryl radicals or alkyl radicals in which the carbon-centered radical is bonded to an electron-withdrawing group (COOR, COR, CONR2, CN, S02R, etc.) do not add to diazonium salts or give only poor results (Citterio et al., 1982 c). This indicates that the radical must be a relatively strong nucleophile in order to be able to react with a diazonium ion. 

The presence of a quaternary carbon atom is frequently encountered in sesquiterpene natural products and it often creates a synthetic challenge when two or more quaternary carbon atoms are present contiguously. The synthetic strategies for the construction of quaternary carbon centers involve sigmatropic rearrangements/ intramolecular cycloaddition/ and the reaction of tertiary carbon nucleophiles with a carbon electrophile. Recently, radical cyclization strategies turned out to be very effective for this purpose. For example, Srikrishna utilized the radical cyclization reaction to prepare tricyclo[6.2.1.0 - ]undecane system, which is present in several sesquiterpenes such as zizaenes and prelacinanes, and Chen demonstrated that a tandem radical cyclization approach is an efficient method for constructing the two quaternary carbon centers in the cedrene skeleton. ... 

Nucleophilic substitution reactions of aniline are also studied at tertiary alkyl carbon centers in MeCN66. The reactions with 2-cyano-2-propyl, 5, and 1-cyanooctyl, 6, arenesulfonates are reported in MeCN at 50.0 °C. 

Although the methacrylate polymer enolate ion is centered on a hindered tertiary carbon, it is reactive enough to participate in nucleophilic substitution reactions with suitably reactive electrophiles. Such reactions must necessarily be carried out at or near -78°C to ensure that the anion is not inactivated by the thermal cyclization reaction. Typical of such reactions is that with-vinyl benzyl iodide which gives the styryl-capped oligomer 14. 

The silyl ether forms by an Sj 2 reaction at a tertiary center. This reaction can occur at a tertiary silicon center because the C —Si bond length is 195 pm, compared to the 154 pm of a C—C bond length. The alkyl groups bonded to the tertiary sihcon atom are farther away from each other than alkyl groups bonded to a tertiary carbon atom. Therefore, they do not present as much steric interference to the approach of a nucleophile as the alkyl groups in the analogous carbon compound, r[Pg.548]

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

The reaction proceeds well with unhindered secondary amines as both nucleophiles and bases. The yield of allylic amine formed depends upon how easily palladium hydride elimination occurs from the intermediate. In cases such as the phenylation of 2,4-pentadienoic acid, elimination is very facile and no allylic amines are formed with secondary amine nucleophiles, while phenylation of isoprene in the presence of piperidine gives 29% phenylated diene and 69% phenylated allylic amine (equation 30).84 Arylation occurs at the least-substituted and least-hindered terminal diene carbon and the amine attacks the least-hindered terminal ir-allyl carbon. If one of the terminal ir-allyl carbons is substituted with two methyl groups, however, then amine substitution takes place at this carbon. The reasons for this unexpected result are not clear but perhaps the intermediate reacts in a a- rather than a ir-form and the tertiary center is more accessible to the nucleophile. Primary amines have been used in this reaction also, but yields are only low to moderate.85 A cyclic version occurs with o-iodoaniline and isoprene.85... 

We have already established that the carbene carbon is an electrophilic center and, hence, it should be very easily attacked by nucleophiles. In most reactions we believe that the first reaction step probably involves attachment of a nucleophile to the carbene carbon. In some cases, for instance with several phosphines (49) and tertiary amines (50), such addition products are isolable analytically pure under certain conditions (1 in Fig. 3). For the second step there exists the possibility that the nucleophilic agent may substitute a carbon monoxide in the complex with preservation of the carbene ligand (2 in Fig. 3). One can also very formally think of the carbene complex as an ester type of system [X=C(R )OR with X = M(CO)j instead of X = 0], because the oxygen atom as well as the metal atom in the M (CO) 6 residue are each missing 2 electrons for attainment of an inert gas configuration. So, it is not surprising that the... 

Another type of chemical reaction that has been investigated is the addition of a nucleophile to a carbonyl center, illustrated for the addition of ammonia to a carbonyl group in Figure 18.10. Nucleophilic addition is an important feature of many biochemical reactions and appears to involve a tetrahedral intermediate. Burgi, Dunitz, and Eli Shelter studied molecules with both a carbonyl group and a tertiary amino group that were separated by varying numbers of carbon atoms. They measured,... 

Also, operating at 200°C tlie reaction occurs at the carbonyl atom only. In fact, when 1-octanol was used in reactions with DMC in the presence of K2CO3, no methyl ether was observed, but methyl octyl carbonate and dioctyl carbonate were the only products formed. Methylation of alcohols was reported to occur also operating in the presence of tertiary amines (N,N -dimethylamino-pyridine, l,4-diazobicyclo[2,2,2]octane). In this case, however, the catalyst modifies the hard-soft character of the two centers, thus allowing the nucleophilic displacement by the alkoxide to occur. 

Nucleophilic anions, i.e. halides, pseudohalides, alkoxides, phenoxides, and thio-phenoxides, are particularly suitable for these reactions. Even anions of lower reactivity in nucleophilic displacements, i.e. carboxylates, nitrates, nitrites and hydroperoxides, find practical application under PTC conditions. Reactions are rigorously Sf,2 in mechanism primary substrates are thus most suitable, since secondary substrates afford elimination products in high yields, especially when reacted at high temperatures, and tertiary substrates only give rise to elimination. This behaviour is consistent with the low polarity of the organic phase, preventing unimolecular mechanisms and favouring elimination over substitution when the reaction center is not a primary carbon atom. 

Most 8 2 reactions are faster in aprotic solvents and slower in protic solvents. Water tends to promote ionization. In pro-tic media, particularly aqueous media, ionization of tertiary halides occurs to give a carbocation intermediate (more slowly with secondary halides) 9,10,11,12,49, 55,69, 70, 77,86. Carbocation intermediates can be trapped by nucleophiles in what is known at an 8 1 reaction. An 8 1 reaction proceeds by ionization to a planar carbocation containing an sp hybridized carbon, follows first-order kinetics, and proceeds with racem-ization of a chiral center. Carbocations are subject to rearrangement to a more stable cation via 1,2 hydrogen or alkyl shifts 24, 25, 26, 27, 29, 50, 65, 67, 76, 77, 78, 79, 80, 81, 83, 84, 85,87,88, 89. A variety of nucleophiles can be used in the substitution reactions, including halides, alkoxides, amines, phosphines, azides, cyanide, acetylides, and enolate anions 2,3,13,14,36,62,63,88, 89,105. 

Propagation proceeds by nucleophilic attack of an oxygen atom in a monomer molecule on a carbon atom in a-position to an oxygen atom bearing formally the positive charge in a tertiary oxonium ion located at the chain end. Even such a simplified scheme indicates the possibility of a side reaction that is a typical feature of cationic polymerization of cyclic ethers. A nucleophilic center (oxygen atom) is present not only in monomers but also in polymer chains. Therefore, the attack of an oxygen atom from the chain on a carbon atom in a... 

---