Enamines - Chapter 4 PDF

Enamines Chapter-4  An enamine is an unsaturated compound formed by the condensation of an aldehyde or ketone with a secondary amine. These compounds are versatile intermediates in organic synthesis. The term "enamine" combines "en-" (referring to the alkene structure) and "amine," and c...

Enamines Chapter-4  An enamine is an unsaturated compound formed by the condensation of an aldehyde or ketone with a secondary amine. These compounds are versatile intermediates in organic synthesis. The term "enamine" combines "en-" (referring to the alkene structure) and "amine," and can be compared to "enol," which combines an alkene (en-) with an alcohol (-ol) functional group. Enamines are thus nitrogen analogs of enols. If one or both substituents on the nitrogen are hydrogen atoms, the compound exists in a tautomeric equilibrium with its imine form. Generally, this equilibrium favors the imine form, but some compounds, like aniline, are exceptions. This enamine-imine tautomerism is analogous to keto-enol tautomerism, where a hydrogen atom shifts between a heteroatom (oxygen or nitrogen) and the adjacent carbon atom. Enamines are notable for their dual nature as good nucleophiles and bases. Their nucleophilicity as carbon-based species can be explained by their resonance structures.  Enamines are formed from the reaction of a secondary amine with an aldehyde or ketone. Because they have a significant resonance form where there is a negative charge on the alpha carbon, they are nucleophilic. Enamines undergo reactions with electrophiles such as alkyl halides and Michael acceptors They are hydrolyzed with strong acid. 1. What Are Enamines And How Are They Made? If there is a proton on the alpha-carbon (i.e. the aldehyde/ketone is “enolizable”), deprotonation can result in a related species known as an enamine. The major difference between enamine formation and imine formation is that instead of forming a C-N pi bond, we form a new C-C pi bond.  The formation of enamines from the combination of aldehydes or ketones with a secondary amine generally requires an acid catalyst to assist in the loss of water (H 2O) from the starting aldehyde/ketone. This is therefore an example of a condensation reaction. As with imine formation, the reaction is an equilibrium, but removing water through distillation or using a desiccant such as molecular sieves (TiCl 4) helps drive the reaction towards the final enamine product. 2. The Mechanism for Enamine Formation In imine formation under acidic conditions, we saw that the mechanism follows the PADPED mnemonic– Protonation Addition Deprotonation Protonation Elimination Deprotonati on. Formation of enamines also follows PADPED – it’s just important to remember that the Deprotonation occurs on carbon, not nitrogen, and there is the formation of a new C-C pi bond. The first step of enamine formation is the protonation of the aldehyde/ketone oxygen, followed by the addition of the secondary amine to the carbonyl carbon. Addition forms a new C-N bond and breaks the C-O pi bond. The addition step results in a positively charged nitrogen. Proton transfer from nitrogen to oxygen is accomplished through Deprotonation of nitrogen with base (e.g. excess amine) followed by Protonation of the OH to give OH2(+).  Now that there is a free lone pair on nitrogen and a good leaving group (OH 2) the stage is set for the reverse of addition, that is Elimination of water to give a new C–N pi bond. This results in an iminium salt. However, deprotonation at the alpha-carbon (CH3 in this example) can result in the formation of a C-C pi bond, and breakage of the C-N pi bond. This final deprotonation step gives us our neutral enamine species and a molecule of water. 3. Properties of Enamines (Nucleophiles): An alkene attached to an amine does have some pretty special properties because that nitrogen lone pair makes enamines capable of all kinds of funky reactions that most alkenes can’t undergo. The nitrogen combines with the pi bond of the alkene to give an extended pi system that is capable of resonance. The nitrogen lone pair of amines is a strong electron donor and can form a new C-N pi bond  That means that carbon in the resonance hybrid will have a significant negative charge density. In other words, it will be highly nucleophilic.  Amino groups (-NH2, -NHR, -NR2) are strongly activating ortho-para directors. Drawing resonance forms where N formed a new pi-bond with the aromatic ring, resulting in a negative charge on the ortho carbon. The same phenomenon is in effect here. If you grey out some of the bonds on the aromatic ring and squint, an enamine greatly resembles a strongly activated aromatic ring: By this analogy we’d similarly expect enamines to be excellent nucleophiles and for them to react with electrophiles. 4. Reactions of Enamines: Alkylation: Enamines are significantly more reactive than alkenes towards electrophiles. Alkenes, for example, won’t react with alkyl halides. But enamines will! For example, an enamine treated with CH3I will form a new C-C bond. This is an example of enamine alkylation. A new carbon-carbon bond is formed.  For convenience, water is often added in the workup, so step 2 shows hydrolysis. Essentially the same way as protonation, above, except that the enamine carbon attacks carbon as the electrophile instead of H+ (or D+). This is an SN2 reaction at carbon, with the enamine alpha-carbon as the nucleophile: formation of N-C (pi), breakage of C-C (pi), formation of C-C and breakage of C-X (iodine in this case). It’s a nice alternative to forming C-C bonds through the alkylation of the ketone enolate. 5. Reactions of Enamines: Michael Addition (Conjugate Addition) : Enamines are also nucleophilic enough to perform conjugate additions (“Michael additions”) with alpha, beta unsaturated species such as this ketone below (methyl vinyl ketone).  As with alkylation, the usual procedure is to just add aqueous acid after the reaction is complete, resulting in hydrolysis of the enamine and formation of a new ketone. Just as nitrogen lone pairs are pi-donors that make alkenes more nucleophilic, you may recall that C=O bonds are pi-acceptors that make alkenes more electrophilic. A classic example is “alpha, beta-unsaturated” ketones (a.k.a. “enones”). For the reaction between enamines and enones, you might find it helpful to imagine the resonance form of the enamine (negative charge on C) forming a bond with the resonance form of the alpha, beta-unsaturated carbon (positive charge on C). 6. Reactions of Enamines: Hydrolysis With Aqueous Acid Enamines are easily transformed back into aldehydes/ketones though hydrolysis with using aqueous acid (H2SO4/H2O is an alternative way of depicting the same thing). Protonation of the enamine at the alpha carbon, followed by Addition of water to the resulting iminium ion. Deprotonation of oxygen Protonation of nitrogen (making it into a better leaving group) Elimination of neutral HNR2 Deprotonation of oxygen to give the neutral carbonyl.  Summary Enamines can be formed through the addition of a secondary amine to an enolizable aldehyde/ketone in the presence of mild acid. The mechanism is PADPED. The nitrogen of enamines is a powerful pi-donor, making the alkene particularly nucleophilic (just like how amine groups like NH2, NHR, and NR2 strongly activate aromatic rings towards electrophilic aromatic substitution). Enamines undergo alkylation at carbon with alkyl halides. They can also perform conjugate addition (“Michael reactions”). Enamines can be hydrolyzed back to aldehydes/ketones with aqueous acid.