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Enamine
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An enamine is a functional group with the formula R2N−C(R')=CR2.[1][2] Enamines are reagents used in organic synthesis and are intermediates in some enzyme-catalyzed reactions.[3]
The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group containing both alkene (en-) and alcohol (-ol). Enamines are nitrogen analogs of enols.[4]
Enamines are both good nucleophiles and good bases. Their behavior as carbon-based nucleophiles is explained with reference to the following resonance structures.
Resonance structures for an enamine
Formation
[edit]
Condensation to give an enamine.[5]
Enamines can be easily produced from commercially available starting reagents. Commonly enamines are produced by condensation of secondary amines with ketones and aldehydes..[3][6] The condensing ketone and aldehyde must contain an α-hydrogen. The associated equations for enamine formation follow:
- R2NH + R'CH2CHO ⇌ R2NC(OH)(H)CH2R' (carbonolamine formation)
- R2NC(OH)(H)CH2R' ⇌ R2NCH=CHR' + H2O (enamine formation)
In some cases, acid-catalysts are employed. Acid catalysis is not always required, if the pKaH of the reacting amine is sufficiently high (for example, pyrrolidine, which has a pKaH of 11.26). If the pKaH of the reacting amine is low, however, then acid catalysis is required through both the addition and the dehydration steps.[7] Common dehydrating agents include MgSO4 and Na2SO4.[8]
Methyl ketone self-condensation is a side-reaction which can be avoided through the addition of TiCl4[9] into the reaction mixture (to act as a water scavenger).[8][10]
Primary amines are usually not used for enamine synthesis.[11] Instead, such reactions give imines:
- RNH2 + R'CH2CHO ⇌ R(H)NC(OH)(H)CH2R' (carbonolamine formation)
- R(H)NC(OH)(H)CH2R' ⇌ RN=C(H)CH2R' + H2O (imine formation)
Imines are tautomers of enamines. The enamine-imine tautomerism is analogous to the keto-enol tautomerism.
Lithiated enamines can be produced by deprotonation of imines using strong bases such as LiNR2. Metalloenamines are highly nucleophlic, e.g., they can be used to open epoxides.[12]) Most prominently, these reactions have allowed for asymmetric alkylations of ketones through transformation to chiral intermediate metalloenamines.[13]
Structure
[edit]
As shown by X-ray crystallography, the C3NC2 portion of enamines is close to planar. This arrangement reflects the sp2 hybridization of the C=CN core.
E vs Z geometry affects the reactivity of enamines.[8]
Reactions
[edit]Enamines are nucleophiles. Ketone enamines are more nucleophilic than their aldehyde counterparts.[15]
Compared to their enolate counterparts, their alkylations often proceed with fewer side reactions. Cyclic ketone enamines follow a reactivity trend where the five membered ring is the most reactive due to its maximally planar conformation at the nitrogen, following the trend 5>8>6>7 (the seven membered ring being the least reactive). This trend has been attributed to the amount of p-character on the nitrogen lone pair orbital - the higher p character corresponding to a greater nucleophilicity because the p-orbital would allow for donation into the alkene π- orbital. Analogously, if the N lone pair participates in stereoelectronic interactions on the amine moiety, the lone pair will pop out of the plane (will pyramidalize) and compromise donation into the adjacent π C-C bond.[16]
Alkylation and acylation
[edit]Alkylation is the predominant reaction sought with enamines. When treated with alkyl halides enamines give the alkylated iminium salts, which then can be hydrolyzes to regenerate a ketone (a starting material in enamine synthesis):
- R2N−CH=CHR' + R"X → [R2N+=CH−CHR'R"]X− (alkylation of enamine)
- [R2N+=CH−CHR'R"]+X− + H2O → R2NH + R'R"CHCHO (hydrolysis of the resulting iminium salt, giving a 2-alkylated aldehyde)
Owing to the pioneering work by Gilbert Stork, this reaction is sometimes referred to as the Stork enamine alkylation. Analogously, this reaction can be used as an effective means of acylation. A variety of alkylating and acylating agents including benzylic, allylic halides can be used in this reaction.[17]
Similar to their alkylation, enamines can be acylated. Hydrolysis of this acylated imine forms a 1,3-dicarbonyl.[18][11]
- R2N−CH=CHR' + R"COCl → [R2N+=CH−CHR'C(O)R"]Cl− (acylation of enamine)
- [R2N+=CH−CHR'C(O)R"]+Cl + H2O → R2NH + O=C(H)CH(R')CR"=O (hydrolysis of the resulting acyl iminium salt, giving a C-acylated aldehyde)
Halogenation
[edit]Chlorination of enamines followed by hydrolysis gives α-halo ketones and aldehydes:
- R2NCH=CHR' + Cl2 → [R2N+=CH−CHR'CCl]Cl− (chlorination of enamine)
- [R2N+=CH−CHR'Cl]Cl− + H2O → R2NH + R'CH(Cl)CHO (hydrolysis of chloroiminium, giving a chloroaldehyde)
In addition to chlorination, bromination and even iodination have been demonstrated.[19]
Oxidative coupling
[edit]Enamines can be efficiently cross-coupled with enol silanes through treatment with ceric ammonium nitrate.[20] Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final pyrrole formation.[21] This method for symmetric pyrrole synthesis was developed in 2010 by the Jia group, as a valuable new pathway for the synthesis of pyrrole-containing natural products.[22]
Annulation
[edit]Enamines chemistry has been implemented for the purposes of producing a one-pot enantioselective version of the Robinson annulation. The Robinson annulation, published by Robert Robinson in 1935, is a base-catalyzed reaction that combines a ketone and a methyl vinyl ketone (commonly abbreviated to MVK) to form a cyclohexenone fused ring system. This reaction may be catalyzed by proline to proceed through chiral enamine intermediates which allow for good stereoselectivity.[23] This is important, in particular in the field of natural product synthesis, for example, for the synthesis of the Wieland-Miescher ketone – a vital building block for more complex biologically active molecules.[24][25]
Biochemistry
[edit]
Nature processes (makes and degrades) sugars using enzymes called aldolases. These enzymes act by reversible formation of enamines.[26][27]
Further reading
[edit]Early literature of historic interest:
- the term "enamine" is coined: Wittig, Georg; Blumenthal, Hermann (1927). "Über die Einwirkung von Ammoniak und Ammoniak-Derivaten auf o -Acetylaceto-phenole". Berichte der Deutschen Chemischen Gesellschaft (A and B Series). 60 (5): 1085–1094. doi:10.1002/cber.19270600515.
- Stork, Gilbert.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. (1963). "The Enamine Alkylation and Acylation of Carbonyl Compounds". Journal of the American Chemical Society. 85 (2): 207–222. Bibcode:1963JAChS..85..207S. doi:10.1021/ja00885a021. ISSN 0002-7863.
- Mannich, C.; Davidsen, H. (1936). "Über einfache Enamine mit tertiär gebundenem Stickstoff" [On simple enamines with triple-bonded nitrogen]. Berichte der Deutschen Chemischen Gesellschaft (A and B Series) (in German). 69 (9): 2106–2112. doi:10.1002/cber.19360690921. ISSN 0365-9488.
See also
[edit]References
[edit]- ^ Clayden, Jonathan (2001). Organic chemistry. Oxford, Oxfordshire: Oxford University Press. ISBN 978-0-19-850346-0.
- ^ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 978-0-471-72091-1
- ^ a b Cook, Gilbert, ed. (1988). Enamines: Synthesis: Structure, and Reactions. Boca Raton: CRC Press. doi:10.1201/9780203758014. ISBN 978-1-351-45251-9.
- ^ Imines and Enamines | PharmaXChange.info
- ^ R. D. Burpitt and J. G. Thweatt (1968). "Cyclodecanone". Organic Syntheses. 48: 56; Collected Volumes, vol. 5, p. 277.
- ^ R. B. Woodward, I. J. Pachter, M. L. Scheinbaum (1974). "2,2- (Trimethylenedithio)cyclohexanone". Organic Syntheses. 54: 39. doi:10.15227/orgsyn.054.0039
{{cite journal}}: CS1 maint: multiple names: authors list (link). - ^ Capon, Brian; Wu, Zhen Ping (April 1990). "Comparison of the tautomerization and hydrolysis of some secondary and tertiary enamines". The Journal of Organic Chemistry. 55 (8): 2317–2324. doi:10.1021/jo00295a017.
- ^ a b c Lockner, James. "Stoichiometric Enamine Chemistry" (PDF). Baran Group, The Scripps Research Institute. Retrieved 26 November 2014.
- ^ Carlson, R; Nilsson, A (1984). "Improved Titanium Tetrachloride Procedure for Enamine Synthesis". Acta Chemica Scandinavica. 38B: 49–53. doi:10.3891/acta.chem.scand.38b-0049.
- ^ White, William Andrew; Weingarten, Harold (January 1967). "A versatile new enamine synthesis". The Journal of Organic Chemistry. 32 (1): 213–214. doi:10.1021/jo01277a052.
- ^ a b Farmer, Steven (2013-10-16). "Enamine Reactions". UC Davis Chem Wiki.
- ^ Evans, D. "Enolates and Metalloenamines II" (PDF). Retrieved 10 December 2014.[permanent dead link]
- ^ Meyers, A. I.; Williams, Donald R. (August 1978). "Asymmetric alkylation of acyclic ketones via chiral metallo enamines. Effect of kinetic vs. thermodynamic metalations". The Journal of Organic Chemistry. 43 (16): 3245–3247. doi:10.1021/jo00410a034.
- ^ Brown, Kevin L.; Damm, Lorenz; Dunitz, Jack D.; Eschenmoser, Albert; Hobi, Reinhard; Kratky, Christoph (1978). "Structural Studies of Crystalline Enamines". Helvetica Chimica Acta. 61 (8): 3108–3135. Bibcode:1978HChAc..61.3108B. doi:10.1002/hlca.19780610839.
- ^ Zvi Rappoport, Zvi (May 1994). Rappoport, Zvi (ed.). Enamines. PATAI'S Chemistry of Functional Groups. doi:10.1002/0470024763. ISBN 9780470024768.
- ^ Mayr, H. (2003). "Structure-Nucleophilicity Relationships for Enamines". Chem. Eur. J. 9 (10): 2209–18. Bibcode:2003ChEuJ...9.2209K. doi:10.1002/chem.200204666. PMID 12772295.
- ^ Wade, L.G. (1999). Organic Chemistry. Saddle River, NJ: Prentice Hall. pp. 1019. ISBN 9780139227417.
- ^ S. Hunig, E. Lucke, W. Brenninger (1963). "Docosanedioic Acid". Organic Syntheses. 43: 34. doi:10.15227/orgsyn.043.0034.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Seufert, Walter; Eiffenberger, Franz (1979). "Zur Halogenierung von Enaminen — Darstellung von β-Halogen-iminium-halogeniden". Chemische Berichte. 112 (5): 1670–1676. doi:10.1002/cber.19791120517.
- ^ Jang, HY; Hong, JB; MacMillan, DWC (2007). "Enantioselective organocatalytic singly occupied molecular orbital activation: the enantioselective alpha-enolation of aldehydes" (PDF). J. Am. Chem. Soc. 129 (22): 7004–7005. Bibcode:2007JAChS.129.7004J. doi:10.1021/ja0719428. PMID 17497866.
- ^ Li, Q; Fan, A; Lu, Z; Cui, Y; Lin, W; Jia, Y (2010). "One-pot AgOAc-mediated synthesis of polysubstituted pyrroles from primary amines and aldehydes: application to the total synthesis of purpurone". Organic Letters. 12 (18): 4066–4069. doi:10.1021/ol101644g. PMID 20734981.
- ^ Guo, Fenghai; Clift, Michael D.; Thomson, Regan J. (September 2012). "Oxidative Coupling of Enolates, Enol Silanes, and Enamines: Methods and Natural Product Synthesis". European Journal of Organic Chemistry. 2012 (26): 4881–4896. doi:10.1002/ejoc.201200665. PMC 3586739. PMID 23471479.
- ^ List, Benjamin (2002). "Proline-catalyzed asymmetric reactions". Tetrahedron. 58 (28): 5573–5590. doi:10.1016/s0040-4020(02)00516-1.
- ^ Bui, Tommy; Barbas (2000). "A proline-catalyzed asymmetric Robinson Annulation". Tetrahedron Letters. 41 (36): 6951–6954. doi:10.1016/s0040-4039(00)01180-1.
- ^ Wiener, Jake. "Enantioselective Organic Catalysis:Non-MacMillan Approaches" (PDF). Archived from the original (PDF) on 26 October 2017. Retrieved 29 November 2014.
- ^ Notz, Wolfgang; Tanaka, Fujie; Barbas, Carlos F. (2004). "Enamine-Based Organocatalysis with Proline and Diamines: The Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels−Alder Reactions". Accounts of Chemical Research. 37 (8): 580–591. doi:10.1021/ar0300468. PMID 15311957.
- ^ Mukherjee, Santanu; Yang, Jung Woon; Hoffmann, Sebastian; List, Benjamin (2007). "Asymmetric Enamine Catalysis". Chemical Reviews. 107 (12): 5471–5569. doi:10.1021/cr0684016. PMID 18072803.
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Enamine
View on Grokipediafrom Grokipedia
An enamine is an organic compound featuring a carbon-carbon double bond directly adjacent to a carbon-nitrogen single bond, with the general structure R₂N–CR=CR₂, where the nitrogen atom of the amine is bonded to one of the carbons of the alkene.[1] These compounds arise from the acid-catalyzed condensation reaction between a secondary amine and an aldehyde or ketone that possesses at least one α-hydrogen, involving the formation of a carbinolamine intermediate, dehydration to an iminium ion, and subsequent deprotonation at the α-carbon to generate the C=C bond while eliminating water.[1][2]
Enamines exhibit nucleophilic character at the β-carbon (the carbon of the C=C bond not directly attached to nitrogen) due to resonance delocalization of the nitrogen lone pair into the double bond, rendering them electron-rich alkenes analogous to enolates but neutral and more stable under non-basic conditions.[2][1] This reactivity allows enamines to undergo electrophilic addition reactions, such as alkylation with alkyl halides or conjugate addition to α,β-unsaturated carbonyls (Michael acceptors), followed by hydrolysis under aqueous acidic conditions to regenerate the corresponding α-substituted carbonyl compound.[2]
The formation and reactions of enamines are typically reversible, with the equilibrium favoring the enamine in anhydrous conditions and shifting back to the amine and carbonyl upon hydrolysis, making them versatile synthetic intermediates.[1] Enamines undergo hydrolysis under acidic conditions, and they often require catalysts like p-toluenesulfonic acid for efficient preparation.[2] In terms of stereochemistry, enamine formation can lead to mixtures of E and Z isomers, but the reactivity at the β-carbon proceeds with high regioselectivity at the α-position of the original carbonyl.[2]
Enamines play a pivotal role in organic synthesis, particularly in the Stork enamine reaction, a method developed in 1954 for the α-alkylation and acylation of carbonyl compounds that avoids the issues of polyalkylation and strong basicity associated with direct enolate chemistry. This approach has been widely applied in the total synthesis of natural products, pharmaceuticals, and complex molecules, enabling selective C–C bond formation at the α-position of ketones and aldehydes.[2] More recently, enamine intermediates have been incorporated into organocatalytic processes, such as asymmetric aldol and Michael additions, expanding their utility in enantioselective synthesis.[3]
In cyclic enamines, such as those from cyclohexanone derivatives, stereoselectivity arises from a preference for axial attack of the electrophile on the enamine double bond, leading to trans diastereomers in the alkylated products due to the chair-like transition state.[33]
A key limitation is the incompatibility with aryl halides, which do not readily undergo SN2 reactions without additional catalytic activation, restricting the method primarily to aliphatic electrophiles.[32]
Structure
General Formula
Enamines are unsaturated organic compounds featuring an amine group connected to a carbon-carbon double bond, with the general structural formula , where R, R', and R'' represent hydrogen atoms or organic substituents such as alkyl or aryl groups.[4] In this arrangement, the nitrogen atom is bonded to one of the sp²-hybridized carbons of the alkene, distinguishing enamines from simple amines or alkenes.[5] This structural motif renders enamines as synthetic equivalents of enolates, wherein the β-carbon (positioned relative to the nitrogen) exhibits nucleophilic reactivity analogous to the α-carbon of an enolate ion. A typical example is N-(1-propenyl)pyrrolidine (), formed from the secondary amine pyrrolidine and propanal.[6] The term "enamine," combining "ene" and "amine," was coined by Georg Wittig and Hermann Blumenthal in 1927.[7] Gilbert Stork popularized their use in synthesis in the 1950s to emphasize their role in facilitating selective carbon-carbon bond formations.Electronic and Stereochemical Features
Enamines exhibit significant electronic delocalization due to the conjugation of the nitrogen lone pair with the adjacent carbon-carbon double bond. This interaction is represented by two primary resonance structures: one with a localized C=C double bond and a neutral nitrogen lone pair, and another where the lone pair donates into the π-system, forming a C-N partial double bond and a carbanion-like character at the β-carbon.[8] The partial double bond character between the nitrogen and the α-carbon restricts rotation, enforcing planarity around the enamine moiety to maximize orbital overlap and stabilize the system.[5] This delocalization results in an electron-rich β-carbon, rendering it nucleophilic and analogous to the α-carbon in enolate ions, which underpins the reactivity of enamines in synthetic applications.[9] The electron distribution in enamines is influenced by the lower electronegativity of nitrogen compared to oxygen, leading to greater electron density at the β-carbon than in corresponding enols. The nitrogen lone pair, being more available for donation, enhances the π-electron density across the C=C bond, with bond lengths consistent with this partial conjugation (shorter than a typical single bond). This electronic arrangement also reduces the basicity of the nitrogen relative to aliphatic amines, as the lone pair is partially involved in resonance rather than fully available for protonation.[10] Stereochemically, enamines derived from unsymmetrical ketones can exist as E or Z isomers about the C=C double bond, depending on the substituents at the α- and β-positions. The Z configuration is often preferred in simple alkyl-substituted enamines due to minimized steric hindrance between the nitrogen substituents and the β-hydrogen or alkyl group, as evidenced by NMR studies showing predominant Z populations in pyrrolidine-derived enamines.[9] In cases of bulkier substituents, the E isomer may predominate to avoid 1,3-diaxial-like interactions in the transition state during formation.[11] These geometric preferences influence the stereoselectivity of subsequent reactions but do not alter the core planarity enforced by the resonance. As nitrogen analogs of enols, enamines display enhanced stability relative to their oxygen counterparts, attributed to the greater basicity and electron-donating ability of amines, which facilitates formation without requiring strong bases.[12] Unlike enols, which exist primarily as tautomers in equilibrium with carbonyls, enamines are isolable and persistent under neutral conditions due to the absence of an acidic α-proton on nitrogen and the stabilizing resonance delocalization.[13] This analogy extends to reactivity, where enamines serve as neutral enolate equivalents, but their stability allows for milder handling in synthesis.[8]Formation
From Carbonyl Compounds
Enamines are primarily synthesized through the condensation reaction of aldehydes or ketones with secondary amines, a process that requires the presence of an α-hydrogen on the carbonyl compound to facilitate the formation of the characteristic C=C bond adjacent to the nitrogen.[14] This method is effective for a wide range of aldehydes and ketones using secondary amines such as pyrrolidine or morpholine, which lack a hydrogen atom on the nitrogen and thus cannot form stable imines.[15] A simplified representation of the reaction, using acetaldehyde as an example, is: where denotes alkyl substituents on the nitrogen.[16] The mechanism proceeds in several discrete steps under acid-catalyzed conditions. Initially, the secondary amine acts as a nucleophile, adding to the protonated carbonyl group of the aldehyde or ketone to form a tetrahedral carbinolamine intermediate.[14] Proton transfer within this intermediate yields a neutral carbinolamine. Subsequent acid-catalyzed protonation of the hydroxyl group enhances its leaving ability, leading to dehydration and formation of an iminium ion intermediate, where the positively charged nitrogen is bonded to the former carbonyl carbon.[15] Finally, deprotonation occurs at the α-carbon position adjacent to the iminium ion, generating the enamine with its conjugated double bond.[16] Acid catalysis, typically employing p-toluenesulfonic acid, is crucial for accelerating the dehydration step by protonating the carbinolamine's hydroxyl group, with optimal conditions around pH 5 to balance activation and avoid over-protonation of the amine.[17] To drive the equilibrium toward enamine formation and remove the byproduct water, reactions are commonly conducted using azeotropic distillation with a Dean-Stark trap or by employing molecular sieves, which also exhibit mild catalytic effects.[17][18] These conditions ensure high yields, particularly for cyclic secondary amines like pyrrolidine reacting with ketones such as cyclohexanone.[19]Alternative Synthetic Routes
These N-silyl enamines are typically generated from imines via transition metal-catalyzed hydrosilylation, offering stability and utility in subsequent transformations. For instance, rhodium or copper catalysts facilitate the addition of silanes across C=N bonds to form these species efficiently.[20] Rearrangement of allylic amines provides another pathway, involving isomerization to the thermodynamically favored enamine tautomer, often promoted by radical or metal catalysts. Thiol-mediated radical processes cleave the allylic C-N bond and rearrange the substrate to simple enamines, with yields up to 80% reported for aliphatic systems. Palladium-catalyzed variants enable selective migration in N-allyl enamine precursors, though typically in the reverse direction for synthetic utility.[21][22] Preformed imines can undergo base-catalyzed tautomerization to enamines when an α-hydrogen is available, deprotonating the α-carbon to form the C=C-N motif. This isomerization is accelerated by strong bases like organolithiums or amidates, contrasting acid-driven classical routes, and is effective for enamine generation from stable imine intermediates. Photochemical and electrochemical techniques represent modern innovations for direct enamine assembly in the 2020s. Visible-light-mediated photocatalyst-free acylation of vinyl azides with 4-acyl-1,4-dihydropyridines (4-acyl-DHPs) yields β-enaminones, proceeding via azide decomposition and enamine trapping without metal additives, achieving up to 90% yields for electron-rich substrates.[23] Electrochemically, undivided cell reactions of vinyl azides with thiols generate gem-bis(sulfenyl)enamines through anodic oxidation and radical addition, with broad substrate scope and efficiencies around 60-80%.[24] Despite their versatility, these alternative routes frequently deliver lower yields (often below 70%) for sterically hindered or multifunctional substrates relative to the classical carbonyl-amine condensation, due to side reactions like over-addition or catalyst deactivation.Properties
Physical Characteristics
Enamines are generally volatile compounds, exhibiting lower boiling points than their corresponding imines owing to reduced intermolecular forces, as the enamine structure lacks the N-H functionality that enables hydrogen bonding in many imines. For example, the representative enamine 1-(1-pyrrolidinyl)cyclohexene boils at 114–115 °C under reduced pressure (15 mmHg).[25] These compounds demonstrate high solubility in a range of organic solvents, including diethyl ether, dichloromethane, and ethanol, which facilitates their use in synthetic applications. Smaller enamines with fewer carbon atoms show moderate solubility in water, attributable to the polar amine moiety enabling hydrogen bonding interactions similar to those in aliphatic amines. Enamines are air-sensitive and particularly prone to hydrolysis upon exposure to moisture, which can revert them to the parent carbonyl compound and amine; consequently, they require storage under an inert atmosphere, such as nitrogen or argon, to preserve stability. They are commonly isolated as colorless oils or low-melting solids.Spectroscopic Properties
Enamines are readily characterized by infrared (IR) spectroscopy, which reveals key absorption bands associated with their functional groups. The characteristic C=C stretching vibration occurs in the range of 1600-1650 cm⁻¹, reflecting the conjugated alkene system influenced by the adjacent nitrogen atom.[26] Additionally, the N-C stretching band appears around 1000-1100 cm⁻¹, typical of the amine linkage. A defining feature is the absence of the strong carbonyl (C=O) absorption near 1700-1750 cm⁻¹, which distinguishes enamines from their precursor carbonyl compounds.[27] In ¹H NMR spectroscopy, enamines display distinctive signals for their vinyl protons, which resonate between 4 and 6 ppm due to the deshielding effect of the double bond and nitrogen conjugation. The beta proton (positioned on the carbon distant from the nitrogen) is particularly shifted downfield compared to non-conjugated alkenes, often appearing around 4.5-5.5 ppm, as a result of the electron-withdrawing influence through conjugation.[6] For example, in pyrrolidine-derived enamines, the olefinic proton has been observed at approximately 4.44 ppm.[6] These shifts provide clear evidence of the enamine structure and its stereoelectronic features. ¹³C NMR spectroscopy further aids in enamine identification by showing signals for the sp²-hybridized carbons of the C=C bond in the 90-150 ppm range, with variations depending on substituents and configuration. The α-carbon directly bound to nitrogen typically appears at 140-160 ppm, while the β-carbon is around 90-110 ppm, reflecting the sp² hybridization and resonance delocalization from the nitrogen lone pair. These chemical shifts help differentiate enamine tautomers and configurations, as the β-carbon is particularly sensitive to steric effects.[28] Ultraviolet-visible (UV-Vis) spectroscopy of enamines features absorption bands around 220-250 nm, arising from the n-π* transition where the nitrogen lone pair interacts with the π-system of the alkene. This extended conjugation leads to bathochromic shifts relative to simple alkenes, enhancing the intensity and wavelength of absorption compared to isolated C=C systems.[29]Reactions
Nucleophilic Alkylation
Enamines serve as versatile nucleophilic equivalents to enolates in the alkylation of carbonyl compounds, enabling selective C-C bond formation at the α-position without the self-condensation problems inherent to direct enolate alkylations.[13] This process, known as the Stork enamine alkylation, involves the β-carbon of the enamine acting as the nucleophile in an SN2 reaction with an alkyl halide, generating an iminium salt intermediate that is subsequently hydrolyzed under aqueous acidic conditions to yield the α-alkylated carbonyl product.[30] The mechanism proceeds via nucleophilic attack by the enamine's electron-rich β-carbon on the electrophilic carbon of the alkyl halide, displacing the halide ion and forming a positively charged iminium species; hydrolysis then regenerates the carbonyl group while releasing the secondary amine catalyst.[31] The reaction scope is broad for primary and secondary alkyl halides, which undergo efficient SN2 displacement due to the enamine's high nucleophilicity, allowing monoalkylation of ketones and aldehydes with minimal overalkylation.[32] Unlike enolates, enamines avoid issues such as O-alkylation or aldol side reactions, providing a milder and more controlled approach to α-alkylation.[13] The classic example of this reaction, reported by Stork and coworkers in 1954, involves the pyrrolidine enamine derived from cyclohexanone reacting with methyl iodide to afford 2-methylcyclohexanone after hydrolysis, demonstrating the method's utility in introducing simple alkyl groups.[30]Cyclohexanone + [pyrrolidine](/page/Pyrrolidine) → enamine → + CH₃I → iminium salt → [hydrolysis](/page/Hydrolysis) → 2-methyl[cyclohexanone](/page/Cyclohexanone)
Cyclohexanone + [pyrrolidine](/page/Pyrrolidine) → enamine → + CH₃I → iminium salt → [hydrolysis](/page/Hydrolysis) → 2-methyl[cyclohexanone](/page/Cyclohexanone)