Baylis-Hillman reaction
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The '''Baylis-Hillman reaction''' is an [[organic reaction]] of an [[aldehyde]] and an α,β-[[saturation (chemistry)|unsaturated]] [[electron-withdrawing group]] catalyzed by [[DABCO]] (1,4-diazabicyclo[2.2.2]octane) to give an [[allyl|allylic]] [[alcohol]] <ref>Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, '''1972'''.</ref>. This reaction is also known as the '''Morita–Baylis–Hillman reaction''' or '''MBH reaction''' <ref>K. Morita, Z. Suzuki and H. Hirose, Bull. Chem. Soc. Jpn.,'''1968''', 41, 2815.</ref>. It is named for the Japanese chemist Ken-ichi Morita, the British chemist Anthony B. Baylis and the German chemist Melville E. D. Hillman.
[[Image:Baylis_Hilman_Reaction_Scheme.png|center|500px|Baylis-Hillman Reaction.]]
In addition to DABCO, additional [[nucleophilic]] [[amine]]s such as [[DMAP]] and [[DBU_(chemistry)|DBU]] as well as [[phosphines]] have been found to successfully catalyze this reaction.
==Reaction mechanism==
The [[nucleophilic addition]] of DABCO '''2''' onto the α,β-unsaturated ketone '''1''' gives a charged [[zwitterionic]] intermediate '''3''', which will add to the [[electrophilic]] [[aldehyde]] producing the keto-alcohol '''4'''. [[Elimination reaction|Elimination]] of the DABCO gives the desired [[allylic alcohol]] '''5'''.
[[Image:Baylis-Hilman_Mechanism_Scheme-1.png|center|800px|The mechanism of the Baylis-Hillman reaction.]]
A simple relationship exists between [[pKa]] of the base (as its [[conjugate acid]]s) and the [[reaction rate]] with [[quinuclidine]] even more effective than DABCO. [[Protic]] additives like [[methanol]], [[triethanolamine]], [[formamide]], and [[water|water (molecule)]] also accelerate the reaction <ref>''Correlation between pKa and Reactivity of Quinuclidine-Based Catalysts in the Baylis-Hillman Reaction: Discovery of Quinuclidine as Optimum Catalyst Leading to Substantial Enhancement of Scope'' Aggarwal, V. K.; Emme, I.; Fulford, S. Y. [[J. Org. Chem.]] (Article); '''2003'''; 68(3); 692-700. {{DOI|10.1021/jo026671s}} </ref>.
An alternative mechanism, based on extensive rate data, has been proposed for some aldehydes.<ref>''Baylis-Hillman Mechanism: A New Interpretation in Aprotic Solvents'' Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T.; ''[[Org. Lett.]]'', '''2005''', ''7(1)'', 147-150. {{DOI|10.1021/ol047739o}}</ref> <ref>''A New Interpretation of the Baylis-Hillman Mechanism'' Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. [[J. Org. Chem.]] (Article); '''2005'''; 70(10); 3980-3987. {{DOI|10.1021/jo050202j}} </ref> <ref>''Synthetic potential of the tertiary-amine-catalysed reaction of activated vinyl carbanions with aldehydes'' Drewes, S. E.; Roos, G. H. P.; ''[[Tetrahedron (journal)|Tetrahedron]]'' '''1988''', ''44'', 4653-4670. {{DOI|10.1016/S0040-4020(01)86168-8}}</ref>. This mechanism (figure below) takes into account experimentally determined second order kinetics for the aldehyde and a substantial [[kinetic isotope effect]] for the enone alpha-proton. In it a second aldehyde molecule reacts to form a [[hemiacetal]] ('''4''') and this step is followed by a [[rate-determining step|rate-determining]] proton transfer step to intermediate '''5'''.
[[Image:Baylis-HillmanReactionMechanismAggerwal2007.svg|600px|center|Baylis-Hillman Reaction Mechanism Aggerwal 2007]]
[[In silico]] experiments confirm this mechanism <ref>''Mechanism of the Morita-Baylis-Hillman Reaction: A Computational Investigation'' Raphael Robiette, Varinder K Aggarwal, and Jeremy N. Harvey [[J. AM. CHEM. SOC.]] '''2007''', 129, 15513-15525 {{DOI|10.1021/ja0717865}}</ref> and also explain how protic additives increase reaction rates by facilitating the proton transfer step.
A related reaction actually predating the Baylis-Hillman reaction utilising phosphines and not DABCO is the lesser known [[Rauhut-Currier reaction]].
== Scope==
The MBH reaction in general is any reaction of electron deficient [[alkene]]s and sp<sup>2</sup> [[orbital hybridization|hybridized]] carbon electrophiles such as aldehydes, ketones and [[aldimine]]s catalyzed by a [[nucleophile]]. Under special reaction conditions the reaction is also found to extend to [[alkyl halide]]s as the electrophilic reagent <ref>''Unprecedented reactivity in the Morita–Baylis–Hillman reaction; intramolecular -alkylation of enones using saturated alkyl halides'' Marie E. Krafft, Kimberly A. Seibert, Thomas F. N. Haxell and Chitaru Hirosawa [[Chemical Communications]], '''2005''', (46), 5772 - 5774 DOI: 10.1039/b512665g [http://www.rsc.org/publishing/journals/CC/article.asp?doi=b512665g Abstract]</ref>. In this variation amine nucleophiles are unsuitable and [[trialkyl phosphine]]s are used instead. Under the given reaction conditions these phosphines do not react directly with the alkyl halide. The added base in the second step of this reaction promotes the [[elimination reaction]] to the [[enone]].
[[Image:MBHreaction.png|center|350px|Intramolecular Baylis-Hillman Reaction displacing an alkyl bromide.]]
In the [[aza-Baylis-Hillman reaction]] the electrophile is an [[imine]].<ref>''Enantioselective aza-Baylis-Hillman Reaction'' Vasco D.B. Bonifacio, Org. Chem. Highlights, '''2006''', [http://www.organic-chemistry.org/Highlights/2006/30JanuaryA.shtm Full Article]</ref>
== Limitations==
The MBH reaction of [[phenyl vinyl ketone]] with [[benzaldehyde]] and [[DABCO]] in [[dimethylformamide|DMF]] is not limited to the monoadduct because the MBH adduct reacts with a second molecule of phenyl vinyl ketone in a [[nucleophilic conjugate addition]] <ref>''Different Reaction Patterns in the Baylis-Hillman Reaction of Aryl Aldehydes with Phenyl Vinyl Ketone, Phenyl Acrylate and Phenyl Thioacrylate'' Min Shi, Chao-Qun Li and Jian-Kang Jiang [[Molecules (journal)|Molecules]] '''2002''', 7, 721-733 [http://www.mdpi.org/molecules/papers/71000721.pdf Full Article]</ref>.
==References==
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[[Category:Addition reactions]]
[[Category:Carbon-carbon bond forming reactions]]
[[Category:Name reactions]]
[[de:Baylis-Hillman-Reaktion]]
[[id:Reaksi Baylis-Hillman]]
[[ja:森田・ベイリス・ヒルマン反応]]