Umpolung
Encyclopedia
Umpolung or polarity inversion in organic chemistry
is the chemical modification of a functional group
with the aim of the reversal of polarity
of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible. The concept was introduced by D. Seebach (hence the German word umpolung for reversed polarity) and E.J. Corey. Classic umpolung applications can be found in Grignard reagents and in the benzoin condensation
.
One consequence of this natural polarization of molecules is that 1,3- and 1,5- heteroatom substituted carbon skeletons are extremely easy to synthesize (Aldol reaction
, Claisen condensation
, Michael reaction
, Claisen rearrangement
, Diels-Alder reaction
), whereas 1,2-, 1,4-, and 1,6- heteroatom substitution patterns are more difficult to access via "normal" reactivity. It is therefore important to understand and develop methods to induce umpolung in organic reactions.
For example, cyanide is a key catalyst in the benzoin condensation
, a classical example of polarity inversion.
The net result of the benzoin reaction is that a bond has been formed between two carbons that are normally electrophiles.
, or NHCs, are similar to cyanide in reactivity. Like cyanide, NHCs have an unusual chemical ambivalence, which allows it to trigger umpolung in reactions where it is involved. The carbene has six electrons - two each in the carbon-nitrogen single bonds, two in its sp2-hybridized orbital, and an empty p-orbital. The sp2 lone pair acts as an electron donor, whereas the empty p-orbital is capable as acting as an electron acceptor.
In this example, the β-carbon of this enone acts as a nucleophile, whereas normally it would be expected to be a Michael acceptor
.
This carbene reacts with the α,β-unsaturated ester
1 at the β-position forming the intermediate enolate 2. Through tautomerization 2b can displace the terminal bromine atom to 3. An elimination reaction
regenerates the carbene and releases the product 4.
For comparison: in the Baylis-Hillman reaction the same electrophilic β-carbon atom is attacked by a reagent but resulting in the activation of the α-position of the enone as the nucleophile.
Enzymes which use TPP as a cofactor can catalyze umpolung reactivity, such as the decarboxylation of pyruvate.
In the absence of TPP, the decarboxylation of pyruvate would result in the placement of a negative charge on the carbonyl carbon, which would run counter to the normal polarization of the carbon-oxygen double bond.
are strained moieties in organic chemistry. When a 3-membered ring contains a heteroatom, such as in an epoxide
or in a bromonium intermediate, the three atoms in the ring become polarized. It is impossible to assign (+) and (-) polarities to a 3-membered ring without having two adjacent atoms with the same polarity. Therefore, whenever a polarized 3-membered ring is opened by a nucleophile, umpolung inevitably results . For example, the opening of ethylene oxide with hydroxide leads to ethylene glycol
.
Ordinarily the oxygen atom in the carbonyl
group is more electronegative than the carbon atom and therefore the carbonyl group reacts as an electrophile
at carbon. This polarity can be reversed when the carbonyl group is converted into a dithiane
or a thioacetal
. In synthon
terminology the ordinary carbonyl group is an acyl
cation and the dithiane is a masked acyl
anion.
When the dithiane is derived from an aldehyde
such as acetaldehyde
the acyl proton can be abstracted by n-butyllithium
in THF at low temperatures. The thus generated 2-lithio-1,3-dithiane reacts as a nucleophile in nucleophilic displacement with alkyl halides such as benzyl bromide
, with other carbonyl compounds such as cyclohexanone
or oxiranes such as phenyl-epoxyethane, shown below. After hydrolysis
of the dithiane group the final reaction products are α-alkyl-ketones or α-hydroxy-ketones
. A common reagent for dithiane hydrolysis is (bis(trifluoroacetoxy)iodo)benzene
.
Dithiane chemistry opens the way to many new chemical transformations. One example is found in so-called anion relay chemistry in which an anionic functional group resulting from one organic reaction is transferred to a different location within the same carbon framework and available for secondary reactions. In this example of a multi-component reaction
both formaldehyde
(1) and isopropylaldehyde (8) are converted into dithianes 3 and 9 with 1,3-propanedithiol
. Sulfide 3 is first silylated by reaction with tert-butyllithium
and then trimethylsilyl chloride
4 and then the second acyl proton is removed and reacted with optically active (-)-epichlorohydrin
6 replacing chlorine. This compound serves as the substrate for reaction with the other dithiane 9 to the oxirane ring opening product 10. Under influence of the string base HMPA, 10 rearranges in a 1,4-Brook rearrangement
to the silyl ether
11 reactivating the formaldehyde dithiane group as an anion (hence the anion relay concept). This dithiane group reacts with oxirane 12 to the alcohol 13 and in the final step the sulfide groups are removed with (bis(trifluoroacetoxy)iodo)benzene
.
such as iodine
. In this total synthesis of enterolactone
, the 1,4- relationship of oxygen substituents is assembled by the oxidative homocoupling of an carboxylate enolate using iodine as the oxidant.
group is reacting as a nucleophile
by way of its lone pair
. This polarity can be reversed when a primary or secondary amine is substituted with a good leaving group
(such as a halogen
atom or an alkoxy group
). The resulting N-substituted compound can behave as an electrophile
at the nitrogen atom and react with a nucleophile
as for example in the electrophilic amination of carbanion
s.
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
is the chemical modification of a functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
with the aim of the reversal of polarity
Chemical polarity
In chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible. The concept was introduced by D. Seebach (hence the German word umpolung for reversed polarity) and E.J. Corey. Classic umpolung applications can be found in Grignard reagents and in the benzoin condensation
Benzoin condensation
The benzoin condensation is a reaction between two aromatic aldehydes, particularly benzaldehyde. The reaction is catalyzed by a nucleophile such as the cyanide anion or an N-heterocyclic carbene. The reaction product is an aromatic acyloin with benzoin as the parent compound...
.
Introduction
The vast majority of important organic molecules contain heteroatoms, which polarize carbon skeletons by virtue of their electronegativity. Therefore, in standard organic reactions, the majority of new bonds are formed between atoms of opposite polarity. This can be considered to be the "normal" mode of reactivity.One consequence of this natural polarization of molecules is that 1,3- and 1,5- heteroatom substituted carbon skeletons are extremely easy to synthesize (Aldol reaction
Aldol reaction
The aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
, Claisen condensation
Claisen condensation
The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone...
, Michael reaction
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
, Claisen rearrangement
Claisen rearrangement
The Claisen rearrangement is a powerful carbon-carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen...
, Diels-Alder reaction
Diels-Alder reaction
The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...
), whereas 1,2-, 1,4-, and 1,6- heteroatom substitution patterns are more difficult to access via "normal" reactivity. It is therefore important to understand and develop methods to induce umpolung in organic reactions.
Examples of Umpolung
It should be noted that the simplest method of obtaining 1,2-, 1,4-, and 1,6- heteroatom substitution patterns is to start with them. Biochemical and industrial processes can provide inexpensive sources of chemicals that have normally inaccessible substitution patterns. For example, amino acids, oxalic acid, succinic acid, adipic acid, tartaric acid, and glucose are abundant and provide nonroutine substitution patterns.Cyanide-type umpolung
The canonical umpolung reagent is the cyanide ion. The cyanide ion is unusual in that a carbon triply bonded to a nitrogen would be expected to have a (+) polarity due to the higher electronegativity of the nitrogen atom. Yet, the negative charge of the cyanide ion is localized on the carbon, giving it a (-) formal charge. This chemical ambivalence results in umpolung in many reactions where cyanide is involved.For example, cyanide is a key catalyst in the benzoin condensation
Benzoin condensation
The benzoin condensation is a reaction between two aromatic aldehydes, particularly benzaldehyde. The reaction is catalyzed by a nucleophile such as the cyanide anion or an N-heterocyclic carbene. The reaction product is an aromatic acyloin with benzoin as the parent compound...
, a classical example of polarity inversion.
The net result of the benzoin reaction is that a bond has been formed between two carbons that are normally electrophiles.
N-heterocyclic carbenes
N-heterocyclic carbenesPersistent carbene
A persistent carbene is a type of carbene demonstrating particular stability. The best-known examples are diaminocarbenes with the general formula 2C:, where the 'R's are various functional groups...
, or NHCs, are similar to cyanide in reactivity. Like cyanide, NHCs have an unusual chemical ambivalence, which allows it to trigger umpolung in reactions where it is involved. The carbene has six electrons - two each in the carbon-nitrogen single bonds, two in its sp2-hybridized orbital, and an empty p-orbital. The sp2 lone pair acts as an electron donor, whereas the empty p-orbital is capable as acting as an electron acceptor.
In this example, the β-carbon of this enone acts as a nucleophile, whereas normally it would be expected to be a Michael acceptor
Nucleophilic conjugate addition
Nucleophilic conjugate addition is a type of organic reaction. Ordinary nucleophilic additions or 1,2-nucleophilic additions deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polarity, unless the alkene is activated with special...
.
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
1 at the β-position forming the intermediate enolate 2. Through tautomerization 2b can displace the terminal bromine atom to 3. An elimination reaction
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
regenerates the carbene and releases the product 4.
For comparison: in the Baylis-Hillman reaction the same electrophilic β-carbon atom is attacked by a reagent but resulting in the activation of the α-position of the enone as the nucleophile.
Thiamine pyrophosphate
The human body can employ cyanide-like umpolung reactivity without having to rely on the toxic cyanide ion. Thiamine pyrophosphate (TPP) serves a functionally identical role. The thiazolium ring in TPP is deprotonated within the hydrophobic core of the enzyme (10.1021/bi00414a015), resulting in a carbene which is capable of umpolung.Enzymes which use TPP as a cofactor can catalyze umpolung reactivity, such as the decarboxylation of pyruvate.
In the absence of TPP, the decarboxylation of pyruvate would result in the placement of a negative charge on the carbonyl carbon, which would run counter to the normal polarization of the carbon-oxygen double bond.
3-membered rings
3-membered ringsCyclopropane
Cyclopropane is a cycloalkane molecule with the molecular formula C3H6, consisting of three carbon atoms linked to each other to form a ring, with each carbon atom bearing two hydrogen atoms...
are strained moieties in organic chemistry. When a 3-membered ring contains a heteroatom, such as in an epoxide
Epoxide
An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...
or in a bromonium intermediate, the three atoms in the ring become polarized. It is impossible to assign (+) and (-) polarities to a 3-membered ring without having two adjacent atoms with the same polarity. Therefore, whenever a polarized 3-membered ring is opened by a nucleophile, umpolung inevitably results . For example, the opening of ethylene oxide with hydroxide leads to ethylene glycol
Ethylene glycol
Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...
.
Carbonyl umpolung
Dithiane chemistry is a classic example of polarity inversion.Ordinarily the oxygen atom in the carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group is more electronegative than the carbon atom and therefore the carbonyl group reacts as an electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
at carbon. This polarity can be reversed when the carbonyl group is converted into a dithiane
Dithiane
A dithiane is a heterocyclic compound composed of a cyclohexane core structure wherein two methylene units are replaced by sulfur centres. The three isomeric parent heterocycles are 1,2-dithiane, 1,3-dithiane and 1,4-dithiane....
or a thioacetal
Thioacetal
Thioacetals are the sulfur analogue of acetals. They are prepared in a similar way to acetals: by reacting a thiol with an aldehyde:Dithioacetals are prepared similarly to thioacetals, which are intermediates:...
. In synthon
Synthon
A synthon is a concept in retrosynthetic analysis. It is defined as a structural unit within a molecule which is related to a possible synthetic operation. The term was coined by E.J. Corey...
terminology the ordinary carbonyl group is an acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
cation and the dithiane is a masked acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
anion.
When the dithiane is derived from an aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
such as acetaldehyde
Acetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...
the acyl proton can be abstracted by n-butyllithium
N-Butyllithium
n-Butyllithium is an organolithium reagent. It is widely used as a polymerization initiator in the production of elastomers such as polybutadiene or styrene-butadiene-styrene...
in THF at low temperatures. The thus generated 2-lithio-1,3-dithiane reacts as a nucleophile in nucleophilic displacement with alkyl halides such as benzyl bromide
Benzyl bromide
Benzyl bromide, or α-bromotoluene, is an organic compound consisting of a benzene ring substituted with a bromomethyl group. It can be prepared by the bromination of toluene at room temperature in air, using manganese oxide as a heterogeneous catalyst...
, with other carbonyl compounds such as cyclohexanone
Cyclohexanone
Cyclohexanone is the organic compound with the formula 5CO. The molecule consists of six-carbon cyclic molecule with a ketone functional group. This colorless oil has an odor reminiscent of peardrop sweets as well as acetone. Over time, samples assume a yellow color due to oxidation...
or oxiranes such as phenyl-epoxyethane, shown below. After hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of the dithiane group the final reaction products are α-alkyl-ketones or α-hydroxy-ketones
Acyloin
Acyloins are a class of organic compounds in organic chemistry sharing a common functional group consisting of a hydroxyl group placed on the α-position of a carbonyl group.- Nomenclature :Common types of ketols include:...
. A common reagent for dithiane hydrolysis is (bis(trifluoroacetoxy)iodo)benzene
(Bis(trifluoroacetoxy)iodo)benzene
benzene, C10H5F6IO4, is a hypervalent iodine compound used as a reagent in organic chemistry. The reagent is used in an acidic modification of the Hofmann rearrangement. One example is the conversion of cyclobutanecarboxamine to cyclobutylamine hydrochloride...
.
Multi-component reaction
In chemistry, a multi-component reaction , sometimes referred to as a "Multi-component Assembly Process" , is a chemical reaction where three or more compounds react to form a single product...
both formaldehyde
Formaldehyde
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...
(1) and isopropylaldehyde (8) are converted into dithianes 3 and 9 with 1,3-propanedithiol
1,3-Propanedithiol
1,3-Propanedithiol is the chemical compound with the formula HSCH2CH2CH2SH. This dithiol is a useful reagent in organic synthesis. This liquid, which is readily available commercially, has an intense stench.-Use in organic synthesis:...
. Sulfide 3 is first silylated by reaction with tert-butyllithium
Tert-Butyllithium
tert-Butyllithium is a chemical compound with the formula 3CLi. As an organometallic compound, it has applications in organic synthesis since it is a sufficiently strong base to deprotonate many carbon acids, including benzene...
and then trimethylsilyl chloride
Trimethylsilyl chloride
Trimethylsilyl chloride, also known as chlorotrimethylsilane is a silyl halide, with a variety of different uses in chemistry. It has the formula 3SiCl, and under standard conditions it is a colourless liquid, which is stable in the absence of water...
4 and then the second acyl proton is removed and reacted with optically active (-)-epichlorohydrin
Epichlorohydrin
Epichlorohydrin is an organochlorine compound and an epoxide. This is a colorless liquid with a pungent, garlic-like odor, moderately soluble in water, but miscible with most polar organic solvents. Epichlorohydrin is a highly reactive compound and is used in the production of glycerol, plastics,...
6 replacing chlorine. This compound serves as the substrate for reaction with the other dithiane 9 to the oxirane ring opening product 10. Under influence of the string base HMPA, 10 rearranges in a 1,4-Brook rearrangement
Brook rearrangement
The Brook rearrangement in organic chemistry is a rearrangement reaction in which a organosilyl group switches position with a hydroxyl proton over a carbon to oxygen covalent bond under the influence of a base . It is named for the Canadian chemist Adrian Gibbs Brook...
to the silyl ether
Silyl ether
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...
11 reactivating the formaldehyde dithiane group as an anion (hence the anion relay concept). This dithiane group reacts with oxirane 12 to the alcohol 13 and in the final step the sulfide groups are removed with (bis(trifluoroacetoxy)iodo)benzene
(Bis(trifluoroacetoxy)iodo)benzene
benzene, C10H5F6IO4, is a hypervalent iodine compound used as a reagent in organic chemistry. The reagent is used in an acidic modification of the Hofmann rearrangement. One example is the conversion of cyclobutanecarboxamine to cyclobutylamine hydrochloride...
.
Oxidative bond formation
It is possible to form a bond between two carbons of (-) polarity by using an oxidantOxidizing agent
An oxidizing agent can be defined as a substance that removes electrons from another reactant in a redox chemical reaction...
such as iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
. In this total synthesis of enterolactone
Enterolactone
Enterolactone is a lignan formed by the action of intestinal bacteria on lignan precursors found in plants. It acts as a phytoestrogen....
, the 1,4- relationship of oxygen substituents is assembled by the oxidative homocoupling of an carboxylate enolate using iodine as the oxidant.
Amine umpolung
Ordinarily the nitrogen atom in the amineAmine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
group is reacting as a nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
by way of its lone pair
Lone pair
In chemistry, a lone pair is a valence electron pair without bonding or sharing with other atoms. They are found in the outermost electron shell of an atom, so lone pairs are a subset of a molecule's valence electrons...
. This polarity can be reversed when a primary or secondary amine is substituted with a good leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
(such as a halogen
Halogen
The halogens or halogen elements are a series of nonmetal elements from Group 17 IUPAC Style of the periodic table, comprising fluorine , chlorine , bromine , iodine , and astatine...
atom or an alkoxy group
Alkoxy group
In chemistry, the alkoxy group is an alkyl group singular bonded to oxygen thus: R—O. The range of alkoxy groups is great, the simplest being methoxy . An ethoxy group is found in the organic compound phenetol, C6H5OCH2CH3 which is also known as ethoxy benzene...
). The resulting N-substituted compound can behave as an electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
at the nitrogen atom and react with a nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
as for example in the electrophilic amination of carbanion
Carbanion
A carbanion is an anion in which carbon has an unshared pair of electrons and bears a negative charge usually with three substituents for a total of eight valence electrons. The carbanion exists in a trigonal pyramidal geometry. Formally a carbanion is the conjugate base of a carbon acid.where B...
s.