Umpolung

Last updated

Umpolung (German: [ˈʔʊmˌpoːlʊŋ] ) 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. [1] [2] This modification allows secondary reactions of this functional group that would otherwise not be possible. [3] The concept was introduced by D. Seebach (hence the German word umpolung for reversed polarity) and E.J. Corey. Polarity analysis during retrosynthetic analysis tells a chemist when umpolung tactics are required to synthesize a target molecule.

Contents

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, 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.

Examples

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, a classical example of polarity inversion.

Mechanism of the benzoin condensation Benzoin mechanism.png
Mechanism of the benzoin condensation

The net result of the benzoin reaction is that a bond has been formed between two carbons that are normally electrophiles.

N-heterocyclic carbenes

Singlet N-heterocyclic carbene electronic structure.png

N-heterocyclic carbenes, 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 the α,β-unsaturated ester 1 formally acts as a nucleophile, [4] whereas normally it would be expected to be a Michael acceptor.

Scheme 3. Umpolung of Michael Acceptors UmpolingMichaelAcceptor.png
Scheme 3. Umpolung of Michael Acceptors

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.

Thiamine pyrophosphate

The human body can employ cyanide-like umpolung reactivity without having to rely on the toxic cyanide ion. Thiamine (which itself is an N-heterocyclic carbene) pyrophosphate (TPP) serves a functionally identical role. The thiazolium ring in TPP is deprotonated within the hydrophobic core of the enzyme, [5] resulting in a carbene which is capable of umpolung.

Deprotonation of thiazole moiety in thiamine pyrophosphate results in ambivalent chemical reactivity Thiazole resonance.png
Deprotonation of thiazole moiety in thiamine pyrophosphate results in ambivalent chemical reactivity

Enzymes which use TPP as a cofactor can catalyze umpolung reactivity, such as the decarboxylation of pyruvate.

Mechanism of pyruvate decarboxylation Pyruvate decarboxylase mechanism.png
Mechanism of pyruvate decarboxylation

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

Opening of ethylene oxide with hydroxide Epoxide opening.png
Opening of ethylene oxide with hydroxide

3-membered rings 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 .[ citation needed ] For example, the opening of ethylene oxide with hydroxide leads to ethylene glycol.

Carbonyl umpolung / anion relay chemistry

Dithiane chemistry is a classic example of polarity inversion.

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.

Scheme 1. Dithiane chemistry Dithiane chemistry.png
Scheme 1. Dithiane chemistry

Dithiane chemistry opens the way to many new chemical transformations. One example is found in so-called anion relay chemistry in which a negative charge of an anionic functional group resulting from one organic reaction is transferred to a different location within the same carbon framework and available for secondary reaction. [6] 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 polar 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.

Scheme 2. Anion relay chemistry, Ph stands for phenyl AnionrelayChemistry.png
Scheme 2. Anion relay chemistry, Ph stands for phenyl

The anion relay chemistry tactic has been applied elegantly in the total synthesis of complex molecules of significant biological activity, such as spongistatin 2 [7] and mandelalide A. [8] [9]

Oxidative bond formation

It is possible to form a bond between two carbons of (-) polarity by using an oxidant such as iodine. In this total synthesis of enterolactone, [10] the 1,4- relationship of oxygen substituents is assembled by the oxidative homocoupling of a carboxylate enolate using iodine as the oxidant.

Enterolactone scheme.png

Amine umpolung

Ordinarily the nitrogen atom in the amine 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 carbanions. [11]

Related Research Articles

A nucleophile is a chemical species that donates an electron pair to form a chemical bond in relation to a reaction. All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases. Nucleophilic describes the affinity of a nucleophile for positively charged atomic nuclei. Nucleophilicity, sometimes referred to as nucleophile strength, refers to a substance's nucleophilic character and is often used to compare the affinity of atoms. Neutral nucleophilic reactions with solvents such as alcohols and water are named solvolysis. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge.

Carbonyl group

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. A compound containing a carbonyl group is often referred to as a carbonyl compound.

Elias James Corey American chemist

Elias James "E.J." Corey is an American organic chemist. In 1990, he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis. Regarded by many as one of the greatest living chemists, he has developed numerous synthetic reagents, methodologies and total syntheses and has advanced the science of organic synthesis considerably.

In organic chemistry and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which a leaving group is replaced by an electron rich compound (nucleophile). The whole molecular entity of which the electrophile and the leaving group are part is usually called the substrate. The nucleophile essentially attempts to replace the leaving group as the primary substituent in the reaction itself, as a part of another molecule.

In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

An ylide or ylid is a neutral dipolar molecule containing a formally negatively charged atom (usually a carbanion) directly attached to a heteroatom with a formal positive charge (usually nitrogen, phosphorus or sulfur), and in which both atoms have full octets of electrons. The result can be viewed as a structure in which two adjacent atoms are connected by both a covalent and an ionic bond; normally written X+–Y. Ylides are thus 1,2-dipolar compounds, and a subclass of zwitterions. They appear in organic chemistry as reagents or reactive intermediates.

In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions differ from electrophilic additions in that the former reactions involve the group to which atoms are added accepting electron pairs, whereas the latter reactions involve the group donating electron pairs.

Organolithium reagent

Organolithium reagents are organometallic compounds that contain carbon – lithium bonds. They are important reagents in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C-Li bond is highly ionic. Owing to the polar nature of the C-Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

Fischer–Speier esterification

Fischer esterification or Fischer–Speier esterification is a special type of esterification by refluxing a carboxylic acid and an alcohol in the presence of an acid catalyst. The reaction was first described by Emil Fischer and Arthur Speier in 1895. Most carboxylic acids are suitable for the reaction, but the alcohol should generally be primary or secondary. Tertiary alcohols are prone to elimination. Contrary to common misconception found in organic chemistry textbooks, phenols can also be esterified to give good to near quantitative yield of products. Commonly used catalysts for a Fischer esterification include sulfuric acid, p-toluenesulfonic acid, and Lewis acids such as scandium(III) triflate. For more valuable or sensitive substrates other, milder procedures such as Steglich esterification are used. The reaction is often carried out without a solvent or in a non-polar solvent to facilitate the Dean-Stark method. Typical reaction times vary from 1–10 hours at temperatures of 60-110 °C.

In chemistry, a carbene is a molecule containing a neutral carbon atom with a valence of two and two unshared valence electrons. The general formula is R-(C:)-R' or R=C: where the R represent substituents or hydrogen atoms.

Enolate

Enolates are organic anions derived from the deprotonation of carbonyl compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.

In retrosynthetic analysis, a synthon is a hypothetical unit within a target molecule that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by E. J. Corey. He noted in 1988 that the "word synthon has now come to be used to mean synthetic building block rather than retrosynthetic fragmentation structures". It was noted in 1998 that the phrase did not feature very prominently in Corey's 1981 book The Logic of Chemical Synthesis, as it was not included in the index. Because synthons are charged, when placed into a synthesis a neutral form is found commercially instead of forming and using the potentially very unstable charged synthons.

Organoboron chemistry

Organoborane or organoboron compounds are chemical compounds of boron and carbon that are organic derivatives of BH3, for example trialkyl boranes. Organoboron chemistry or organoborane chemistry is the chemistry of these compounds.

A transition metal carbene complex is an organometallic compound featuring a divalent organic ligand. The divalent organic ligand coordinated to the metal center is called a carbene. Carbene complexes for almost all transition metals have been reported. Many methods for synthesizing them and reactions utilizing them have been reported. The term carbene ligand is a formalism since many are not derived from carbenes and almost none exhibit the reactivity characteristic of carbenes. Described often as M=CR2, they represent a class of organic ligands intermediate between alkyls (−CR3) and carbynes (≡CR). They feature in some catalytic reactions, especially alkene metathesis, and are of value in the preparation of some fine chemicals.

Benzoin condensation

The benzoin addition is an addition reaction involving two aldehydes. The reaction generally occurs between aromatic aldehydes or glyoxals. The reaction produces an acyloin. In the classic application benzaldehyde is converted to benzoin.

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 substituents. With α,β-unsaturated carbonyl compounds such as cyclohexenone it can be deduced from resonance structures that the β position is an electrophilic site which can react with a nucleophile. The negative charge in these structures is stored as an alkoxide anion. Such a nucleophilic addition is called a nucleophilic conjugate addition or 1,4-nucleophilic addition. The most important active alkenes are the aforementioned conjugated carbonyls and acrylonitriles.

Thioacetals are the sulfur analogues of acetals. There are two classes: monothioacetals and dithioacetals. Monothioacetals are less common, have the functional group RC(OR')(SR")H. Dithioacetals have the formula RC(SR')2H (symmetric dithioacetals) and RC(SR')(SR")H (asymmetric dithioacetals).

Dakin oxidation

The Dakin oxidation is an organic redox reaction in which an ortho- or para-hydroxylated phenyl aldehyde or ketone reacts with hydrogen peroxide in base to form a benzenediol and a carboxylate. Overall, the carbonyl group is oxidized, and the hydrogen peroxide is reduced.

An insertion reaction is a chemical reaction where one chemical entity interposes itself into an existing bond of typically a second chemical entity e.g.:

In organic chemistry, the Corey–Link reaction is a name reaction that converts a 1,1,1-trichloro-2-keto structure into a 2-aminocarboxylic acid or other acyl functional group with control of the chirality at the alpha position. The reaction is named for E.J. Corey and John Link, who first reported the reaction sequence.

References

  1. Seebach, D. (1979). "Methods of Reactivity Umpolung". Angewandte Chemie International Edition in English. 18 (4): 239–258. doi:10.1002/anie.197902393.
  2. Gröbel, B. T.; Seebach, D. (1977). "Umpolung of the Reactivity of Carbonyl Compounds Through Sulfur-Containing Reagents". Synthesis. 1977 (6): 357. doi:10.1055/s-1977-24412.
  3. Seebach, D.; Corey, E. J. (1975). "Generation and synthetic applications of 2-lithio-1,3-dithianes". The Journal of Organic Chemistry. 40 (2): 231. doi:10.1021/jo00890a018.
  4. Fischer, C.; Smith, S. W.; Powell, D. A.; Fu, G. C. (2006). "Umpolung of Michael Acceptors Catalyzed by N-Heterocyclic Carbenes". Journal of the American Chemical Society. 128 (5): 1472–1473. doi:10.1021/ja058222q. PMC   2553003 . PMID   16448117.
  5. Washabaugh, M. W.; Jencks, W. P. (1988). "Thiazolium C(2)-proton exchange: Structure-reactivity correlations and the pKa of thiamin C(2)-H revisited". Biochemistry. 27 (14): 5044–5053. doi:10.1021/bi00414a015. PMID   2844248.
  6. Smith A. B. , III, Xian M. (2006). "Anion Relay Chemistry: An Effective Tactic for Diversity Oriented Synthesis". Journal of the American Chemical Society . 128 (1): 66–67. doi:10.1021/ja057059w. PMID   16390124.CS1 maint: multiple names: authors list (link)
  7. Smith A. B. , III., Lin Q., Doughty V. A., Zhuang L., McBriar M. D., Kerns J. K., Brook C. S., Murase N.,Nakayama K. (2001). "The Spongistatins: Architecturally Complex Natural Products—Part Two: Synthesis of the C(29–51) Subunit, Fragment Assembly, and Final Elaboration to (+)-Spongistatin 2". Angewandte Chemie International Edition . 40 (1): 196–199. doi:10.1002/1521-3773(20010105)40:1<196::AID-ANIE196>3.0.CO;2-T. PMID   11169711.CS1 maint: multiple names: authors list (link)
  8. Nguyen M. H., Imanishi M., Kurogi T., Smith A. B. , III. (2016). "Total Synthesis of (−)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol". Journal of the American Chemical Society . 138 (11): 3675–3678. doi:10.1021/jacs.6b01731. PMC   4819492 . PMID   26954306.CS1 maint: multiple names: authors list (link)
  9. Nguyen M. H., Imanishi M., Kurogi T., Wan, X., Ishmael, J., McPhail, K., Smith A. B. , III. (2018). "Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy". The Journal of Organic Chemistry . 83 (8): 4287–4306. doi:10.1021/acs.joc.8b00268. PMC   5910188 . PMID   29480727.CS1 maint: multiple names: authors list (link)
  10. Belletire, J.L.; Fremont, S.L. (1986). "Oxidative coupling". Tetrahedron Letters. 27 (2): 127. doi:10.1016/S0040-4039(00)83958-1.
  11. Erdik, E.; Ay, M. (1989). "Electrophilic amination of carbanions". Chemical Reviews. 89 (8): 1947–1980. doi:10.1021/cr00098a014.