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Umpolung

Inorganic chemistry,umpolung(German:[ˈʔʊmˌpoːlʊŋ]) orpolarity inversionis the chemical modification of afunctional groupwith the aim of the reversal ofpolarityof that group.[1][2]This modification allows secondary reactions of this functional group that would otherwise not be possible.[3]The concept was introduced byD. Seebach(hence the German wordumpolungfor reversed polarity) andE.J. Corey.Polarity analysis duringretrosynthetic analysistells a chemist when umpolung tactics are required to synthesize a target molecule.

Introduction

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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

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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

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The canonical umpolung reagent is thecyanide 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 thebenzoin condensation,a classical example of polarity inversion.

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

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N-heterocyclic carbenesare similar to cyanide in reactivity. Like cyanide, they have an unusual chemical ambivalence, which allows them to trigger umpolung in reactions where they are 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 sp2lone 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 ester1formally acts as a nucleophile,[4]whereas normally it would be expected to be aMichael acceptor.

Scheme 3. Umpolung of Michael Acceptors

This carbene reacts with the α,β-unsaturatedester1at the β-position forming the intermediate enolate2.Throughtautomerization2bcandisplacethe terminal bromine atom to3.Anelimination reactionregenerates the carbene and releases the product4.

For comparison: in theBaylis-Hillman reactionthe 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

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Biological processes can employ cyanide-like umpolung reactivity without having to rely on the toxic cyanide ion.Thiamine(which itself is anN-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

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

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

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Opening of ethylene oxide with hydroxide

3-membered ringsare strained moieties in organic chemistry. When a 3-membered ring contains a heteroatom, such as in anepoxideor in abromoniumintermediate, 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.[6]For example, the opening of ethylene oxide with hydroxide leads toethylene glycol.

Carbonyl umpolung / anion relay chemistry

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Dithiane chemistry is a classic example of polarity inversion. This can be observed in theCorey-Seebach reaction.

Ordinarily the oxygen atom in thecarbonylgroup is moreelectronegativethan the carbon atom and therefore the carbonyl group reacts as anelectrophileat carbon. This polarity can be reversed when the carbonyl group is converted into adithianeor athioacetal.Insynthonterminology the ordinary carbonyl group is anacylcationand the dithiane is a maskedacylanion.

When the dithiane is derived from analdehydesuch asacetaldehydethe acyl proton can be abstracted byn-butyllithiumin THF at low temperatures. The thus generated 2-lithio-1,3-dithiane reacts as a nucleophile innucleophilic displacementwithalkyl halidessuch asbenzyl bromide,with other carbonyl compounds such ascyclohexanoneoroxiranessuch as phenyl-epoxyethane, shown below. Afterhydrolysisof the dithiane group the final reaction products are α-alkyl-ketones orα-hydroxy-ketones.A common reagent for dithiane hydrolysis is(bis(trifluoroacetoxy)iodo)benzene.

Scheme 1. Dithiane chemistry

Dithiane chemistry opens the way to many new chemical transformations. One example is found in so-calledanion relay chemistryin 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.[7]In this example of amulti-component reactionbothformaldehyde(1) and isopropylaldehyde (8) are converted into dithianes3and9with1,3-propanedithiol.Sulfide3is first silylated by reaction withtert-butyllithiumand thentrimethylsilyl chloride4and then the second acyl proton is removed and reacted withoptically active(−)-epichlorohydrin6replacing chlorine. This compound serves as the substrate for reaction with the other dithiane9to theoxiranering opening product10.Under influence of the polar baseHMPA,10rearranges in a1,4-Brook rearrangementto thesilyl ether11reactivating the formaldehyde dithiane group as an anion (hence the anion relay concept). This dithiane group reacts with oxirane12to the alcohol13and in the final step the sulfide groups are removed with(bis(trifluoroacetoxy)iodo)benzene.

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[8]and mandelalide A.[9][10]

Oxidative bond formation

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It is possible to form a bond between two carbons of (-) polarity by using anoxidantsuch asiodine.In this total synthesis ofenterolactone,[11]the 1,4- relationship of oxygen substituents is assembled by the oxidative homocoupling of a carboxylate enolate using iodine as the oxidant.

Amine umpolung

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Ordinarily the nitrogen atom in theaminegroup is reacting as anucleophileby way of itslone pair.This polarity can be reversed when a primary or secondary amine is substituted with a goodleaving group(such as ahalogenatom or analkoxy group). The resulting N-substituted compound can behave as anelectrophileat the nitrogen atom and react with anucleophileas for example in the electrophilic amination ofcarbanions.[12]

Hydrazone umpolung

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Recently, various carbonyls have been turned into organometallic reagent surrogates via hydrazone umpolung by C.-J. Li et al. In the presence of a catalyst, similar to organometallic reagents, hydrazones can undergo nucleophilic additions, conjugate additions, and transition-metal catalyzed cross-couplings with various electrophiles to form new C-C bonds.[13]

References

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  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.S2CID95705677.
  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.PMC2553003.PMID16448117.
  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.PMID2844248.
  6. ^Clayden, Jonathan (2012).Organic Chemistry(2nd ed.).Oxford University Press.p. 720.
  7. ^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.PMID16390124.{{cite journal}}:CS1 maint: multiple names: authors list (link)
  8. ^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.PMID11169711.{{cite journal}}:CS1 maint: multiple names: authors list (link)
  9. ^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.PMC4819492.PMID26954306.{{cite journal}}:CS1 maint: multiple names: authors list (link)
  10. ^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.PMC5910188.PMID29480727.{{cite journal}}:CS1 maint: multiple names: authors list (link)
  11. ^Belletire, J.L.; Fremont, S.L. (1986). "Oxidative coupling".Tetrahedron Letters.27(2): 127.doi:10.1016/S0040-4039(00)83958-1.
  12. ^Erdik, E.; Ay, M. (1989). "Electrophilic amination of carbanions".Chemical Reviews.89(8):1947–1980.doi:10.1021/cr00098a014.
  13. ^Dai, X.J.; Li, C.C.; Li, C.-J. (2021). "Carbonyl umpolung as an organometallic reagent surrogate".Chemical Society Reviews.50(19):10733–10742.doi:10.1039/D1CS00418B.PMID34382626.S2CID236989985.
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