Wikipedia

Aldol reaction

Not to be confused withAldol reactions.

Thealdol reaction(aldol addition) is areactioninorganic chemistrythat combines twocarbonylcompounds (e.g.aldehydesorketones) to form a new β-hydroxy carbonyl compound. Its simplest form might involve thenucleophilic additionof anenolizedketoneto another:

Aldol Addition
Reaction type Coupling reaction
Reaction
KetoneorAldehyde
+
KetoneorAldehyde
↓
β-hydroxy Aldehyde
or
β-hydroxy Ketone
Conditions
Temperature
-Δ, ~-70°C[a]
Catalyst
-OH or H+
Identifiers
Organic Chemistry Portal aldol-addition
RSContology ID RXNO:0000016
Prototype aldol reaction

These products are known asaldols,from thealdehyde + alcohol,a structural motif seen in many of the products. The use of aldehyde in the name comes from its history: aldehydes are more reactive than ketones, so that the reaction was discovered first with them.[2][3][4]

The aldol reaction isparadigmaticin organic chemistry and perhaps the most common means of formingcarbon–carbon bondsinorganic chemistry.[5][6][7]It lends its name to the family ofaldol reactionsand similar techniques analyze a whole family ofcarbonyl α-substitution reactions,as well as thediketone condensations.When the nucleophile and electrophile are different, the reaction is called acrossed aldol reaction;on the converse, when the nucleophile and electrophile are the same, the reaction is called analdoldimerization.

Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.[8][9]The reaction is used in several industrial syntheses, notably ofpentaerythritol,[10]trimethylolpropane,the plasticizer2-ethylhexanol,and the drug Lipitor (atorvastatin,calcium salt).[11]For many of the commodity applications, the stereochemistry of the aldol reaction is unimportant, but the topic is of intense interest for the synthesis of many specialty chemicals.

A typical experimental setup for an aldol reaction in a research laboratory.
The flask on the right is a solution oflithium diisopropylamide(LDA) intetrahydrofuran(THF). The flask on the left is a solution of the lithium enolate oftert-butyl propionate (formed by addition of LDA totert-butyl propionate). An aldehyde can then be added to the enolate flask to initiate an aldol addition reaction.
Both flasks are submerged in a dry ice/acetonecooling bath(−78 °C) the temperature of which is being monitored by a thermocouple (the wire on the left).

Mechanisms

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The aldol reaction has one underlying mechanism, but it appears in different forms depending on pH:[12]

If thecatalystis a moderate base such ashydroxideion or analkoxide,the aldol reaction occurs via nucleophilic attack by theresonance-stabilizedenolate on the carbonyl group of another molecule. The product is thealkoxidesalt of the aldol product. The aldol itself is then formed, and it may then undergo dehydration to give the unsaturated carbonyl compound. The scheme shows a simple mechanism for the base-catalyzed aldol reaction of an aldehyde with itself.

Simple mechanism for base-catalyzed aldol reaction of an aldehyde with itself

Although only a catalytic amount of base is required in some cases, the more usual procedure is to use astoichiometricamount of a strong base such asLDAorNaHMDS.In this case, enolate formation is irreversible, and the aldol product is not formed until the metal alkoxide of the aldol product is protonated in a separate workup step.

When an acid catalyst is used, the initial step in thereaction mechanisminvolves acid-catalyzedtautomerizationof the carbonyl compound to the enol. The acid also serves to activate the carbonyl group ofanother moleculeby protonation, rendering it highly electrophilic. The enol is nucleophilic at the α-carbon, allowing it to attack the protonated carbonyl compound, leading to the aldol afterdeprotonation.Some may also dehydrate past the intended product to give the unsaturated carbonyl compound throughaldol condensation.

Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself

Crossed-aldol reactant control

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Despite the attractiveness of the aldol manifold, there are several problems that need to be addressed to render the process effective. The first problem is a thermodynamic one: most aldol reactions are reversible. Furthermore, the equilibrium is also just barely on the side of the products in the case of simple aldehyde–ketone aldol reactions.[13]If the conditions are particularly harsh (e.g.: NaOMe/MeOH/reflux), condensation may occur, but this can usually be avoided with mild reagents and low temperatures (e.g., LDA (a strong base), THF, −78 °C). Although the aldol addition usually proceeds to near completion under irreversible conditions, the isolated aldol adducts are sensitive to base-induced retro-aldol cleavage to return starting materials. In contrast, retro-aldol condensations are rare, but possible.[14]This is the basis of the catalytic strategy of class I aldolases in nature, as well as numerous small-molecule amine catalysts.[15]

When a mixture of unsymmetrical ketones are reacted, four crossed-aldol (addition) products can be anticipated:

Crossed aldol (addition) reaction

Thus, if one wishes to obtain only one of the cross-products, one must control which carbonyl becomes the nucleophilic enol/enolate and which remains in its electrophilic carbonyl form. The simplest control is if only one of the reactants has acidic protons, and only this molecule forms the enolate. For example, the addition ofdiethyl malonateintobenzaldehydeproduces only one product:

Acidic control of the aldol (addition) reaction

If one group is considerably more acidic than the other, the most acidic proton is abstracted by the base and an enolate is formed at that carbonyl while the less-acidic carbonyl remains electrophilic. This type of control works only if the difference in acidity is large enough and base is thelimiting reactant.A typical substrate for this situation is when the deprotonatable position is activated by more than one carbonyl-like group. Common examples include a CH2group flanked by two carbonyls or nitriles (see for example theKnoevenagel condensationand the first steps of themalonic ester synthesisandacetoacetic ester synthesis).

Otherwise, the most acidic carbonyls are typically also the most active electrophiles: firstaldehydes,thenketones,thenesters,and finallyamides.Thus cross-aldehyde reactions are typically most challenging because they canpolymerizeeasily or react unselectively to give a statistical mixture of products.[16]

One common solution is to form the enolate of one partner first, and then add the other partner underkinetic control.[17]Kinetic control means that the forward aldol addition reaction must be significantly faster than the reverse retro-aldol reaction. For this approach to succeed, two other conditions must also be satisfied; it must be possible to quantitatively form the enolate of one partner, and the forward aldol reaction must be significantly faster than the transfer of the enolate from one partner to another. Common kinetic control conditions involve the formation of the enolate of a ketone withLDAat −78 °C, followed by the slow addition of an aldehyde.

Stereoselectivity

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The aldol reaction unites two relatively simplemoleculesinto a more complex one. Increased complexity arises because each end of the new bond may become astereocenter.Modern methodology has not only developed high-yieldingaldol reactions, but also completely controls both the relative andabsolute configurationof these new stereocenters.[6]

To describe relative stereochemistry at the α- and β-carbon, older papers use saccharide chemistry'serythro/threonomenclature; more modern papers use the followingsyn/anticonvention. When propionate (or higher order) nucleophiles add to aldehydes, the reader visualizes theRgroup of the ketone and theR'group of the aldehyde aligned in a "zig zag" pattern on the paper (or screen). The disposition of the formed stereocenters is deemedsynoranti,depending if they are on the same or opposite sides of the main chain:

Syn and anti products from an aldol (addition) reaction

The principal factor determining an aldol reaction'sstereoselectivityis the enolizing metalcounterion.Shorter metal-oxygen bonds "tighten" thetransition stateand effects greater stereoselection.[18]Boronis often used[19][20]because itsbond lengthsare significantly shorter than other cheap metals (lithium,aluminium,ormagnesium). The following reaction gives asyn:antiratio of 80:20 using a lithium enolate compared to 97:3 using a bibutylboron enolate.

Where the counterion determinesstereoinductionstrength, theenolate isomerdetermines itsdirection.Eisomersgiveantiproducts andZgivesyn:[21]

Anti-aldol formation through E-enolate
Syn-aldol formation through Z-enolate

Zimmermann-Traxler model

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If the two reactants have carbonyls adjacent to a pre-existing stereocenter, then the new stereocenters mayform at a fixed orientation relative to the old.This "substrate-based stereocontrol" has seen extensive study and examples pervade the literature. In many cases, a stylizedtransition state,called theZimmerman–Traxler model,can predict the new orientation from theconfiguration of a 6-membered ring.[22]

On the enol

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If the enol has an adjacent stereocenter, then the two stereocenters flanking the carbonyl in the product are naturallysyn:[23]

The underlying mechanistic reason depends on the enol isomer. For anEenolate, the stereoinduction is necessary to avoid 1,3-allylic strain,while aZenolate instead seeks to avoid 1,3-diaxial interactions:[24]

For clarity, the stereocenter on the enolate has beenepimerized;in reality, the opposite diastereoface of the aldehyde would have been attacked.

However,Fráter & Seebach showedthat a chelatingLewis basicmoiety adjacent to the enol will instead causeantiaddition.

On the electrophile

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Eenolates exhibitFelkin diastereoface selection,whileZenolates exhibit anti-Felkin selectivity. The general model is presented below:[25][26]

The general model of the aldol reaction with carbonyl-based stereocontrol

Since thetransition stateforZenolates must contain either a destabilizingsyn-pentane interaction or an anti-Felkinrotamer,Z-enolates are less diastereoselective:[27][28]

Examples of the aldol reaction with carbonyl-based stereocontrol

On both

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If both the enolate and the aldehyde contain pre-existing chirality, then the outcome of the "double stereodifferentiating" aldol reaction may be predicted using a merged stereochemical model that takes into account all the effects discussed above.[29]Several examples are as follows:[28]

Oxazolidinone chiral auxiliaries

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In the late 1970s and 1980s,David A. Evansand coworkers developed a technique for stereoselection in the aldol syntheses of aldehydes andcarboxylic acids.[30][31]The method works by temporarily appending a chiraloxazolidinoneauxiliaryto create a chiral enolate. The pre-existing chirality from the auxiliary is then transferred to the aldol adduct through Zimmermann-Traxler methods, and then the oxazolidinone cleaved away.

Aldol reaction creates stereoisomers
Four possible stereoisomers of the aldol reaction

Commercial oxazolidinones are relatively expensive, but derive in 2 synthetic steps from comparatively inexpensive amino acids. (Economical large-scale syntheses prepare the auxiliary in-house.) First, a borohydride reduces the acidmoiety.Then the resulting amino alcohol dehydratively cyclises with a simple carbonate ester, such as diethylcarbonate.

Theacylationof an oxazolidinone is informally referred to as "loading done".

Antiadducts, which require anEenolate, cannot be obtained reliably with the Evans method. However,Zenolates, leading tosynadducts, can be reliably formed using boron-mediated soft enolization:[32]

Often, a singlediastereomermay be obtained by onecrystallizationof the aldol adduct.

Many methods cleave the auxiliary:[33]

Evans' chiral oxazolidinone cleavage

Variations

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A common additional chiral auxiliary is athioethergroup:[33][b]

Crimmins thiazolidinethione aldol

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In theCrimmins thiazolidinethioneapproach,[34][35]a thiazolidinethione is the chiral auxiliary[36]and can produce the "Evans syn" or "non-Evans syn" adducts by simply varying the amount of(−)-sparteine.The reaction is believed to proceed via six-membered, titanium-boundtransition states,analogous to the proposed transition states for the Evans auxiliary.

NOTE: the structure ofsparteineis missing an N atom

"Masked" enols

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A common modification of the aldol reaction uses other, similar functional groups asersatzenols. In theMukaiyama aldol reaction,[37]silyl enol ethersadd to carbonyls in the presence of aLewis acidcatalyst, such asboron trifluoride(asboron trifluoride etherate) ortitanium tetrachloride.[38][39]

In theStork enamine alkylation,secondary amines formenamineswhen exposed to ketones. These enamines then react (possibly enantio­selectively[40]) with suitable electrophiles. This strategy offers simple enantioselection without transition metals. In contrast to the preference forsynadducts typically observed in enolate-based aldol additions, these aldol additions areanti-selective.

In aqueous solution, the enamine can then be hydrolyzed from the product, making it asmall organic molecule catalyst.In a seminal example,prolineefficiently catalyzed the cyclization of a triketone:

This combination is theHajos-Parrish reaction[41][42][43]Under Hajos-Parrish conditions only a catalytic amount of proline is necessary (3 mol%). There is no danger of an achiral background reaction because the transient enamine intermediates are much more nucleophilic than their parent ketone enols.

A Stork-type strategy also allows the otherwise challenging cross-reactions between two aldehydes. In many cases, the conditions are mild enough to avoid polymerization:[44]

However, selectivity requires the slow syringe-pump controlled addition of the desired electrophilic partner because both reacting partners typically have enolizable protons. If one aldehyde has no enolizable protons or Alpha - or beta-branching, additional control can be achieved.

"Direct" aldol additions

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In the usual aldol addition, a carbonyl compound is deprotonated to form the enolate. The enolate is added to an aldehyde or ketone, which forms an alkoxide, which is then protonated on workup. A superior method, in principle, would avoid the requirement for a multistep sequence in favor of a "direct" reaction that could be done in a single process step.

If one coupling partner preferentially enolizes, then the general problem is that the addition generates an alkoxide, which is much more basic than the starting materials. This product binds tightly to the enolizing agent, preventing it from catalyzing additional reactants:

One approach, demonstrated by Evans, is to silylate the aldol adduct.[45][46]A silicon reagent such asTMSClis added in the reaction, which replaces the metal on the alkoxide, allowingturnoverof the metal catalyst:

Use in carbohydrate synthesis

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Traditional syntheses ofhexosesuse variations of iterativeprotection-deprotectionstrategies, requiring 8–14 steps, organocatalysis can access many of the same substrates by a two-step protocol involving the proline-catalyzed dimerization of Alpha -oxyaldehydes followed by tandem Mukaiyama aldol cyclization.

The aldol dimerization of Alpha -oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions.[47] Earlier studies revealed that aldehydes bearing Alpha -alkyloxy or Alpha -silyloxysubstituentswere suitable for this reaction, while aldehydes bearingElectron-withdrawing groupssuch asacetoxywere unreactive. The protectederythroseproduct could then be converted to four possible sugars via Mukaiyama aldol addition followed bylactolformation. This requires appropriate diastereocontrol in the Mukaiyama aldol addition and the productsilyloxycarbenium ionto preferentially cyclize, rather than undergo further aldol reaction. In the end,glucose,mannose,andallosewere synthesized:

Biological aldol reactions

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Examples of aldol reactions in biochemistry include the splitting offructose-1,6-bisphosphateintodihydroxyacetoneandglyceraldehyde-3-phosphatein the fourth stage ofglycolysis,which is an example of a reverse ( "retro" ) aldol reaction catalyzed by the enzymealdolase A(also known as fructose-1,6-bisphosphate aldolase).

In theglyoxylate cycleof plants and some prokaryotes,isocitrate lyaseproducesglyoxylateandsuccinatefromisocitrate.Following deprotonation of the OH group, isocitrate lyase cleaves isocitrate into the four-carbon succinate and the two-carbon glyoxylate by an aldol cleavage reaction. This cleavage is similar mechanistically to the aldolase A reaction of glycolysis.

History

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The aldol reaction was discovered independently by the Russian chemist (and Romantic composer)Alexander Borodinin 1869[48][49][50]and by the French chemistCharles-Adolphe Wurtzin 1872, which originally used aldehydes to perform the reaction.[2][3][4]

Howard Zimmermanand Marjorie D. Traxler proposed their model for stereoinduction in a 1957 paper.[22]

See also

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Notes

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  1. ^It is typically best to minimize heat for this reaction. As removal of water from excess heat risks shifting the equilibrium in favor of a dehydration reaction, leading to the aldol condensation product.
    By avoiding heat, it can help avoid dehydration so that the majority of product produced is the aldol addition product.[1]
  2. ^In this reaction the nucleophile is a boron enolate derived from reaction withdibutylboron triflate(nBu2BOTf), the base isN,N-diisopropylethylamine.The thioether is removed in step 2 byRaney Nickel/ hydrogenreduction

References

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  2. ^abWurtz, C. A.(1872)."Sur un aldéhyde-alcool"[On an aldehyde alcohol].Bulletin de la Société Chimique de Paris.2nd series (in French).17:436–442.
  3. ^abWurtz, C. A.(1872)."Ueber einen Aldehyd-Alkohol"[About an aldehyde alcohol].Journal für Praktische Chemie(in German).5(1): 457–464.doi:10.1002/prac.18720050148.
  4. ^abWurtz, C. A.(1872)."Sur un aldéhyde-alcool"[On an aldehyde alcohol].Comptes rendus de l'Académie des sciences(in French).74:1361.
  5. ^Wade, L. G. (2005).Organic Chemistry(6th ed.). Upper Saddle River, New Jersey: Prentice Hall. pp. 1056–66.ISBN978-0-13-236731-8.
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  8. ^Heathcock, C. H.(1991). "The Aldol Reaction: Acid and General Base Catalysis". InTrost, B. M.;Fleming, I.(eds.).Comprehensive Organic Synthesis.Vol. 2. Elsevier Science. pp. 133–179.doi:10.1016/B978-0-08-052349-1.00027-5.ISBN978-0-08-052349-1.
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  24. ^Heathcock, C. H.;Buse, C. T.; Kleschnick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. (1980). "Acyclic stereoselection. 7. Stereoselective synthesis of 2-alkyl-3-hydroxy carbonyl compounds by aldol condensation".Journal of Organic Chemistry.45(6): 1066–1081.doi:10.1021/jo01294a030.
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  44. ^Northrup, Alan B.; MacMillan David W. C. (2002)."The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes"(PDF).Journal of the American Chemical Society.124(24): 6798–6799.doi:10.1021/ja0262378.PMID12059180.
  45. ^Evans, D. A.;Tedrow, J. S.; Shaw, J. T.; Downey, C. W. (2002). "Diastereoselective Magnesium Halide-Catalyzed anti-Aldol Reactions of Chiral N-Acyloxazolidinones".Journal of the American Chemical Society.124(3): 392–393.doi:10.1021/ja0119548.PMID11792206.
  46. ^Evans, David A.;Downey, C. Wade; Shaw, Jared T.; Tedrow, Jason S. (2002). "Magnesium Halide-Catalyzed Anti-Aldol Reactions of Chiral N-Acylthiazolidinethiones".Organic Letters.4(7): 1127–1130.doi:10.1021/ol025553o.PMID11922799.
  47. ^Northrup A. B.; Mangion I. K.; Hettche F.; MacMillan D. W. C. (2004)."Enantioselective Organocatalytic Direct Aldol Reactions of -Oxyaldehydes: Step One in a Two-Step Synthesis of Carbohydrates".Angewandte Chemie International Edition in English.43(16): 2152–2154.doi:10.1002/anie.200453716.PMID15083470.
  48. ^Borodin reported on the condensation ofpentanal(Valerianaldehyd) withheptanal(Oenanthaldehyd) in: von Richter, V. (1869)"V. von Richter, aus St. Petersburg am 17. October 1869"(V. von Richter [reporting] from St. Petersburg on 17. October 1869),Berichte der deutschen chemischen Gesellschaft(in German),2:552-553.
  49. ^Garner, Susan Amy (2007) "Hydrogen-mediated carbon-carbon bond formations: Applied to reductive aldol and Mannich reactions," Ph.D. dissertation, University of Texas (Austin),pp. 4and51.
  50. ^Borodin, A. (1873)"Ueber einen neuen Abkömmling des Valerals"(On a new derivative of valerian aldehyde),Berichte der deutschen chemischen Gesellschaft(in German),6:982–985.

Further reading

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