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The aldol reaction (aldol addition) is a
reaction Reaction may refer to a process or to a response to an action, event, or exposure. Physics and chemistry *Chemical reaction *Nuclear reaction *Reaction (physics), as defined by Newton's third law * Chain reaction (disambiguation) Biology and ...
in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
that combines two
carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
compounds (e.g.
aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
s or
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
s) to form a new β-hydroxy carbonyl compound. Its simplest form might involve the
nucleophilic addition In organic chemistry, a nucleophilic addition (AN) 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 addit ...
of an enolized
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
to another: These products are known as '' aldols'', from the ''ald''ehyde + alcoh''ol'', 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. The aldol reaction is paradigmatic in organic chemistry and one of the most common means of forming
carbon–carbon bond A carbon–carbon bond is a covalent bond between two carbon atoms. The most common form is the single bond: a bond composed of two electrons, one from each of the two atoms. The carbon–carbon single bond is a sigma bond and is formed between on ...
s in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
. It lends its name to the family of aldol reactions and similar techniques analyze a whole family of carbonyl α-substitution reactions, as well as the diketone condensations.


Scope

Aldol structural units are found in many important molecules, whether naturally occurring or synthetic. The reaction is well used on an industrial scale, notably of
pentaerythritol Pentaerythritol is an organic compound with the formula C(CH2OH)4. The molecular structure can be described as a neopentane with one hydrogen atom in each methyl group replaced by a hydroxyl (–OH) group. It is therefore a polyol, specifically a ...
, trimethylolpropane, the plasticizer precursor
2-ethylhexanol 2-Ethylhexanol (abbreviated 2-EH) is an organic compound with the chemical formula . It is a branched, eight-carbon chiral alcohol. It is a colorless liquid that is poorly soluble in water but soluble in most organic solvents. It is produced on a l ...
, and the drug Lipitor (
atorvastatin Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a ...
, calcium salt). 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.


Aldol dimerization

In its simplest implementation, base induces conversion of an aldehyde or a ketone to the aldol product. One example involves the aldol condensation of
propionaldehyde Propionaldehyde or propanal is the organic compound with the formula CH3CH2CHO. It is the 3-carbon aldehyde. It is a colourless, flammable liquid with a pungent and fruity odour. It is produced on a large scale industrially. Production Propiona ...
: : Featuring the RCH(OH)CHR'C(O)R" grouping, the product is an aldol. In this case R = , R' = , and R" = H. Such reactions are called aldol aldol dimerization.


Cross-aldol

With a mixture of carbonyl precursors, complicated mixtures can occur. Addition of base to a mixture of propionaldehyde and acetaldehyde, one obtains four products: : The first two products are the result of aldol dimerization but the latter two result from a crossed aldol reaction. Complicated mixtures from cross aldol reactions can be avoided by using one component that cannot form an enolate, examples being
formaldehyde Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...
and
benzaldehyde Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is among the simplest aromatic aldehydes and one of the most industrially useful. It is a colorless liquid with a characteristic almond-li ...
. This approach is used in one stage in the production of
trimethylolethane Trimethylolethane (TME) is the organic compound with the formula CH3C(CH2OH)3. This colorless solid is a triol, as it contains three hydroxy functional groups. More specifically, it features three primary alcohol groups in a compact neopentyl str ...
, which entails crossed aldol condensation of butyraldehyde and formaldehyde: :


Reactions of aldols

Aldols dehydrate: : Because this conversion is facile, it is sometimes assumed. It is for this reason that the aldol reaction is sometimes called the aldol condensation.


Mechanisms

The aldol reaction has one underlying mechanism: a carbanion-like nucleophile attacks a carbonyl center. If the base is of only moderate strength such as
hydroxide Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water. It ...
ion or an
alkoxide In chemistry, an alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They are written as , where R is the organyl substituent. Alkoxides are strong bases and, whe ...
, the aldol reaction occurs via nucleophilic attack by the resonance-stabilized enolate on the carbonyl group of another molecule. The product is the
alkoxide In chemistry, an alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They are written as , where R is the organyl substituent. Alkoxides are strong bases and, whe ...
salt 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. Although only a catalytic amount of base is required in some cases, the more usual procedure is to use a
stoichiometric Stoichiometry () is the relationships between the masses of reactants and products before, during, and following chemical reactions. Stoichiometry is based on the law of conservation of mass; the total mass of reactants must equal the total m ...
amount of a strong base such as LDA or NaHMDS. 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 the
reaction mechanism In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical reaction occurs. A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage ...
involves acid-catalyzed tautomerization of the carbonyl compound to the enol. The acid also serves to activate the carbonyl group of ''another molecule'' by 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 after
deprotonation Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.ed ...
. Some may also dehydrate past the intended product to give the unsaturated carbonyl compound through aldol condensation.


Crossed-aldol reactant control

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. If the conditions are particularly harsh (e.g.: NaOMe/MeOH/
reflux Reflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations. It is also used in chemistry to supply energy to Chemical ...
), 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. This is the basis of the catalytic strategy of class I aldolases in nature, as well as numerous small-molecule amine catalysts. When a mixture of unsymmetrical ketones are reacted, four crossed-aldol (
addition Addition (usually signified by the Plus and minus signs#Plus sign, plus symbol, +) is one of the four basic Operation (mathematics), operations of arithmetic, the other three being subtraction, multiplication, and Division (mathematics), divis ...
) products can be anticipated: 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 of diethyl malonate into
benzaldehyde Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is among the simplest aromatic aldehydes and one of the most industrially useful. It is a colorless liquid with a characteristic almond-li ...
produces only one product: 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 the limiting 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 CH2 group flanked by two carbonyls or nitriles (see for example the Knoevenagel condensation and the first steps of the malonic ester synthesis and acetoacetic ester synthesis). Otherwise, the most acidic carbonyls are typically also the most active electrophiles: first
aldehydes In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
, then
ketones In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
, then
esters In chemistry, an ester is a chemical compound, compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds c ...
, and finally amides. Thus cross-aldehyde reactions are typically most challenging because they can
polymerize In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many form ...
easily or react unselectively to give a statistical mixture of products. One common solution is to form the enolate of one partner first, and then add the other partner under kinetic control.Bal, B.; Buse, C. T.; Smith, K.; Heathcock, C. H.
(2SR,3RS)-2,4-Dimethyl-3-Hydroxypentanoic Acid
, '' Org. Synth.'', Coll. Vol. 7, p.185 (1990); Vol. 63, p.89 (1985).
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 with LDA at −78 °C, followed by the slow addition of an aldehyde.


Stereoselectivity

The aldol reaction unites two relatively simple
molecules A molecule is a group of two or more atoms that are held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemistry ...
into a more complex one. Increased complexity arises because each end of the new bond may become a
stereocenter In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...
. Modern methodology has not only developed high- yielding aldol reactions, but also completely controls both the relative and
absolute configuration In chemistry, absolute configuration refers to the spatial arrangement of atoms within a molecular entity (or Functional group, group) that is chirality (chemistry), chiral, and its resultant stereochemical description. Absolute configuration is ...
of these new stereocenters. To describe relative stereochemistry at the α- and β-carbon, older papers use saccharide chemistry's '' erythro/threo'' nomenclature; more modern papers use the following ''syn''/''anti'' convention. When propionate (or higher order) nucleophiles add to aldehydes, the reader visualizes the ''R'' group of the ketone and the ''R group of the aldehyde aligned in a "zig zag" pattern on the paper (or screen). The disposition of the formed stereocenters is deemed ''syn'' or ''anti'', depending if they are on the same or opposite sides of the main chain: The principal factor determining an aldol reaction's
stereoselectivity In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation ...
is the enolizing metal counterion. Shorter metal-oxygen bonds "tighten" the
transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...
and effects greater stereoselection.
Boron Boron is a chemical element; it has symbol B and atomic number 5. In its crystalline form it is a brittle, dark, lustrous metalloid; in its amorphous form it is a brown powder. As the lightest element of the boron group it has three ...
is often used because its
bond length In molecular geometry, bond length or bond distance is defined as the average distance between Atomic nucleus, nuclei of two chemical bond, bonded atoms in a molecule. It is a Transferability (chemistry), transferable property of a bond between at ...
s are significantly shorter than other cheap metals (
lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
,
aluminium Aluminium (or aluminum in North American English) is a chemical element; it has chemical symbol, symbol Al and atomic number 13. It has a density lower than that of other common metals, about one-third that of steel. Aluminium has ...
, or
magnesium Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
). The following reaction gives a ''syn:anti'' ratio of 80:20 using a lithium enolate compared to 97:3 using a dibutylboron enolate. Where the counterion determines stereoinduction strength, the enolate isomer determines its direction. ''E'' isomers give ''anti'' products and ''Z'' give ''syn'':


Zimmermann–Traxler model

If the two reactants have carbonyls adjacent to a pre-existing stereocenter, then the new stereocenters may form 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 stylized
transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...
, called the Zimmerman–Traxler model, can predict the new orientation from the configuration of a 6-membered ring.


On the enol

If the enol has an adjacent stereocenter, then the two stereocenters flanking the carbonyl in the product are naturally ''syn'': The underlying mechanistic reason depends on the enol isomer. For an ''E'' enolate, the stereoinduction is necessary to avoid 1,3- allylic strain, while a ''Z'' enolate instead seeks to avoid 1,3- diaxial interactions: However, Fráter & Seebach showed that a chelating Lewis basic moiety adjacent to the enol will instead cause ''anti'' addition.


On the electrophile

''E'' enolates exhibit Felkin diastereoface selection, while ''Z'' enolates exhibit anti-Felkin selectivity. The general model is presented below: Since the
transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...
for ''Z'' enolates must contain either a destabilizing ''syn''-pentane interaction or an anti-Felkin rotamer, ''Z''-enolates are less diastereoselective:


On both

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. Several examples are as follows:


Oxazolidinone chiral auxiliaries

In the late 1970s and 1980s, David A. Evans and coworkers developed a technique for stereoselection in the aldol syntheses of aldehydes and
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
s.Gage J. R.; Evans D. A.
Diastereoselective Aldol Condensation Using A Chiral Oxazolidinone Auxiliary: (2S*,3S*)-3-Hydroxy-3-Phenyl-2-Methylpropanoic Acid
,
Organic Syntheses ''Organic Syntheses'' is a peer-reviewed scientific journal that was established in 1921. It publishes detailed and checked procedures for the synthesis of organic compounds. A unique feature of the review process is that all of the data and expe ...
, Coll. Vol. 8, p.339 (1993); Vol. 68, p.83 (1990).
The method works by temporarily appending a chiral oxazolidinone
auxiliary Auxiliary may refer to: In language * Auxiliary language (disambiguation) * Auxiliary verb In military and law enforcement * Auxiliary police * Auxiliaries, civilians or quasi-military personnel who provide support of some kind to a military se ...
to 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. 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 acid moiety. Then the resulting amino alcohol dehydratively cyclises with a simple carbonate ester, such as diethylcarbonate. The acylation of an oxazolidinone is informally referred to as "loading done". ''Anti'' adducts, which require an ''E'' enolate, cannot be obtained reliably with the Evans method. However, ''Z'' enolates, leading to ''syn'' adducts, can be reliably formed using boron-mediated soft enolization: Often, a single
diastereomer In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have di ...
may be obtained by one
crystallization Crystallization is a process that leads to solids with highly organized Atom, atoms or Molecule, molecules, i.e. a crystal. The ordered nature of a crystalline solid can be contrasted with amorphous solids in which atoms or molecules lack regu ...
of the aldol adduct. Many methods cleave the auxiliary:


Variations

A common additional chiral auxiliary is a
thioether In organic chemistry, a sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, Volatile organic compound, volatile sulfides have ...
group:


Crimmins thiazolidinethione aldol

In the Crimmins thiazolidinethione approach, a thiazolidinethione is the chiral auxiliary 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-bound
transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...
s, analogous to the proposed transition states for the Evans auxiliary.


"Masked" enols

A common modification of the aldol reaction uses other, similar functional groups as ''ersatz'' enols. In the Mukaiyama aldol reaction, silyl enol ethers add to carbonyls in the presence of a
Lewis acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any ...
catalyst, such as
boron trifluoride Boron trifluoride is the inorganic compound with the formula . This pungent, colourless, and toxic gas forms white fumes in moist air. It is a useful Lewis acid and a versatile building block for other boron compounds. Structure and bonding The g ...
(as boron trifluoride etherate) or
titanium tetrachloride Titanium tetrachloride is the inorganic compound with the formula . It is an important intermediate in the production of titanium metal and the pigment titanium dioxide. is a volatile liquid. Upon contact with humid air, it forms thick clouds o ...
. In the Stork enamine alkylation, secondary amines form
enamine An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates. The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and the r ...
s when exposed to ketones. These enamines then react (possibly enantio­selectively) with suitable electrophiles. This strategy offers simple enantioselection without transition metals. In contrast to the preference for ''syn'' adducts typically observed in enolate-based aldol additions, these aldol additions are ''anti''-selective. In aqueous solution, the enamine can then be hydrolyzed from the product, making it a small organic molecule catalyst. In a seminal example,
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
efficiently catalyzed the cyclization of a triketone: This combination is the Hajos-Parrish reaction 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: 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

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. A silicon reagent such as TMSCl is added in the reaction, which replaces the metal on the alkoxide, allowing turnover of the metal catalyst:


Use in carbohydrate synthesis

Traditional syntheses of
hexose In chemistry, a hexose is a monosaccharide (simple sugar) with six carbon atoms. The chemical formula for all hexoses is , and their molecular weight is 180.156 g/mol. Hexoses exist in two forms, open-chain or cyclic, that easily convert into ...
s use variations of iterative protection-deprotection strategies, 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. Earlier studies revealed that aldehydes bearing alpha-alkyloxy or alpha- silyloxy
substituent In organic chemistry, a substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. The suffix ''-yl'' is used when naming organic compounds that contain a single bond r ...
s were suitable for this reaction, while aldehydes bearing Electron-withdrawing groups such as acetoxy were unreactive. The protected
erythrose Erythrose is a tetrose saccharide with the chemical formula C4H8O4. It has one aldehyde group, and is thus part of the aldose family. The natural isomer is D-erythrose; it is a diastereomer of D -threose. Erythrose was first isolated in 1849 ...
product could then be converted to four possible sugars via Mukaiyama aldol addition followed by lactol formation. This requires appropriate diastereocontrol in the Mukaiyama aldol addition and the product silyloxycarbenium ion to preferentially cyclize, rather than undergo further aldol reaction. In the end,
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
,
mannose Mannose is a sugar with the formula , which sometimes is abbreviated Man. It is one of the monomers of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylatio ...
, and allose were synthesized:


Biological aldol reactions

Examples of aldol reactions in biochemistry include the splitting of fructose-1,6-bisphosphate into
dihydroxyacetone Dihydroxyacetone (; DHA), also known as glycerone, is a simple saccharide (a triose) with formula . DHA is primarily used as an ingredient in sunless tanning products. It is often derived from plant sources such as sugar beets and sugar cane, ...
and glyceraldehyde-3-phosphate in the fourth stage of
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...
, which is an example of a reverse ("retro") aldol reaction catalyzed by the enzyme aldolase A (also known as fructose-1,6-bisphosphate aldolase). In the glyoxylate cycle of plants and some prokaryotes, isocitrate lyase produces glyoxylate and
succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into Fuma ...
from isocitrate. 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

The first aldol-type reaction was discovered in 1838 by Robert Kane from the reaction of mesityl alcohol in sulfuric acid to produce mesitylene. It was later discovered independently by the Russian chemist (and Romantic composer) Alexander Borodin in 1869Borodin, 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.
and by the French chemist Charles-Adolphe Wurtz in 1872, which originally used aldehydes to perform the reaction.
Howard Zimmerman Howard E. Zimmerman (July 5, 1926 – February 12, 2012) was a professor of chemistry at the University of Wisconsin–Madison. He was elected to the National Academy of Sciences in 1980 and the recipient of the 1986 American Institute of Chemis ...
and Marjorie D. Traxler proposed their model for stereoinduction in a 1957 paper.


See also

* Aldol–Tishchenko reaction * Baylis–Hillman reaction * Ivanov reaction * Reformatsky reaction * Claisen–Schmidt condensation


Notes


References


Further reading

* Chem 206, 215 Lecture Notes (2003, 2006) by D. A. Evans, A. G. Myers, ''et al.'', Harvard University (pp. 345, 936) {{Organic reactions Addition reactions Carbon-carbon bond forming reactions Alexander Borodin