View source for Chemistry:Aldol reaction

{{Short description|Chemical reaction}}
{{Reactionbox
| Name = Aldol Addition
| Type = Coupling reaction
| Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = aldol-addition
   | RSC_ontology_id = 0000016
 }}
|Reaction={{Reactionbox Reaction
   | Reactant1 = [[Chemistry:Ketone|Ketone]] or [[Chemistry:Aldehyde|Aldehyde]]
   | Reactant2 =  [[Chemistry:Ketone|Ketone]] or [[Chemistry:Aldehyde|Aldehyde]]
   | Reagent1= 
   | Product1 =[[Chemistry:Aldol|β-hydroxy Aldehyde]] {{br}}or{{br}} [[Chemistry:Aldol|β-hydroxy Ketone]]
   | Sideproduct1 = 
}}|Section1={{Reactionbox Conditions
   | Reference =
   | Solvent = 
   | Catalyst = {{center|<sup>-</sup>OH or H<sup>+</sup>}}
   | Temperature = {{center|-Δ, ~-70°C{{Efn| 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.<br>By avoiding heat, it can help avoid dehydration so that the majority of product produced is the aldol addition product.<ref>{{Cite book |last=Klein |first=David R. |url=https://www.worldcat.org/oclc/1201694230 |title=Organic chemistry |date=December 22, 2020 |publisher=Wiley |isbn=978-1-119-65959-4 |edition=4th |location=Hoboken, NJ |pages=1014 |oclc=1201694230}}</ref>}}}}
}}}}

The '''aldol reaction''' ('''aldol addition''') is a reaction that combines two carbonyl compounds ([[Chemistry:Aldehyde|aldehyde]]s or [[Chemistry:Ketone|ketone]]s) to form a new β-hydroxy carbonyl compound.  

[[File:Aldol_Addition_reaction_equation.svg|center|frameless|573x573px]]

These products are known as ''[[Chemistry:Aldol|aldol]]s'', 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 discovery history, where aldehydes were first used in the reaction and not ketones.<ref name="Wurtz1872" /><ref name="Wurtz1872b" /><ref name="Wurtz1872c" />

Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.<ref name="Heathcock1991">{{cite book
|last = Heathcock | first = C. H.
|chapter = The Aldol Reaction: Acid and General Base Catalysis
|title = Comprehensive Organic Synthesis 
|volume = 2| publisher = Elsevier Science| year = 1991| pages = 133–179| isbn = 978-0-08-052349-1| doi = 10.1016/B978-0-08-052349-1.00027-5}}</ref><ref name="Paterson1988">{{cite journal| title = New Asymmetric Aldol Methodology Using Boron Enolates| author = Paterson, I.| journal = Chem. Ind.| year = 1988| volume = 12| pages = 390–394}}</ref> The aldol reaction is a common means of forming [[Chemistry:Carbon–carbon bond|carbon–carbon bond]]s in [[Chemistry:Organic chemistry|organic chemistry]].<ref name="Wade">{{cite book| last = Wade | first = L. G.| title = Organic Chemistry| publisher = Prentice Hall| year = 2005| edition = 6th| location = Upper Saddle River, New Jersey| pages = 1056–66| isbn = 978-0-13-236731-8}}</ref><ref name="March">{{cite book |doi=10.1002/0470084960|title=March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure |year=2006 |last1=Smith |first1=Michael B. |last2=March |first2=Jerry |isbn=9780470084960 }}</ref><ref name="Mahrwald2004">{{cite book| last = Mahrwald| first = R.| title = Modern Aldol Reactions, Volumes 1 and 2| publisher = Wiley-VCH Verlag GmbH & Co. KGaA| year = 2004| location = Weinheim, Germany| pages = [https://archive.org/details/modernaldolreact00rain/page/1218 1218–23]| isbn = 978-3-527-30714-2| url-access = registration| url = https://archive.org/details/modernaldolreact00rain/page/1218}}</ref>

The reaction is used in several industrial syntheses, notably of [[Chemistry:Pentaerythritol|pentaerythritol]],<ref name="mestres">{{cite journal| title = A green look at the aldol reaction| author = Mestres R.| journal = Green Chemistry| year = 2004| volume = 6| pages = 583–603| doi = 10.1039/b409143b| issue = 12}}</ref> [[Chemistry:Trimethylolpropane|trimethylolpropane]], the plasticizer [[Chemistry:2-Ethylhexanol|2-ethylhexanol]], and the drug Lipitor ([[Biology:Atorvastatin|atorvastatin]], calcium salt).<!--what is this here for?<ref name=Braun5031>{{cite journal| title = (R) and (S)-2-acetoxy-1,1,2-triphenylethanol – effective synthetic equivalents of a chiral acetate enolate| author = M. Braun|author2=R. Devant| journal = Tetrahedron Letters| year = 1984| volume = 25| pages = 5031–4| doi = 10.1016/S0040-4039(01)91110-4| issue = 44}}
</ref>--><ref name="jackli2004">{{cite book| author = Jie Jack Li| title = Contemporary Drug Synthesis| publisher = Wiley-Interscience| year = 2004| pages = 118–| isbn = 978-0-471-21480-9| display-authors=0}}</ref>  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.

==Stereochemistry==
The aldol reaction unites two relatively simple molecules into a more complex one. Increased complexity arises because up to two new stereogenic centers (on the α- and β-carbon of the aldol adduct, marked with asterisks in the scheme below) are formed. Modern methodology is capable of not only allowing aldol reactions to proceed in high [[Chemistry:Yield|yield]] but also controlling both the relative and [[Chemistry:Absolute configuration|absolute configuration]] of these [[Chemistry:Stereocenter|stereocenter]]s.<ref name="March"/>  This ability to selectively synthesize a particular stereoisomer is significant because stereoisomers can have distinctive chemical and biological properties.

For example, stereogenic aldol units are especially common in [[Biology:Polyketide|polyketide]]s, a class of molecules found in biological organisms. In nature, polyketides are synthesized by [[Biology:Enzymes|enzymes]] that effect iterative [[Chemistry:Claisen condensation|Claisen condensation]]s. The 1,3-dicarbonyl products of these reactions can then be variously derivatized to produce a wide variety of interesting structures. Often, such derivatization involves the reduction of one of the carbonyl groups, producing the aldol subunit. Some of these structures have potent biological properties: the [[Chemistry:Immunosuppressant|immunosuppressant]] FK506, the anti-tumor agent [[Chemistry:Discodermolide|discodermolide]], or the antifungal agent [[Chemistry:Amphotericin B|amphotericin B]], for example. Although the synthesis of many such compounds was once considered nearly impossible, aldol methodology has allowed their efficient [[Chemistry:Total synthesis|synthesis]] in many cases.<ref name=MahrwaldSchetter2006>{{cite journal| title = Modern Aldol Methods for the Total Synthesis of Polyketides| author = Schetter, B.|author2=Mahrwald, R.| journal =Angew. Chem. Int. Ed.| year =2006| volume =45| pages =7506–7525| doi = 10.1002/anie.200602780| pmid = 17103481| issue = 45}}</ref>

[[File:Typical aldol-en.svg|600px|center]]

A typical modern aldol [[Chemistry:Addition reaction|addition reaction]], shown above at the top, might involve the [[Chemistry:Nucleophilic addition|nucleophilic addition]] of a [[Chemistry:Ketone enolate|ketone enolate]] to an [[Chemistry:Aldehyde|aldehyde]]. Once formed, the aldol product can sometimes [[Chemistry:Dehydration reaction|lose a molecule of water]] to form an α,β-unsaturated carbonyl compound. This is called ''[[Chemistry:Aldol condensation|aldol condensation]]''. A variety of nucleophiles may be employed in the aldol reaction, including the [[Biology:Enol|enol]]s, [[Chemistry:Enolate|enolate]]s, and enol [[Chemistry:Ether|ether]]s of ketones, aldehydes, and many other carbonyl compounds. The [[Chemistry:Electrophile|electrophilic]] partner is usually an aldehyde or ketone (many variations, such as the [[Chemistry:Mannich reaction|Mannich reaction]], exist). When the nucleophile and electrophile are different, the reaction is called a ''crossed aldol reaction''; on the converse, when the nucleophile and electrophile are the same, the reaction is called an ''aldol [[Chemistry:Dimer|dimerization]]''.
[[File:aldolrxnpic.jpg|thumb|right|300px|A typical experimental setup for an aldol reaction in a research laboratory.<br /> The flask on the right is a solution of [[Chemistry:Lithium diisopropylamide|lithium diisopropylamide]] (LDA) in tetrahydrofuran (THF). The flask on the left is a solution of the lithium enolate of ''tert''-butyl propionate (formed by addition of LDA to ''tert''-butyl propionate). An aldehyde can then be added to the enolate flask to initiate an aldol addition reaction.<br /> Both flasks are submerged in a dry ice/acetone [[Cooling bath|cooling bath]] (−78&nbsp;°C) the temperature of which is being monitored by a thermocouple (the wire on the left).]]

==Mechanisms==
The aldol reaction may proceed by two distinct mechanisms. Carbonyl compounds, such as aldehydes and ketones, can be converted to enols or enol ethers. These species, being nucleophilic at the α-carbon, can attack especially reactive protonated carbonyls such as protonated aldehydes. This is the 'enol mechanism'. Carbonyl compounds, being carbon acids, can also be deprotonated to form enolates, which are much more nucleophilic than enols or enol ethers and can attack electrophiles directly. The usual electrophile is an aldehyde, since ketones are much less reactive. This is the 'enolate mechanism'.

Despite the attractiveness of the aldol manifold, there are several problems that need to be addressed to render the process catalytic and 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.<ref>{{Cite book|url=http://www.thieme-connect.de/DOI/DOI?10.1055/b-003-125712|title=Stereoselective Synthesis 2: Stereoselective Reactions of Carbonyl and Imino Groups|date=2011|publisher=Georg Thieme Verlag|isbn=978-3-13-154121-5|editor-last=Molander|editor-first=G. A.|edition=1|location=Stuttgart|language=en|doi=10.1055/sos-sd-202-00331}}</ref> If the conditions are particularly harsh (e.g.: NaOMe/MeOH/[[Reflux|reflux]]), condensation may occur, but this can usually be avoided with mild reagents and low temperatures (e.g., LDA (a strong base), THF, −78&nbsp;°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.<ref name=Guthrie1984>{{cite journal| title = The retroaldol reaction of cinnamaldehyde| author = Guthrie, J.P.|author2= Cooper, K.J.|author3= Cossar, J.|author4= Dawson, B.A.|author5= Taylor, K.F.| doi = 10.1139/v84-243| journal =Can. J. Chem.| year =1984| volume =62| pages =1441–1445| issue = 8| doi-access = free}}</ref> This is the basis of the catalytic strategy of class I aldolases in nature, as well as numerous small-molecule amine catalysts.<ref>{{Cite book|url=http://www.thieme-connect.de/products/ebooks/book/10.1055/b-003-125712|title=Stereoselective Synthesis 2: Stereoselective Reactions of Carbonyl and Imino Groups|date=2011|publisher=Georg Thieme Verlag|isbn=978-3-13-154121-5|editor-last=Molander|edition=1|location=Stuttgart|language=en|doi=10.1055/sos-sd-202-00331}}</ref>

[[File:Simple aldol reaction.svg|750px|A generalized view of the aldol reaction|center]]

===Enolate mechanism===
If the [[Chemistry:Catalyst|catalyst]] is a moderate base such as [[Chemistry:Hydroxide|hydroxide]] ion or an [[Chemistry:Alkoxide|alkoxide]], the aldol reaction occurs via nucleophilic attack by the [[Chemistry:Resonance|resonance-stabilized]] enolate on the carbonyl group of another molecule. The product is the [[Chemistry:Alkoxide|alkoxide]] 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.

'''Base-catalyzed aldol reaction'''
[[File:Aldol addition base-catalyzed.svg|795x795px|Simple mechanism for base-catalyzed aldol reaction of an aldehyde with itself|center]]

Although only a catalytic amount of base is required in some cases, the more usual procedure is to use a stoichiometric amount of a strong base such as [[Chemistry:Lithium diisopropylamide|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.

===Enol mechanism===
When an acid catalyst is used, the initial step in the [[Physics:Reaction mechanism|reaction mechanism]] involves acid-catalyzed [[Chemistry:Tautomer|tautomer]]ization 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 [[Chemistry:Deprotonation|deprotonation]]. Some may also dehydrate past the intended product to give the unsaturated carbonyl compound through [[Chemistry:Aldol condensation|aldol condensation]].

'''Acid-catalyzed aldol mechanism''' 
[[File:Aldol addition acid-catalyzed.svg|880x880px|Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself|center]]

===Zimmerman–Traxler model===
More refined forms of the mechanism are known. In 1957, Howard Zimmerman and Marjorie D. Traxler proposed that some aldol reactions have "six-membered transition states having a chair conformation."<ref name=Zimmerman1920>{{cite journal| title = The Stereochemistry of the Ivanov and Reformatsky Reactions. I| author = Zimmerman, H. E.|author2=Traxler, M. D.| doi = 10.1021/ja01565a041| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| year =1957| volume =79| pages =1920–1923| issue = 8}}</ref> This is now known as the '''Zimmerman–Traxler model'''. ''E''-enolates give rise to anti products, whereas ''Z''-enolates give rise to syn products. The factors that control selectivity are the preference for placing substituents equatorially in six-membered transition states and the avoidance of [[Chemistry:Pentane interference|syn-pentane interactions]], respectively.<ref name=Heathcock1980>{{cite journal|title = Acyclic stereoselection. 7. Stereoselective synthesis of 2-alkyl-3-hydroxy carbonyl compounds by aldol condensation|  last1 = Heathcock | first1 = C. H.| last2 = Buse |first2 =C. T.| last3=Kleschnick|first3=W. A.| last4=Pirrung| first4= M. C.| last5=Sohn|first5=J. E.| last6= Lampe |first6=J.| doi = 10.1021/jo01294a030| journal = Journal of Organic Chemistry| year = 1980| volume =45| pages = 1066–1081|issue = 6}}</ref> E and Z refer to the cis-trans stereochemical relationship between the enolate oxygen bearing the positive counterion and the highest priority group on the alpha carbon. In reality, only some metals such as lithium reliably follow the Zimmerman–Traxler model. Thus, in some cases, the [[Chemistry:Stereochemistry|stereochemical]] outcome of the reaction may be unpredictable.

[[File:Zimmerman-Traxler model scheme.svg|The Zimmerman–Traxler model|center]]

==Crossed-aldol reactant control==

When a mixture of unsymmetrical ketones are reacted, four crossed-aldol ([[Chemistry:Addition reaction|addition]]) products can be anticipated:
[[File:Aldol_control_2_update.svg|center|625x625px|Crossed aldol (addition) reaction|frameless]]
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 [[Chemistry:Diethyl malonate|diethyl malonate]] into [[Chemistry:Benzaldehyde|benzaldehyde]] produces only one product:

[[File:Aldol control 3.svg|center|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 carbonyl that is less acidic is not affected by the base. This type of control works only if the difference in acidity is large enough and no excess of base is used for the reaction. A typical substrate for this situation is when the deprotonatable position is activated by more than one carbonyl-like group. Common examples include a CH<sub>2</sub> group flanked by two carbonyls or nitriles (see for example the [[Chemistry:Knoevenagel condensation|Knoevenagel condensation]] and the first steps of the [[Chemistry:Malonic ester synthesis|malonic ester synthesis]] and [[Chemistry:Acetoacetic ester synthesis|acetoacetic ester synthesis]]).

One common solution is to form the enolate of one partner first, and then add the other partner under kinetic control.<ref name=OS1985>Bal, B.; Buse, C. T.; Smith, K.; Heathcock, C. H., [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0185 (2SR,3RS)-2,4-Dimethyl-3-Hydroxypentanoic Acid] {{Webarchive|url=https://web.archive.org/web/20110606033118/http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0185 |date=2011-06-06 }}, ''Org. Synth.'', Coll. Vol. 7, p.185 (1990); Vol. 63, p.89 (1985).</ref> 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 [[Chemistry:Lithium diisopropylamide|LDA]] at −78&nbsp;°C, followed by the slow addition of an aldehyde.

==Stereoselectivity==
The aldol reaction is particularly useful because two new stereogenic centers are generated in one reaction.  The ''syn''/''anti'' convention is commonly used to denote the relative stereochemistry at the α- and β-carbon.

[[File:Aldol_syn-anti.svg|500px|Syn and anti products from an aldol (addition) reaction|center]]

The convention applies when propionate (or higher order) nucleophiles are added to aldehydes. The ''R'' group of the ketone and the ''R''' group of the aldehyde are aligned in a "zig zag" pattern in the plane of the paper (or screen), and 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.

Older papers use the ''[[Chemistry:Diastereomer#Erythro / threo|erythro/threo]]'' nomenclature familiar from saccharide chemistry.

===Enolate geometry===
There is no significant difference between the level of stereoinduction observed with ''E'' and ''Z'' enolates. Each alkene geometry leads primarily to one specific relative stereochemistry in the product, ''E'' giving ''anti'' and ''Z'' giving ''syn'':<ref name=Brown1989>{{cite journal
| title = Major effect of the leaving group in dialkylboron chlorides and triflates in controlling the stereospecific conversion of ketones into either E- or Z-enol borinates
| last1 = Brown | first1 = H. C. 
| last2 = Dhar | first2 = R. K. 
| last3 = Bakshi | first3 = R. K. 
| last4 = Pandiarajan | first4 = P. K. 
| last5 = Singaram | first5 = B. 
| doi = 10.1021/ja00191a058
| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
| year =1989
| volume =111
| pages =3441–3442
| issue = 9
}}</ref>

[[File:Stereoselective E-enolate formation of esters in aldol addtion reactions.svg|center|500px|Anti-aldol formation through E-enolate]]


[[File:Stereoselective Z-enolate formation of esters in aldol addtion reactions.svg|center|700px|Syn-aldol formation through Z-enolate]]

===Metal ion===
The enolate metal cation may play a large role in determining the level of stereoselectivity in the aldol reaction. [[Chemistry:Boron|Boron]] is often used<ref>Cowden, C. J.; Paterson, I. ''Org. React.'' '''1997''', ''51'', 1.</ref><ref>{{cite book| last1 = Cowden | first1 = C. J.| last2 = Paterson | first2 = I.| series = Organic Reactions| pages = 1–200| doi = 10.1002/0471264180.or051.01| title = Asymmetric Aldol Reactions Using Boron Enolates| year = 2004| isbn = 978-0471264187}}</ref> because its [[Bond length|bond length]]s are significantly shorter than that of metals such as [[Chemistry:Lithium|lithium]], [[Chemistry:Aluminium|aluminium]], or [[Chemistry:Magnesium|magnesium]].
[[File:Enolate metal ion.svg|510px|center]]
For example, boron–carbon and boron–oxygen bonds are 1.4–1.5 Å and 1.5–1.6 Å in length, respectively, whereas typical metal-carbon and metal-oxygen bonds are 1.9–2.2 Å and 2.0–2.2 Å in length, respectively. The use of boron rather than a metal "tightens" the [[Chemistry:Transition state|transition state]] and gives greater stereoselectivity in the reaction.<ref name=JACS1981_3099>{{cite journal| title = Stereoselective aldol condensations via boron enolates|  last = Evans| first = D. A.|author2=Nelson J. V. |author3=Vogel E. |author4=Taber T. R.| doi = 10.1021/ja00401a031| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| year =1981| volume =103| pages =3099–3111| issue = 11}}</ref> Thus the above reaction gives a ''syn:anti'' ratio of 80:20 using a lithium enolate compared to 97:3 using a bibutylboron enolate.

===Alpha stereocenter on the enolate===
The aldol reaction may exhibit "substrate-based stereocontrol", in which existing [[Biology:Chirality|chirality]] on either reactant influences the stereochemical outcome of the reaction. This has been extensively studied, and in many cases, one can predict the sense of [[Physics:Asymmetric induction|asymmetric induction]], if not the absolute level of diastereoselectivity. If the enolate contains a [[Chemistry:Stereocenter|stereocenter]] in the alpha position, excellent stereocontrol may be realized.

[[File:enolate alpha center.svg|center|Aldol reaction with enolate-based stereocontrol]]

In the case of an E enolate, the dominant control element is [[Chemistry:Allylic strain|allylic 1,3-strain]] whereas in the case of a Z enolate, the dominant control element is the avoidance of 1,3-diaxial interactions. The general model is presented below:

[[File:enolate alpha center model.svg|center|General model of the aldol reaction with enolate-based stereocontrol]]

For clarity, the stereocenter on the enolate has been [[Chemistry:Epimer|epimer]]ized; in reality, the opposite diastereoface of the aldehyde would have been attacked. In both cases, the 1,3-syn diastereomer is favored. There are many examples of this type of stereocontrol:<ref name=JACS1991_1047>{{cite journal
| title = Stereoselective aldol reactions of chlorotitanium enolates. An efficient method for the assemblage of polypropionate-related synthons
| last = Evans
| first = D. A.
|author2=Rieger D. L. |author3=Bilodeau M. T. |author4=Urpi F.
| doi = 10.1021/ja00003a051
| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
| year =1991|volume =113
| pages =1047–1049
| issue = 3}}</ref>

[[File:enolate alpha center eg.svg|center|Aldol reaction with enolate-based stereocontrol]]

===Alpha stereocenter on the electrophile===
When enolates attacks aldehydes with an alpha stereocenter, excellent stereocontrol is also possible. The general observation is that ''E'' enolates exhibit Felkin diastereoface selection, while ''Z'' enolates exhibit anti-Felkin selectivity. The general model<ref name=Evans1982TS>Evans D. A. ''et al.'' ''Top. Stereochem.'' '''1982''', ''13'', 1–115. (Review)</ref><ref name=Roush1991>{{cite journal
 | title = Concerning the diastereofacial selectivity of the aldol reactions of .alpha.-methyl chiral aldehydes and lithium and boron propionate enolates
 | author = Roush W. R.
 | journal = Journal of Organic Chemistry
 | year = 1991
 | volume = 56
 | pages = 4151–4157
 | doi = 10.1021/jo00013a015
 | issue = 13}}</ref> is presented below:

[[File:Aldehydealphamodel.png|center|The general model of the aldol reaction with carbonyl-based stereocontrol]]

Since ''Z'' enolates must react through a [[Chemistry:Transition state|transition state]] that contains either a destabilizing syn-pentane interaction or an anti-Felkin rotamer, ''Z''-enolates exhibit lower levels of diastereoselectivity in this case. Some examples are presented below:<ref name=JACS1982_5526>{{cite journal
 | title = Aldol strategy: coordination of the lithium cation with an alkoxy substituent
 | author = Masamune S.
 |author2=Ellingboe J. W. |author3=Choy W.
 | doi = 10.1021/ja00384a062
 | journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
 | year =1982
 | volume =104
 | pages = 1047–1049
 | issue = 20}}</ref><ref name=JACS1995_9073>{{cite journal
|title = Double Stereodifferentiating Aldol Reactions. The Documentation of "Partially Matched" Aldol Bond Constructions in the Assemblage of Polypropionate Systems
| last = Evans
| first = D. A.
|author2=Dart M. J. |author3=Duffy J. L. |author4=Rieger D. L.
| doi = 10.1021/ja00140a027
| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
| year =1995
| volume =117
| pages =9073–9074
|issue = 35}}</ref>

[[File:Aldehydealphaeg.png|center|Examples of the aldol reaction with carbonyl-based stereocontrol]]

===Unified model of stereoinduction===
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 the enolate facial bias, enolate geometry, and aldehyde facial bias.<ref name=Masamune1985>{{cite journal
| title = Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis
| author = Masamune S.
|author2=Choy W. |author3=Petersen J. S. |author4=Sita L. R.
| doi = 10.1002/anie.198500013
| journal =Angew. Chem. Int. Ed. Engl.
| year =1985
| volume =24
| pages =1–30}}</ref> Several examples of the application of this model are given below:<ref name=JACS1995_9073 />
[[File:Mergedmodel.gif|center]]

==Evans' oxazolidinone chemistry==
A widely used method is the Evans' acyl oxazolidinone method.<ref name=Evans1982AldrichActa>{{cite journal|last =Evans|first= D. A.|journal = [[Chemistry:Aldrichimica Acta|Aldrichimica Acta]]|year =1982|volume =15|page = 23|url = https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/marketing/global/documents/296/074/acta-vol15.pdf|title=Studies in Asymmetric Synthesis: The Development of Practical Chiral Enolate Synthons}}</ref><ref name=OS1990>Gage J. R.; Evans D. A., [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv8p0339 Diastereoselective Aldol Condensation Using A Chiral Oxazolidinone Auxiliary: (2S*,3S*)-3-Hydroxy-3-Phenyl-2-Methylpropanoic Acid] {{Webarchive|url=https://web.archive.org/web/20120929193419/http://www.orgsyn.org/orgsyn/prep.asp?prep=cv8p0339 |date=2012-09-29 }}, [[Chemistry:Organic Syntheses|Organic Syntheses]], Coll. Vol. 8, p.339 (1993); Vol. 68, p.83 (1990).</ref> Developed in the late 1970s and 1980s by David A. Evans and coworkers, the method works by temporarily creating a chiral enolate by appending a [[Chemistry:Chiral auxiliary|chiral auxiliary]]. The pre-existing chirality from the auxiliary is then transferred to the aldol adduct by performing a diastereoselective aldol reaction. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed.

[[File:Evansaldol1.gif|center|Aldol reaction creates stereoisomers]]

[[File:Evansaldol2.gif|center|Four possible stereoisomers of the aldol reaction]]

[[File:Evansaldol3.gif|center]]

In the case of the Evans' method, the chiral auxiliary appended is an oxazolidinone, and the resulting carbonyl compound is an [[Chemistry:Imide|imide]]. A number of oxazolidinones are now readily available in both enantiomeric forms. They are relatively expensive. However, enantiopure oxazolidinones are derived in 2 synthetic steps from comparatively inexpensive amino acids, which means that large-scale syntheses can be made more economical by in-house preparation. This usually involves borohydride mediated reduction of the acid [[Chemistry:Moiety|moiety]], followed by condensation/cyclisation of the resulting amino alcohol with a simple carbonate ester such as diethylcarbonate.

[[File:Evansaldol4.gif|center]]

The [[Chemistry:Acylation|acylation]] of an oxazolidinone is a convenient procedure, and is informally referred to as "loading done". ''Z''-enolates, leading to syn-aldol adducts, can be reliably formed using boron-mediated soft enolization:<ref name=Bartroli1981>{{cite journal
| title = Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates
| last = Evans
| first = D. A.
|author2=Bartroli J. |author3=Shih T. L.
| doi = 10.1021/ja00398a058
| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
| year =1981
| volume =103
| pages =2127–2129
| issue = 8}}</ref>

[[File:Evansaldol5.gif|center]]

Often, a single [[Chemistry:Diastereomer|diastereomer]] may be obtained by one [[Physics:Crystallization|crystallization]] of the aldol adduct. However, anti-aldol adducts cannot be obtained reliably with the Evans method. Despite the cost and the limitation to give only ''syn'' adducts, the method's superior reliability, ease of use, and versatility render it the method of choice in many situations. Many methods are available for the cleavage of the auxiliary:<ref name=JACS882506>{{cite journal
| title = The total synthesis of the polyether antibiotic X-206
| last = Evans
| first = D. A.
|author2=Bender S. L. |author3=Morris J.
| doi = 10.1021/ja00216a026
| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
| year =1988
| volume =110
| pages =2506–2526
| issue = 8}}</ref>

[[File:Evansaldol6.gif|center|Evans' chiral oxazolidinone cleavage]]

Upon construction of the imide, both syn- and anti-selective aldol addition reactions may be performed, allowing the assemblage of three of the four possible stereoarrays: syn selective:<ref name=JACS90866>{{cite journal| title = Diastereoselective aldol reactions using .beta.-keto imide derived enolates. A versatile approach to the assemblage of polypropionate systems|  last = Evans| first = D. A.|author2=Clark J.S. |author3=Metternich R. |author4=Sheppard G.S.| doi = 10.1021/ja00158a056| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| year =1990| volume =112| pages =866–868| issue = 2}}</ref> and anti selective:<ref name=JACS922127>{{cite journal|title = Diastereoselective anti aldol reactions of chiral ethyl ketones. Enantioselective processes for the synthesis of polypropionate natural products| author-link = David A. Evans| last1 = Evans| first1 = D. A.| last2 = Ng |first2=H.P.| last3=Clark|first3= J.S.| last4=Rieger|first4= D.L.| journal = Tetrahedron| year = 1992|volume = 48| pages = 2127–2142| doi =10.1016/S0040-4020(01)88879-7|issue = 11}}</ref>

[[File:Evans aldol 7.svg|center]]

In the syn-selective reactions, both enolization methods give the ''Z'' enolate, as expected; however, the stereochemical outcome of the reaction is controlled by the methyl stereocenter, rather than the chirality of the oxazolidinone.{{citation needed|date=March 2016}} The methods described allow the stereoselective assembly of [[Biology:Polyketide|polyketide]]s, a class of natural products that often feature the aldol retron.

==Variations and methods==
===Acetate aldol reactions===
A key limitation to the chiral auxiliary approach described previously is the failure of N-acetyl [[Chemistry:Imide|imide]]s to react selectively. An early approach was to use a temporary [[Chemistry:Thioether|thioether]] group:<ref name=JACS882506 /><ref>In this reaction the nucleophile is a boron enolate derived from reaction with dibutylboron triflate (nBu<sub>2</sub>BOTf), the base is N,N-diisopropylethylamine. The thioether is removed in step 2 by Raney Nickel / hydrogen reduction</ref>

[[File:Acetatealdol1.gif|center]]

===Mukaiyama aldol reaction===
The Mukaiyama aldol reaction<ref>{{cite journal| title = The Impact of the Mukaiyama Aldol Reaction in Total Synthesis| author = S. B. Jennifer Kan| author2=Kenneth K.-H. Ng|author3=Ian Paterson| journal = Angewandte Chemie International Edition| volume = 52| issue = 35| pages = 9097–9108| year = 2013| doi = 10.1002/anie.201303914| pmid = 23893491}}</ref> is the [[Chemistry:Nucleophilic addition|nucleophilic addition]] of [[Chemistry:Silyl enol ether|silyl enol ether]]s to aldehydes catalyzed by a [[Chemistry:Lewis acid|Lewis acid]] such as [[Chemistry:Boron trifluoride|boron trifluoride]] (as [[Chemistry:Boron trifluoride etherate|boron trifluoride etherate]]) or [[Chemistry:Titanium tetrachloride|titanium tetrachloride]].<ref>{{cite journal| title = Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride| author = Teruaki Mukaiyama| author2=Kazuo Banno|author3=Koichi Narasaka| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| volume = 96| issue = 24| pages = 7503–7509| year = 1974| doi = 10.1021/ja00831a019}}</ref><ref>[http://www.orgsynth.org/orgsyn/pdfs/CV8P0323.pdf 3-Hydroxy-3-Methyl-1-Phenyl-1-Butanone by Crossed Aldol Reaction] Teruaki Mukaiyama and Koichi Narasaka [[Chemistry:Organic Syntheses|Organic Syntheses]], Coll. Vol. 8, p.323 ('''1993'''); Vol. 65, p.6 ('''1987''')</ref> The Mukaiyama aldol reaction does not follow the Zimmerman-Traxler model. Carreira has described particularly useful asymmetric methodology with silyl ketene acetals, noteworthy for its high levels of enantioselectivity and wide substrate scope.<ref name=carreira1994>{{cite journal| title = Catalytic, enantioselective aldol additions with methyl and ethyl acetate ''O''-silyl enolates — a chira; tridentate chelate as a ligand for titanium(IV)| author = Carreira E.M.| author2=Singer R.A. | author3=Lee W.S.| doi = 10.1021/ja00098a065| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| year =1994| volume =116| pages =8837–8| issue = 19| url = https://authors.library.caltech.edu/86768/2/ja8837.pdf}}</ref>

The method works on [[Chemistry:Branching (polymer chemistry)|unbranched]] aliphatic aldehydes, which are often poor [[Chemistry:Electrophile|electrophile]]s for catalytic, asymmetric processes. This may be due to poor electronic and steric differentiation between their enantiofaces.

[[File:Acetatealdol2.gif|center]]

The analogous vinylogous Mukaiyama aldol process can also be rendered catalytic and asymmetric. The example shown below works efficiently for aromatic (but not aliphatic) aldehydes and the mechanism is believed to involve a chiral, metal-bound dienolate.<ref name=Carreira1998>{{cite journal| title = Apparent catalytic generation of chiral metal enolates: Enantioselective dienolate additions to aldehydes mediated by Tol-BINAP center Cu(II) fluoride complexes| author = Kruger J.| author2=Carreira E.M.| doi = 10.1021/ja973331t| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| year =1998| volume =120| pages =837–8| issue = 4}}</ref><ref name=Carreira1998-2>{{cite journal| title = Mechanistic insights into Cu-catalyzed asymmetric aldol reactions: Chemical and spectroscopic evidence for a metalloenolate intermediate| author = Pagenkopf B.L.| author2=Kruger J. |author3=Stojanovic A. |author4=Carreira E.M.| doi = 10.1002/(SICI)1521-3773(19981204)37:22<3124::AID-ANIE3124>3.0.CO;2-1| journal = Angew. Chem. Int. Ed.| year =1998| volume =37| pages =3124–6| issue = 22| pmid = 29711324}}</ref>

[[File:Acetatealdol3.gif|center]]

===Crimmins thiazolidinethione aldol===
In the '''Crimmins thiazolidinethione''' approach<ref name=Crimmins1997>{{cite journal| title = Asymmetric Aldol Additions with Titanium Enolates of Acyloxazolidinethiones: Dependence of Selectivity on Amine Base and Lewis Acid Stoichiometry| author = Crimmins M. T.|author2=King B. W. |author3=Tabet A. E.| doi = 10.1021/ja9716721| journal = Journal of the American Chemical Society| year = 1997| volume =119| issue = 33| pages =7883–7884}}</ref><ref name=Crimmins2000>{{cite journal| title = Titanium enolates of thiazolidinethione chiral auxiliaries: Versatile tools for asymmetric aldol additions| author = Crimmins M. T.| author2=Chaudhary K.| doi = 10.1021/ol9913901| journal = Organic Letters| year = 2000| volume =2| issue = 6| pages =775–777| pmid = 10754681}}</ref>
a thiazolidinethione performs acetate aldol reactions.<ref>{{cite journal |first1= Michael T. |last1= Crimmins |first2= Mariam |last2= Shamszad |title= Highly Selective Acetate Aldol Additions Using Mesityl-Substituted Chiral Auxiliaries |journal= Org. Lett. |year= 2007 |volume= 9 |issue= 1 |ref= 1 |pages= 149–152 |doi= 10.1021/ol062688b |pmid= 17192107 }}</ref> and can produce the "Evans syn" or "non-Evans syn" adducts by simply varying the amount of [[Chemistry:Sparteine|(−)-sparteine]]. The reaction is believed to proceed via six-membered, titanium-bound [[Chemistry:Transition state|transition state]]s, analogous to the proposed transition states for the Evans auxiliary. NOTE: the structure of sparteine shown below is missing a N atom.

[[File:Crimminsaldol1.png|center]]

===Organocatalysis===
Chiral secondary [[Chemistry:Amine|amine]] catalysts catalyze some aldol reactions. These secondary amines form transient [[Chemistry:Enamine|enamine]]s when exposed to ketones, which may react enantioselectively<ref>{{cite book
| first= E. M.
| last= Carreira
|author2= Fettes, A.|author3= Martl, C.
| series= Org. React.
| year= 2006
| volume= 67
| pages= 1–216
| doi= 10.1002/0471264180.or067.01
| title= Catalytic Enantioselective Aldol Addition Reactions | isbn= 978-0471264187
}}</ref> with suitable aldehyde electrophiles. The amine reacts with the carbonyl to form an enamine, the enamine acts as an enol-like nucleophile, and then the amine is released from the product all—the amine itself is a catalyst. This enamine catalysis method is a type of [[Chemistry:Organocatalysis|organocatalysis]], since the catalyst is entirely based on a small organic molecule. In a seminal example, [[Chemistry:Proline|proline]] efficiently catalyzed the cyclization of a triketone:

[[File:organocatalytic1.gif|center]]

This reaction is known as the Hajos-Parrish reaction<ref>Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 '''1971'''</ref><ref>{{cite journal
| title = Asymmetric synthesis of bicyclic intermediates of natural product chemistry
| first = Zoltan G. | last = Hajos
|author2=Parrish, David R.
| journal = Journal of Organic Chemistry
| year =1974
| volume =39
| issue = 12
| pages =1615–1621
| doi = 10.1021/jo00925a003 }}</ref> (also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, referring to a contemporaneous report from Schering of the reaction under harsher conditions).<ref>{{cite journal
| title = New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures
| first = Ulrich | last = Eder
|author2= Sauer, Gerhard|author3= Wiechert, Rudolf
| journal =Angewandte Chemie International Edition in English
| year =1971
| volume =10
| issue = 7
| pages =1615–1621
| doi = 10.1002/anie.197104961 }}</ref> Under the Hajos-Parrish conditions only a catalytic amount of proline is necessary (3&nbsp;mol%). There is no danger of an achiral background reaction because the transient enamine intermediates are much more nucleophilic than their parent ketone enols. This strategy offers a simple way of generating enantioselectivity in reactions without using transition metals, which have the possible disadvantages of being toxic or expensive.

Proline-catalyzed aldol reactions do not show any non-linear effects (the enantioselectivity of the products is directly proportional to the enantiopurity of the catalyst). Combined with isotopic labelling evidence and [[Chemistry:Computational chemistry|computational studies]], the proposed [[Physics:Reaction mechanism|reaction mechanism]] for proline-catalyzed aldol reactions is as follows:<ref>{{cite journal
| title = The ying and yang of asymmetric aminocatalysis
| first = Benjamin | last = List
| journal = Chemical Communications
| year =2006
| issue = 8
| pages =819–824
| doi = 10.1039/b514296m
| pmid = 16479280 }}</ref>

[[File:organocatalytic2.gif|center]]

This strategy allows the otherwise challenging cross-aldol reaction between two aldehydes. In general, cross-aldol reactions between aldehydes are typically challenging because they can [[Chemistry:Polymerization|polymerize]] easily or react unselectively to give a statistical mixture of products. The first example is shown below:<ref>{{cite journal
| title = The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes
| first = Alan B. | last = Northrup
|author2=MacMillan David W. C.
| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
| year =2002
| volume = 124
| issue = 24
| pages =6798–6799
| pmid = 12059180
| doi = 10.1021/ja0262378 | url = https://authors.library.caltech.edu/76965/2/ja0262378_s.pdf }}</ref>

[[File:organocatalytic3.gif|center]]

In contrast to the preference for syn adducts typically observed in enolate-based aldol additions, these organocatalyzed aldol additions are anti-selective. In many cases, the organocatalytic 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.

An elegant demonstration of the power of asymmetric organocatalytic aldol reactions was disclosed by MacMillan and coworkers in 2004 in their synthesis of differentially protected [[Chemistry:Carbohydrate|carbohydrate]]s. While traditional synthetic methods accomplish the synthesis of [[Chemistry:Hexose|hexose]]s using variations of iterative protection-deprotection strategies, requiring 8–14 steps, organocatalysis can access many of the same substrates using an efficient two-step protocol involving the proline-catalyzed dimerization of alpha-oxyaldehydes followed by tandem Mukaiyama aldol cyclization.

[[File:organocatalytic4.gif|center]]

The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions.<ref>{{cite journal
| author = Northrup A. B.
|author2=Mangion I. K. |author3=Hettche F. |author4=MacMillan D. W. C.
 | title = Enantioselective Organocatalytic Direct Aldol Reactions of -Oxyaldehydes: Step One in a Two-Step Synthesis of Carbohydrates
| journal = Angewandte Chemie International Edition in English
| volume = 43
| issue = 16
| pages = 2152–2154
| year = 2004
| doi = 10.1002/anie.200453716
| pmid = 15083470| doi-access = free
}}
</ref>
Earlier studies revealed that aldehydes bearing alpha-alkyloxy or alpha-silyloxy [[Chemistry:Substituent|substituent]]s were suitable for this reaction, while aldehydes bearing [[Chemistry:Electron-withdrawing group|Electron-withdrawing group]]s such as acetoxy were unreactive. The protected [[Chemistry:Erythrose|erythrose]] product could then be converted to four possible sugars via Mukaiyama aldol addition followed by [[Chemistry:Lactol|lactol]] formation. This requires appropriate diastereocontrol in the Mukaiyama aldol addition and the product [[Physics:Carbenium ion|silyloxycarbenium ion]] to preferentially cyclize, rather than undergo further aldol reaction. In the end, [[Chemistry:Glucose|glucose]], [[Chemistry:Mannose|mannose]], and [[Chemistry:Allose|allose]] were synthesized:

[[File:organocatalytic5.gif|center]]

==="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. One idea is to generate the enolate using a metal [[Chemistry:Catalyst|catalyst]] that is released after the aldol addition mechanism. 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 metal, preventing it from reacting with additional carbonyl reactants.

[[File:Aldol alkoxide product.png|360px|center]]

One approach, demonstrated by Evans, is to silylate the aldol adduct.<ref>{{cite journal
| last = Evans
| first = D. A.
|author2= Tedrow, J. S.|author3= Shaw, J. T.|author4= Downey, C. W.
| title = Diastereoselective Magnesium Halide-Catalyzed anti-Aldol Reactions of Chiral N-Acyloxazolidinones
| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]
| volume = 124
| issue = 3
| pages = 392–393
| year = 2002
| doi = 10.1021/ja0119548
| pmid = 11792206 }}</ref><ref>{{cite journal
| last = Evans
| first = David A.
|author2= Downey, C. Wade|author3= Shaw, Jared T.|author4= Tedrow, Jason S.
| title = Magnesium Halide-Catalyzed Anti-Aldol Reactions of Chiral N-Acylthiazolidinethiones
| journal = [[Chemistry:Organic Letters|Organic Letters]]
| volume = 4
| issue = 7
| pages = 1127–1130
| year = 2002
| doi = 10.1021/ol025553o
| pmid = 11922799 }}</ref> A silicon reagent such as TMSCl is added in the reaction, which replaces the metal on the alkoxide, allowing [[Chemistry:Turnover number|turnover]] of the metal catalyst. Minimizing the number of reaction steps and amount of reactive chemicals used leads to a cost-effective and industrially useful reaction.

[[File:Directaldol2.png|center]]

==Biological aldol reactions==
Examples of aldol reactions in biochemistry include the splitting of fructose-1,6-bisphosphate into [[Chemistry:Dihydroxyacetone|dihydroxyacetone]] and glyceraldehyde-3-phosphate in the fourth stage of [[Biology:Glycolysis|glycolysis]], which is an example of a reverse ("retro") aldol reaction catalyzed by the enzyme [[Biology:Aldolase A|aldolase A]] (also known as fructose-1,6-bisphosphate aldolase).

In the [[Biology:Glyoxylate cycle|glyoxylate cycle]] of plants and some prokaryotes, [[Biology:Isocitrate lyase|isocitrate lyase]] produces glyoxylate and succinate 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 aldol reaction was discovered independently by the Russian chemist (and Romantic composer) Alexander Borodin in 1869<ref>See:

* Borodin reported on the condensation of [[Chemistry:Pentanal|pentanal]] (''Valerianaldehyd'') with [[Chemistry:Heptanal|heptanal]] (''Oenanthaldehyd'') in:  von Richter, V. (1869) [https://babel.hathitrust.org/cgi/pt?id=hvd.cl1hyq;view=1up;seq=600 "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.
* English version of Richter's report:  (Staff) (December 10, 1869) [https://books.google.com/books?id=e1dKAAAAYAAJ&pg=PA286 "Chemical notices from foreign sources:  Berichte der Deutschen Chemischen Gesellschaft zu Berlin, no. 16, 1869:  Valerian aldehyde and Oenanth aldehyde – M. Borodin,"] ''The Chemical News and Journal of Industrial Science'', '''20''' :  286.
* Garner, Susan Amy (2007) "Hydrogen-mediated carbon-carbon bond formations: Applied to reductive aldol and Mannich reactions,"  Ph.D. dissertation, University of Texas (Austin), [https://books.google.com/books?id=wc8dTz820AIC&pg=PA4 pp. 4] and [https://books.google.com/books?id=wc8dTz820AIC&pg=PA51 51.]
* Borodin, A. (1873) [https://babel.hathitrust.org/cgi/pt?id=uc1.b3481752;view=1up;seq=116 "Ueber einen neuen Abkömmling des Valerals"] (On a new derivative of valerian aldehyde), ''Berichte der deutschen chemischen Gesellschaft'' (in German), '''6''' :  982–985.</ref> and by the French chemist Charles-Adolphe Wurtz in 1872, which originally used aldehydes to perform the reaction.<ref name=Wurtz1872>{{cite journal| last = Wurtz | first = C. A.|  journal = Bulletin de la Société Chimique de Paris| year = 1872| title = Sur un aldéhyde-alcool | trans-title = On an aldehyde alcohol | language = fr| series = 2nd series| volume = 17| pages = 436–442| url = https://babel.hathitrust.org/cgi/pt?id=iau.31858003147356;view=1up;seq=446}}</ref><ref name=Wurtz1872b>{{cite journal | last = Wurtz | first = C. A.| author-link = Charles-Adolphe Wurtz| journal = Journal für Praktische Chemie| year = 1872| title = Ueber einen Aldehyd-Alkohol | trans-title = About an aldehyde alcohol | language = de| volume = 5| issue = 1| pages = 457–464| url = https://babel.hathitrust.org/cgi/pt?id=njp.32101076786381;view=1up;seq=471| doi = 10.1002/prac.18720050148}}</ref><ref name=Wurtz1872c>{{cite journal| last = Wurtz | first = C. A.| author-link = Charles-Adolphe Wurtz| journal = Comptes rendus de l'Académie des sciences| year = 1872| title = Sur un aldéhyde-alcool | trans-title = On an aldehyde alcohol | language = fr| volume = 74| pages =1361| url = http://gallica.bnf.fr/ark:/12148/bpt6k3031q/f1361.table }}</ref>

==See also==
* [[Chemistry:Aldol–Tishchenko reaction|Aldol–Tishchenko reaction]]
* [[Chemistry:Baylis–Hillman reaction|Baylis–Hillman reaction]]
* [[Chemistry:Ivanov reaction|Ivanov reaction]]
* [[Chemistry:Reformatsky reaction|Reformatsky reaction]]
* [[Chemistry:Claisen-Schmidt condensation|Claisen-Schmidt condensation]]

== Notes ==
{{notelist}}

==References==
{{Reflist|colwidth=30em}}

==External links==
* Chem 206, 215 Lecture Notes (2003, 2006) by D. A. Evans, A. G. Myers, ''et al.'', Harvard University (pp.&nbsp;345, 936)
{{Organic reactions}}
[[Category:Addition reactions]]
[[Category:Carbon-carbon bond forming reactions]]

{{Sourceattribution|Aldol reaction}}