The Hajos–Parrish–Eder–Sauer–Wiechert and Barbas-List reactions 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 ...
are a family of
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 ...
-catalysed
asymmetric aldol reactions
In organic chemistry, aldol reactions are acid- or base-catalyzed reactions of aldehydes or ketones.
Aldol addition or aldolization refers to the addition of an enolate or enolation as a nucleophile to a Carbonyl group, carbonyl Moiety (chemistry ...
.
In the 1970s, two research groups discovered (and published) almost simultaneously their discoveries of two related
intramolecular reactions:
Zoltan Hajos and David Parrish at
Hoffmann-La Roche
F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...
[Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971] and
Rudolf Wiechert ''et al'' at
Schering AG
Schering AG was a research-centered German multinational pharmaceutical company headquartered in Wedding, Berlin, which operated as an independent company from 1851 to 2006. In 2006, it was bought by Bayer AG and merged to form the Bayer su ...
.
The original Hajos-Parrish procedure begins with an achiral
triketone in
dimethylformamide
Dimethylformamide, DMF is an organic compound with the chemical formula . Its structure is . Commonly abbreviated as DMF (although this initialism is sometimes used for 2,5-dimethylfuran, dimethylfuran, or dimethyl fumarate), this colourless liqui ...
and 3% (molar)
catalytic
Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...
(S)(−)proline. The product is a chiral
ketol with 93%
enantiomeric excess
In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a sing ...
:

In the Eder-Sauer-Wiechert modification, the product shown above
loses water to give the
conjugated alkene.
Three decades later,
Carlos Barbas and
Benjamin List
Benjamin List (; born 11 January 1968) is a German chemist who is one of the directors of the Max Planck Institute for Coal Research and professor of organic chemistry at the University of Cologne. He co-developed organocatalysis, a method of acc ...
demonstrated that larger catalyst concentrates could enable a similar
intermolecular
An intermolecular force (IMF; also secondary force) is the force that mediates interaction between molecules, including the electromagnetic forces of attraction
or repulsion which act between atoms and other types of neighbouring particles (e.g. ...
reaction.
The reaction has seen extensive use in many
enantiomerically-pure
molecular syntheses.
Indeed, it presaged the modern field of
asymmetric organocatalysis.
History
Researches on asymmetric enamine catalysis applied to important intermediates in steroids synthesis is due to an increased interest for efficient and convenient steroid total syntheses in the 1960s. In particular, two industrial groups in the early 1970s reported proline-catalyzed intramolecular aldol reactions.
In 1971, Escher headed a
research group
A research group is a group of researchers often from the same faculty, specialized on the same subject, working together on the issue or topic.
The success of a research group depends on several factors: clearly defined goals, research emphasi ...
at
Schering AG
Schering AG was a research-centered German multinational pharmaceutical company headquartered in Wedding, Berlin, which operated as an independent company from 1851 to 2006. In 2006, it was bought by Bayer AG and merged to form the Bayer su ...
examining reactions under non-biological conditions: (S)-Proline (47 mol%) and 1N
perchloric acid
Perchloric acid is a mineral acid with the formula H Cl O4. It is an oxoacid of chlorine. Usually found as an aqueous solution, this colorless compound is a stronger acid than sulfuric acid, nitric acid and hydrochloric acid. It is a powerful oxid ...
in
acetonitrile
Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not class ...
at 80 °C. They observed condensation to the conjugated alkene,
but discarded the result as not particularly useful. Their work would not become
common knowledge
Common knowledge is knowledge that is publicly known by everyone or nearly everyone, usually with reference to the community in which the knowledge is referenced. Common knowledge can be about a broad range of subjects, such as science, litera ...
for another 37 years, when a new group at Schering analyzed extensions to the reaction, by then associated with Hajos and Parrish.
Meanwhile, Hajos and Parrish examined similar reactions at
Hoffmann-La Roche
F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...
under quasi-biological conditions. Their reaction sequence produced bicyclic ketol intermediates in good
yield, which, to their surprise, exhibited
circular dichroism
Circular dichroism (CD) is dichroism involving circular polarization, circularly polarized light, i.e., the differential Absorption (electromagnetic radiation), absorption of left- and right-handed light. Left-hand circular (LHC) and right-hand ci ...
corresponding to a large
enantiomeric excess
In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a sing ...
.
A single-crystal X-ray diffraction study confirmed this hypothesis,
showing an axial methyl and equatorial hydroxyl group, as in
digitoxigenin
Digitoxigenin, a cardenolide, is the aglycone of digitoxin.
Digitoxigenin can be used to prepare actodigin.
In Lednicer's book on steroids, it is made from deoxycholic acid
Deoxycholic acid is a bile acid. Deoxycholic acid is one of the sec ...
's CD-ring:

Hajos and Parrish published and patented their results in 1974,
and then the field lay dormant.
In 2000,
Barbas Barbas is a Spanish surname
Spanish might refer to:
* Items from or related to Spain:
**Spaniards are a nation and ethnic group indigenous to Spain
**Spanish language, spoken in Spain and many countries in the Americas
**Spanish cuisine
**Spanis ...
' group at
Scripps began investigating antibodies for
a series of aldolase
enzymes
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
, known to operate through an
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 ...
intermediate, and discovered that one of their antibodies catalyzed an
intermolecular
An intermolecular force (IMF; also secondary force) is the force that mediates interaction between molecules, including the electromagnetic forces of attraction
or repulsion which act between atoms and other types of neighbouring particles (e.g. ...
Hajos-Parrish-Eder-Saurt-Wiechert reaction. Searching the literature, they noticed that Hajos ''et al'' had already identified a similar reaction, and began investigating whether simple enamines could substitute for their antibodies. Indeed, proline did, albeit at higher concentrations than in the original 1970s reports:

The flurry of research sparked by this publication clarified multiple long-standing questions. The mechanism of the reaction had remained in question, but Barbas' group showed that it occurred through combined iminium-enamine catalysis. Barbas' collaborator
List
A list is a Set (mathematics), set of discrete items of information collected and set forth in some format for utility, entertainment, or other purposes. A list may be memorialized in any number of ways, including existing only in the mind of t ...
also extended the reaction to asymmetric prochiral ketones:

List and Notz also revealed that proline and
5,5-dimethyl thiazolidinium-4-carboxylate appeared to be optimal catalysts within a large group of
screened amines.
In 2002 the Macmillan group demonstrated a proline-catalyzed aldol reaction between
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. This reaction is unusual because in general aldehydes will self-condense.

(S)-1-(2-pyrrolidinylmethyl)-pyrrolidine salts would forme the basis for the development of diamine organocatalysts that have proven effective in a wide variety or organocatalytic reactions.
Reaction mechanism
Several reaction mechanisms for the triketone reaction have been proposed over the years. Hajos and Parrish proposed the enamine mechanism in their paper
/sup>. However, their experiment with a stoichiometric amount of labeled water (H218O) supported a carbinolamine mechanism. Therefore, Hajos put forward (1974) a hemiaminal
In organic chemistry, a hemiaminal (also carbinolamine) is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: . R can be hydrogen or an alkyl group. Hemiaminals are intermediat ...
intermediate. /sup> The Agami mechanism (1984) has an 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 ...
intermediate with two proline units involved in 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 ...
(based on experimental reaction kinetics
Chemical kinetics, also known as reaction kinetics, is the branch of physical chemistry that is concerned with understanding the rates of chemical reactions. It is different from chemical thermodynamics, which deals with the direction in which a ...
) and according to a mechanism by Houk (2001) a single proline unit suffices with a cyclic transition state and with the proline carboxyl group involved in hydrogen bonding
In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
.
:
The hemiaminal
In organic chemistry, a hemiaminal (also carbinolamine) is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: . R can be hydrogen or an alkyl group. Hemiaminals are intermediat ...
(carbinolamine) put forward by Hajos in 1974 can change to a tautomeric iminium hydroxide intermediate. The iminium hydroxide ion caused enolization of the side chain methyl ketone would be followed by ring closure to the above shown optically active bicyclic ketol product (see Figure 1.) under the influence of the catalytic amount of (S)-(−)-proline.
Pengxin Zhou, Long Zhang, Sanzhong Luo, and Jin-Pei Cheng obtained excellent results using the simple chiral primary amine t-Bu-CH(NH2)-CH2-NEt2.TfOH for the synthesis of both the Wieland-Miescher ketone and the Hajos-Parrish ketone as well as their analogues. This supports the iminium mechanism, because it is textbook chemistry that primary amines form imines rather than enamines with carbonyl compounds.
The Hajos 1974 carbinolamine mechanism has had an unwitting support in a more recent paper by Michael Limbach. The triketone starting material 2- methyl-2-(3-oxobutyl)-1,3-cyclopentanedione gave the expected optically active bicyclic ketol (+)-(3aS,7aS)-3a,4,7,7a-tetrahydro-3a-hydroxy-7a-methyl-1,5(6H)-indanedione with (S)-(−)-proline catalyst. On the other hand, the stereochemical outcome is reversed with ee selectivities of up to 83% by using the homologue amino acid catalysts, such as (S)-β-homoproline, pyrrolidine-(2S)-yl) acetic acid The virtual anomaly can be explained with a top side approach of the bulkier beta amino acids to the above triketone starting material of reflective symmetry. The top side approach results in the formation of an enantiotopic carbinolamine to give the (−)-(3aR,7aR)-3a,4,7,7a-tetrahydro-3a-hydroxy-7a-methyl-1,5(6H)-indanedione bicyclic ketol enantiomer identical to the one obtained with unnatural (R)-(+)-proline. List in 2010 on the other hand is ''perplexed'' and ''surprised'' that Hajos rejected the enamine mechanism, certainly in light of earlier work by Spencer in 1965 on amine catalysed aldol reactions. It is interesting and surprising that Eder, Sauer and Wiechert have not attempted to explain the reaction mechanism.
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 ...
as proposed by the Barbas group in 2000 for the intermolecular reactions[ is based also on ]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 ...
formation and the observed 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 ...
based on the Zimmerman-Traxler model favoring ''Re''-face approach. This is the same mechanism proposed by Barbas for aldolase antibodies reported by the group in 1995:
:
This enamine mechanism also drives the original Hajos-Parrish triketone reaction but the involvement of two proline molecules in it as proposed by Agami[ is disputed by Barbas based on the lack of a non-linear effects] and supported by later studies of List based on reaction kinetics
Chemical kinetics, also known as reaction kinetics, is the branch of physical chemistry that is concerned with understanding the rates of chemical reactions. It is different from chemical thermodynamics, which deals with the direction in which a ...
. The general mechanism is further supported by List by the finding that in a reaction carried out in labeled water (H218O), the oxygen isotope finds its way into the reaction product. The Hajos and Parrish experiment with a stoechiometric amount of labeled water (H218O) supported the carbinolamine mechanism. /sup>
In the same study 0 the reaction of proline with acetone
Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...
to the oxazolidinone (in DMSO
Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...
) was examined:
:
The equilibrium constant
The equilibrium constant of a chemical reaction is the value of its reaction quotient at chemical equilibrium, a state approached by a dynamic chemical system after sufficient time has elapsed at which its composition has no measurable tendency ...
for this reaction is only 0.12 leading List to conclude that the involvement of oxazolidinone is only parasitic.
Blackmond in 2004 also found oxazolidinones as intermediates (NMR) in a related proline-catalysed α-aminooxylation of propanal
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
Propional ...
with nitrosobenzene
Nitrosobenzene is the organic compound with the chemical formula, formula C6H5NO. It is one of the prototypical organic nitroso compounds. Characteristic of its functional group, it is a dark green species that exists in equilibrium with its pale ...
:
:
Chiong Teck Wong of the Institute of High Performance Computing Singapore studied the similar oxyamination reaction of nitrosobenzene with butanal using a chiral prolinol
Prolinol is a chiral amino-alcohol that is used as a chiral building block in organic synthesis. It exists as two enantiomers: the D and L forms.
Preparation
Prolinol is obtained by reduction of the amino acid proline using lithium aluminium hydr ...
silyl ether catalyst. His studies strongly suggest that the catalyst generates the enol
In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
, and forms an enol-catalyst complex. Nitsosobenzene subsequently reacts with the enol-catalyst complex to afford the (S)-N-nitroso aldol product in agreement with Pauling’s chart of electronegativity
Electronegativity, symbolized as , is the tendency for an atom of a given chemical element to attract shared electrons (or electron density) when forming a chemical bond. An atom's electronegativity is affected by both its atomic number and the ...
. Sodiumborohydride reduction of the primarily formed aldol products gave the corresponding alcohols in good yield and excellent enantioselectivity in the ratio of PN/PO=>99:1 as shown in the Scheme below. Wong suggests that the reaction mechanism of the (S)-Cat catalyzed N-nitroso aldol reaction between nitrosobenzene and butanal proceeds via an enol intermediate and not via an enamine intermediate.
:
The view of oxazolidinones as a parasitic species is contested by Seebach and Eschenmoser who in 2007 published an article in which they argue that oxazolidinones in fact play a pivotal role in proline catalysis. One of the things they did was reacting an oxazolidinone with the activated aldehyde chloral
Chloral, also known as trichloroacetaldehyde or trichloroethanal, is the organic compound with the formula Cl3CCHO. This aldehyde is a colourless liquid that is soluble in a wide range of solvents. It reacts with water to form chloral hydrate, a o ...
in an aldol addition:
:
In 2008, Barbas in an essay addressed the question why it took until the year 2000 before interest regenerated for this seemingly simple reaction 30 years after the pioneering work by Hajos and Parrish and why the proline catalysis mechanism appeared to be an enigma for so long. One explanation has to do with different scientific cultures: a proline mechanism in the context of aldolase catalysis already postulated in 1964 by a biochemist was ignored by organic chemists. Another part of the explanation was the presumed complexity of aldolase catalysis that dominated chemical thinking for a long time. Finally, research did not expand in this area at Hoffmann-La Roche after the resignation of ZGH in November, 1970.
Origin of the name of the reaction
The name for this reaction took some time to develop. In 1985 Professor Agami and associates were the first to name the proline catalyzed Robinson annulation
The Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson (organic chemist), Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–c ...
the Hajos-Parrish reaction. In 1986 Professor Henri B. Kagan and Professor Agami still called it the Hajos-Parrish reaction in the Abstract of this paper. In 2001 Kagan published a paper entitled "Nonlinear Effects in Asymmetric Catalysis: A Personal Account" in ''Synlett
''Synlett'' is an international scientific journal for accounts and rapid communications of original contributions of fundamental research in synthetic organic chemistry. The impact factor of this journal is 2.419 (2017). ''Nature'' featured a br ...
''. In this paper he introduced the new title the Hajos-Parrish-Wiechert reaction. In 2002 Benjamin List
Benjamin List (; born 11 January 1968) is a German chemist who is one of the directors of the Max Planck Institute for Coal Research and professor of organic chemistry at the University of Cologne. He co-developed organocatalysis, a method of acc ...
added two more names and introduced the term Hajos–Parrish–Eder–Sauer–Wiechert reaction. Scientific papers published as late as 2008 in the field of organocatalysis use either the 1985, 2001 or 2002 names of the reaction.
A June, 2014 search limited to the years 2009–2014 by Google Scholar
Google Scholar is a freely accessible web search engine that indexes the full text or metadata of Academic publishing, scholarly literature across an array of publishing formats and disciplines. Released in Beta release, beta in November 2004, th ...
returns 44 hits for Hajos-Parrish reaction, 3 for Hajos-Parrish-Wiechert reaction and 184 for Hajos–Parrish–Eder–Sauer–Wiechert reaction. The term 'Hajos-Parrish ketone' (and similar) remains common, however.
References
{{Reflist, 2
Addition reactions