In
organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, ...
, organocatalysis is a form of
catalysis
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
in which the rate of a
chemical reaction
A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
is increased by an
organic catalyst. This "organocatalyst" consists of
carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon mak ...
,
hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
,
sulfur and other nonmetal elements found in organic compounds.
[Special Issue: ] Because of their similarity in composition and description, they are often mistaken as a
misnomer for
enzyme
Enzymes () are proteins that act as biological catalysts 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 products ...
s due to their comparable effects on reaction rates and forms of catalysis involved.
Organocatalysts which display secondary
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen
Hydrogen is the chemical element wi ...
functionality can be described as performing either
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 t ...
catalysis (by forming catalytic quantities of an active enamine
nucleophile) or
iminium
In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology.
Structure
Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...
catalysis (by forming catalytic quantities of an activated iminium electrophile). This mechanism is typical for covalent organocatalysis. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20–30 mol%).
Noncovalent interactions such as hydrogen-bonding facilitates low catalyst loadings (down to 0.001 mol%).
Organocatalysis offers several advantages. There is no need for metal-based catalysis thus making a contribution to
green chemistry
Green chemistry, also called sustainable chemistry, is an area of chemistry and chemical engineering focused on the design of products and processes that minimize or eliminate the use and generation of hazardous substances. While environmental che ...
. In this context, simple organic acids have been used as catalyst for the modification of cellulose in water on multi-ton scale. When the organocatalyst is
chiral
Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable from i ...
an avenue is opened to
asymmetric catalysis
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...
; for example, the use of
proline in
aldol reaction
The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.
Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two c ...
s is an example of chirality and green chemistry. Organic chemists
David MacMillan
Sir David William Cross MacMillan (born 16 March 1968) is a Scottish chemist and the James S. McDonnell Distinguished University Professor of Chemistry at Princeton University, where he was also the chair of the Department of Chemistry from 20 ...
and
Benjamin List
Benjamin ( he, ''Bīnyāmīn''; "Son of (the) right") blue letter bible: https://www.blueletterbible.org/lexicon/h3225/kjv/wlc/0-1/ H3225 - yāmîn - Strong's Hebrew Lexicon (kjv) was the last of the two sons of Jacob and Rachel (Jacob's thir ...
were both awarded the 2021 Nobel Prize in chemistry for their work on asymmetric organocatalysis.
Introduction
Regular achiral organocatalysts are based on nitrogen such as
piperidine
Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...
used in the
Knoevenagel condensation
In organic chemistry, the Knoevenagel condensation () reaction is a type of chemical reaction named after German chemist Emil Knoevenagel. It is a modification of the aldol condensation.
A Knoevenagel condensation is a nucleophilic addition o ...
.
DMAP used in
esterification
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
s
and
DABCO
DABCO (1,4-diazabicyclo .2.2ctane), also known as triethylenediamine or TEDA, is a bicyclic organic compound with the formula N2(C2H4)3. This colorless solid is a highly nucleophilic tertiary amine base, which is used as a catalyst and reagen ...
used in the
Baylis-Hillman reaction.
Thiazolium salt
Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular for ...
s are employed in the
Stetter reaction. These catalysts and reactions have a long history but current interest in organocatalysis is focused on
asymmetric catalysis
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...
with chiral catalysts, called asymmetric organocatalysis or enantioselective organocatalysis. A pioneering reaction developed in the 1970s is called the
Hajos–Parrish–Eder–Sauer–Wiechert reaction The Hajos–Parrish–Eder–Sauer–Wiechert reaction in organic chemistry is a proline catalysed asymmetric aldol reaction. The reaction is named after its principal investigators, Zoltan Hajos others, from Hoffmann-La RocheZ. G. Hajos, D. R. P ...
. Between 1968 and 1997, there were only a few reports of the use of small organic molecules as catalysts for asymmetric reactions (the Hajos–Parrish reaction probably being the most famous), but these chemical studies were viewed more as unique chemical reactions than as integral parts of a larger, interconnected field.
:
In this reaction, naturally occurring chiral
proline is the chiral catalyst in an
Aldol reaction
The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.
Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two c ...
. The starting material is an achiral
triketone and it requires just 3% of proline to obtain the reaction product, a ketol in 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 si ...
. This is the first example of an amino acid-catalyzed asymmetric aldol reaction.
The asymmetric synthesis of the
Wieland-Miescher ketone (1985) is also based on proline and another early application was one of the transformations in the
total synthesis
Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...
of
Erythromycin by
Robert B. Woodward (1981). A mini-review digest article focuses on selected recent examples of total synthesis of natural and pharmaceutical products using organocatalytic reactions.
Many chiral organocatalysts are an adaptation of
chiral ligand
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecu ...
s (which together with a metal center also catalyze asymmetric reactions) and both concepts overlap to some degree.
A breakthrough in the field of organocatalysis came in 1997 when Yian Shi reported the first general, highly enantioselective organocatalytic
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 m ...
with the catalytic asymmetric epoxidation of ''trans-'' and trisubstituted olefins with chiral dioxiranes. Since that time, several different types of reactions have been developed.
Organocatalyst classes
Organocatalysts for asymmetric synthesis can be grouped in several classes:
*
Biomolecules:
proline,
phenylalanine.
Secondary amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
s in general. The
cinchona alkaloids, certain
oligopeptide
An oligopeptide, often just called peptide ('' oligo-'', "a few"), consists of two to twenty amino acids and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some of the major classes of naturally occurring oligopeptides in ...
s.
* Synthetic catalysts derived from biomolecules.
*
Hydrogen bonding catalysts, including
TADDOLS, derivatives of
BINOL such as
NOBIN, and organocatalysts based on
thiourea
Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), except that the oxygen atom is replaced by a sulfur atom (as implied by the ''thio-'' prefix); however, the properties of urea a ...
s
* Triazolium salts as next-generation
Stetter reaction catalysts
Examples of asymmetric reactions involving organocatalysts are:
*
Asymmetric Diels-Alder reactions
*
Asymmetric Michael reactions
*
Asymmetric Mannich reactions
*
Shi epoxidation
The Shi epoxidation is a chemical reaction described as the asymmetric epoxidation of alkenes with oxone (potassium peroxymonosulfate) and a fructose-derived catalyst (1). This reaction is thought to proceed via a dioxirane intermediate, generated ...
*
Organocatalytic transfer hydrogenation
Proline
Proline catalysis has been reviewed.
Imidazolidinone organocatalysis
Imidazolidinone
Imidazolidinones or imidazolinones are a class of 5-membered ring heterocycles structurally related to imidazole. Imidazolidinones feature a saturated C3N2 nucleus, except for the presence of a urea or amide functional group in the 2 or 4 positi ...
s are catalysts for many transformations such as
asymmetric Diels-Alder reactions and
Michael addition
In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...
s. Chiral catalysts induce
asymmetric reaction
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecu ...
s, often with high enantioselectivities. This catalyst works by forming an
iminium ion
In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology.
Structure
Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...
with
carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
groups of α,β-unsaturated aldehydes (
enals) and
enones in a rapid
chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which both the Reagent, reactants and Product (chemistry), products are present in concentrations which have no further tendency to change with time, so that there is no observable chan ...
. This iminium activation is similar to activation of carbonyl groups by a
Lewis acid and both catalysts lower the substrate's
LUMO
In chemistry, HOMO and LUMO are types of molecular orbitals. The acronyms stand for ''highest occupied molecular orbital'' and ''lowest unoccupied molecular orbital'', respectively. HOMO and LUMO are sometimes collectively called the ''frontie ...
:
:
The transient iminium intermediate is chiral which is transferred to the reaction product via
chiral induction. The catalysts have been used in
Diels-Alder reactions,
Michael addition
In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...
s,
Friedel-Crafts alkylations,
transfer hydrogenation
In chemistry, transfer hydrogenation is a chemical reaction involving the addition of hydrogen to a compound from a source other than molecular . It is applied in laboratory and industrial organic synthesis to saturate organic compounds and redu ...
s and
epoxidation
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...
s.
One example is the asymmetric synthesis of the drug
warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
(in equilibrium with the
hemiketal
A hemiacetal or a hemiketal has the general formula R1R2C(OH)OR, where R1 or R2 is hydrogen or an organic substituent. They generally result from the addition of an alcohol to an aldehyde or a ketone, although the latter are sometimes called hemi ...
) in a
Michael addition
In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...
of
4-hydroxycoumarin
4-Hydroxycoumarin is a coumarin derivative with a hydroxy group at the 4-position.
Occurrence
4-Hydroxycoumarin is an important fungal metabolite from the precursor coumarin, and its production leads to further fermentative production of the na ...
and
benzylideneacetone
Benzylideneacetone is the organic compound described by the formula C6H5CH=CHC(O)CH3. Although both ''cis''- and ''trans''-isomers are possible for the α,β-unsaturated ketone, only the trans isomer is observed. Its original preparation demon ...
:
:
A recent exploit is the
vinyl
Vinyl may refer to:
Chemistry
* Polyvinyl chloride (PVC), a particular vinyl polymer
* Vinyl cation, a type of carbocation
* Vinyl group, a broad class of organic molecules in chemistry
* Vinyl polymer, a group of polymers derived from vinyl ...
alkylation of
crotonaldehyde
Crotonaldehyde is a chemical compound with the formula CH3CH=CHCHO. The compound is usually sold as a mixture of the ''E''- and ''Z''-isomers, which differ with respect to the relative position of the methyl and formyl groups. The ''E''-isomer ...
with an
organotrifluoroborate salt:
:
For other examples of its use: see
organocatalytic transfer hydrogenation and
asymmetric Diels-Alder reactions.
Thiourea organocatalysis
A large group of organocatalysts incorporate the
urea
Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid.
Urea serves an important ...
or the
thiourea
Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), except that the oxygen atom is replaced by a sulfur atom (as implied by the ''thio-'' prefix); however, the properties of urea a ...
moiety. These catalytically effective (thio)urea derivatives termed (thio)urea organocatalysts provide explicit double
hydrogen-bonding
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
interactions to coordinate and activate H-bond accepting substrates.
References
External links
*
*
*
{{chiral synthesis
Catalysis
Organic chemistry