The
Passerini reaction is a
chemical reactionA chemical reaction is a process that leads to the transformation of one set of chemical substances to another. They are studied by chemists under a field of science called chemistry. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, often coming about...
involving an
isocyanideAn isocyanide is an organic compound with the functional group R-N≡C. The CN functionality is connected to the organic fragment via the nitrogen atom, not via carbon as is found in the isomeric nitriles, which have the connectivity R-C≡N. Hence the prefix iso...
, an
aldehydeAn aldehyde is an organic compound containing a terminal carbonyl group. This functional group, which consists of a carbon atom bonded to a hydrogen atom and double-bonded to an oxygen atom , is called the aldehyde group...
(or
ketoneIn organic chemistry, a ketone is a type of compound that features a carbonyl group bonded to two other carbon atoms, i.e., R3CCO-CR3 where R can be a variety of atoms and groups of atoms...
), and a
carboxylic acidCarboxylic acids are organic acids characterized by the presence of a carboxyl group, which has the formula -COH, usually written -COOH or -CO2H. Carboxylic acids are Brønsted-Lowry acids — they are proton donors. Salts and anions of carboxylic acids are called...
to form a α-acyloxy
amideIn chemistry, an amide is usually an organic compound that contains the functional group consisting of an acyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds...
.
This
organic reactionOrganic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions. In organic synthesis, organic reactions are used...
was discovered by Mario Passerini in 1921 in
FlorenceFlorence is the capital city of the Italian region of Tuscany and of the province of Florence...
,
ItalyItaly , officially the Italian Republic , is a country located on the Italian Peninsula in Southern Europe and on the two largest islands in the Mediterranean Sea, Sicily and Sardinia. Italy shares its northern, Alpine boundary with France, Switzerland, Austria and Slovenia...
. It is the first
multi-component reactionIn chemistry, a multi-component reaction is a chemical reaction where three or more compounds react to form a single product.Examples of three component reactions:* Alkyne trimerisation* Biginelli reaction* Bucherer-Bergs reaction...
developed, and currently plays a central role in
combinatorial chemistryCombinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials.-Introduction:...
.
Recently, Denmark
et al. have developed an enantioselective catalyst for aymmetric Passerini reactions.
In polar solvents such as
methanolMethanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with formula CH3OH . It is toxic: drinking 10 ml will cause blindness, and as little as 100 ml will cause death...
or water, the reaction proceeds by protonation of the carbonyl followed by nucleophilic addition of the isocyanide to give the nitrilium ion
3.
The
Passerini reaction is a
chemical reactionA chemical reaction is a process that leads to the transformation of one set of chemical substances to another. They are studied by chemists under a field of science called chemistry. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, often coming about...
involving an
isocyanideAn isocyanide is an organic compound with the functional group R-N≡C. The CN functionality is connected to the organic fragment via the nitrogen atom, not via carbon as is found in the isomeric nitriles, which have the connectivity R-C≡N. Hence the prefix iso...
, an
aldehydeAn aldehyde is an organic compound containing a terminal carbonyl group. This functional group, which consists of a carbon atom bonded to a hydrogen atom and double-bonded to an oxygen atom , is called the aldehyde group...
(or
ketoneIn organic chemistry, a ketone is a type of compound that features a carbonyl group bonded to two other carbon atoms, i.e., R3CCO-CR3 where R can be a variety of atoms and groups of atoms...
), and a
carboxylic acidCarboxylic acids are organic acids characterized by the presence of a carboxyl group, which has the formula -COH, usually written -COOH or -CO2H. Carboxylic acids are Brønsted-Lowry acids — they are proton donors. Salts and anions of carboxylic acids are called...
to form a α-acyloxy
amideIn chemistry, an amide is usually an organic compound that contains the functional group consisting of an acyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds...
.
This
organic reactionOrganic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions. In organic synthesis, organic reactions are used...
was discovered by Mario Passerini in 1921 in
FlorenceFlorence is the capital city of the Italian region of Tuscany and of the province of Florence...
,
ItalyItaly , officially the Italian Republic , is a country located on the Italian Peninsula in Southern Europe and on the two largest islands in the Mediterranean Sea, Sicily and Sardinia. Italy shares its northern, Alpine boundary with France, Switzerland, Austria and Slovenia...
. It is the first
multi-component reactionIn chemistry, a multi-component reaction is a chemical reaction where three or more compounds react to form a single product.Examples of three component reactions:* Alkyne trimerisation* Biginelli reaction* Bucherer-Bergs reaction...
developed, and currently plays a central role in
combinatorial chemistryCombinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials.-Introduction:...
.
Recently, Denmark
et al. have developed an enantioselective catalyst for aymmetric Passerini reactions.
Ionic mechanism
In polar solvents such as
methanolMethanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with formula CH3OH . It is toxic: drinking 10 ml will cause blindness, and as little as 100 ml will cause death...
or water, the reaction proceeds by protonation of the carbonyl followed by nucleophilic addition of the isocyanide to give the nitrilium ion
3. Addition of a carboxylate gives intermediate
4. Acyl group transfer and amide tautomerization give the desired ester
5 .
Concerted mechanism
In non-polar solvents and at high concentration a concerted mechanism is likely :
This mechanism involves a trimolecular reaction between the
isocyanideAn isocyanide is an organic compound with the functional group R-N≡C. The CN functionality is connected to the organic fragment via the nitrogen atom, not via carbon as is found in the isomeric nitriles, which have the connectivity R-C≡N. Hence the prefix iso...
(R-NC), the carboxylic acid, and the carbonyl in a sequence of
nucleophilic additionIn organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
s . The
transition stateThe transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate...
TS# is depicted as a 5-membered ring with partial covalent or double bonding. The second step of the Passerini reaction is an acyl transfer to the neighboring hydroxyl group. There is support for this reaction mechanism: the reaction proceeds in relatively non-polar
solventA solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution.The most common solvent in everyday life is water. Most other commonly-used solvents are organic chemicals. These are called organic solvents...
s (in line with transition state) and the reaction kinetics depend on all three reactants. This reaction is a good example of a
convergent synthesisIn chemistry a convergent synthesis is a strategy that aims to improve the efficiency of multi-step chemical synthesis, most often in organic synthesis...
.
Scope
The Passerini reactions is used in many multicomponent reactions for instance one preceded by a
Horner-Wadsworth-Emmons reactionThe Horner-Wadsworth-Emmons reaction is the chemical reaction of stabilized phosphonate carbanions with aldehydes to produce predominantly E-alkenes....
and forming a
depsipeptideA depsipeptide is a peptide in which one or more of the amide bonds are replaced by ester bonds.Depsipeptides have often been used in research to probe the importance of hydrogen bond networks in protein folding kinetics and thermodynamics. They are also found in nature as natural products...
: