Aldol condensation
An aldol condensation is a condensation reaction in organic chemistry in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone. Aldol condensations are important in organic synthesis, because they provide a good way to form carbon–carbon bonds. For example, the Robinson annulation reaction sequence features an aldol condensation. Aldol condensations are commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms. In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol", a structural unit found in many occurring molecules and pharmaceuticals; the name aldol condensation is commonly used in biochemistry, to refer to just the first stage of the process—the aldol reaction itself—as catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small molecule.
The reaction between an aldehyde or ketone having an alpha-hydrogen with an aromatic carbonyl compound lacking an alpha hydrogen is called the Claisen–Schmidt condensation. This reaction is named after two of its pioneering investigators Rainer Ludwig Claisen and J. G. Schmidt, who independently published on this topic in 1880 and 1881. An example is the synthesis of dibenzylideneacetone. Quantitative yields in Claisen–Schmidt reactions have been reported in the absence of solvent using sodium hydroxide as the base and plus benzaldehydes; because the enolizeable nucleophilic carbonyl compound and the electrophilic carbonyl compound are two different chemicals, the Claisen–Schmidt reaction is an example of a crossed aldol process. The first part of this reaction is an aldol reaction, the second part a dehydration—an elimination reaction. Dehydration may be accompanied by decarboxylation; the aldol addition product can be dehydrated via two mechanisms. Depending on the nature of the desired product, the aldol condensation may be carried out under two broad types of conditions: kinetic control or thermodynamic control.: It is important to distinguish the aldol condensation from other addition reactions of carbonyl compounds.
When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a Knoevenagel condensation. In a Perkin reaction the aldehyde is aromatic and the enolate generated from an anhydride. A Claisen condensation involves two ester compounds. A Dieckmann condensation involves two ester groups in the same molecule and yields a cyclic molecule A Henry reaction involves an aldehyde and an aliphatic nitro compound. A Robinson annulation involves a α,β-unsaturated ketone and a carbonyl group, which first engage in a Michael reaction prior to the aldol condensation. In the Guerbet reaction, an aldehyde, formed in situ from an alcohol, self-condenses to the dimerized alcohol. In the Japp–Maitland condensation water is removed not by an elimination reaction but by a nucleophilic displacement In industry the Aldox process developed by Royal Dutch Shell and Exxon, converts propylene and syngas directly to 2-ethylhexanol via hydroformylation to butyraldehyde, aldol condensation to 2-ethylhexenal and hydrogenation.
In one study crotonaldehyde is directly converted to 2-ethylhexanal in a palladium / Amberlyst / supercritical carbon dioxide system: Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation. The synthetic procedure is typical for this type of reaction. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in decarboxylation. Ethyl glyoxylate 2 and diethyl 2-methylglutaconate 1 react to isoprenetricarboxylic acid 3 with sodium ethoxide; this reaction product is unstable with initial loss of carbon dioxide and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the carboxylic group in the cis-dienoid structure. An aldol condensation is buried in a multistep reaction or in catalytic cycle such as the one sketched below: In this reaction an alkynal 1 is converted into a cycloalkene 7 with a ruthenium catalyst and the actual condensation takes place with intermediate 3 through 5.
Support for the reaction mechanism is based on isotope labeling. The reaction between menthone and anisaldehyde is complicated due to steric shielding of the ketone group; this obstacle is overcome by using a strong base such as potassium hydroxide and a polar solvent such as DMSO in the reaction below: Due to epimerization through a common enolate ion the reaction product has -cis-configuration and not -trans-configuration as in the starting material. Because it is only the cis isomer that precipitates from solution, this product is formed exclusively. Organic reaction and chemical reaction The Auwers synthesis Organic Chemistry Portal Reformatsky reaction
Hydrogen bond
A hydrogen bond is a electrostatic force of attraction between a hydrogen atom, covalently bound to a more electronegative atom or group the second-row elements nitrogen, oxygen, or fluorine —the hydrogen bond donor —and another electronegative atom bearing a lone pair of electrons—the hydrogen bond acceptor. Such an interacting system is denoted Dn–H···Ac, where the solid line denotes a covalent bond, the dotted line indicates the hydrogen bond. There is general agreement that there is a minor covalent component to hydrogen bonding for moderate to strong hydrogen bonds, although the importance of covalency in hydrogen bonding is debated. At the opposite end of the scale, there is no clear boundary between a weak hydrogen bond and a van der Waals interaction. Weaker hydrogen bonds are known for hydrogen atoms bound to elements such as chlorine; the hydrogen bond is responsible for many of the anomalous physical and chemical properties of compounds of N, O, F. Hydrogen bonds can be intramolecular.
Depending on the nature of the donor and acceptor atoms which constitute the bond, their geometry, environment, the energy of a hydrogen bond can vary between 1 and 40 kcal/mol. This makes them somewhat stronger than a van der Waals interaction, weaker than covalent or ionic bonds; this type of bond can occur in inorganic molecules such as water and in organic molecules like DNA and proteins. Intermolecular hydrogen bonding is responsible for the high boiling point of water compared to the other group 16 hydrides that have much weaker hydrogen bonds. Intramolecular hydrogen bonding is responsible for the secondary and tertiary structures of proteins and nucleic acids, it plays an important role in the structure of polymers, both synthetic and natural. It was recognized that there are many examples of weaker hydrogen bonding involving donor Dn other than N, O, or F and/or acceptor Ac with close to or the same electronegativity as hydrogen. Though they are quite weak, they are ubiquitous and are recognized as important control elements in receptor-ligand interactions in medicinal chemistry or intra-/intermolecular interactions in materials sciences.
Thus, there is a trend of gradual broadening for the definition of hydrogen bonding. In 2011, an IUPAC Task Group recommended a modern evidence-based definition of hydrogen bonding, published in the IUPAC journal Pure and Applied Chemistry; this definition specifies: The hydrogen bond is an attractive interaction between a hydrogen atom from a molecule or a molecular fragment X–H in which X is more electronegative than H, an atom or a group of atoms in the same or a different molecule, in which there is evidence of bond formation. Most introductory textbooks still restrict the definition of hydrogen bond to the "classical" type of hydrogen bond characterized in the opening paragraph. A hydrogen atom attached to a electronegative atom is the hydrogen bond donor. C-H bonds only participate in hydrogen bonding when the carbon atom is bound to electronegative substituents, as is the case in chloroform, CHCl3. In a hydrogen bond, the electronegative atom not covalently attached to the hydrogen is named proton acceptor, whereas the one covalently bound to the hydrogen is named the proton donor.
In the donor molecule, the H center is protic. The donor is a Lewis base. Hydrogen bonds are represented as H · · · Y system. Liquids that display hydrogen bonding are called associated liquids; the hydrogen bond is described as an electrostatic dipole-dipole interaction. However, it has some features of covalent bonding: it is directional and strong, produces interatomic distances shorter than the sum of the van der Waals radii, involves a limited number of interaction partners, which can be interpreted as a type of valence; these covalent features are more substantial when acceptors bind hydrogens from more electronegative donors. Hydrogen bonds can vary in strength from weak to strong. Typical enthalpies in vapor include: F−H···:F, illustrated uniquely by HF2−, bifluoride O−H···:N, illustrated water-ammonia O−H···:O, illustrated water-water, alcohol-alcohol N−H···:N, illustrated by ammonia-ammonia N−H···:O, illustrated water-amide HO−H···:OH+3 The strength of intermolecular hydrogen bonds is most evaluated by measurements of equilibria between molecules containing donor and/or acceptor units, most in solution.
The strength of intramolecular hydrogen bonds can be studied with equilibria between conformers with and without hydrogen bonds. The most important method for the identification of hydrogen bonds in complicated molecules is crystallography, sometimes NMR-spectroscopy. Structural details, in particular distances between donor and acceptor which are smaller than the sum of the van der Waals radii can be taken as indication of the hydrogen bond strength. One scheme gives the following somewhat arbitrary classification: those that are 15 to 40 kcal/mol, 5 to 15 kcal/mol, >0 to 5 kcal/mol are considered strong, moder
Silyl enol ether
Silyl enol ethers in organic chemistry are a class of organic compounds that share a common functional group composed of an enolate bonded through its oxygen end to an organosilicon group. They are important intermediates in organic synthesis. Trimethylsilyl enol ethers can be prepared from ketones in presence of a strong base and trimethylsilyl chloride or a weak base and trimethylsilyl triflate. Alternatively, enolate salts react with silyl electrophiles. A rather exotic way to generate silyl enol ethers is via the Brook rearrangement of appropriate substrates. Silyl enol ethers react as nucleophiles in many reactions resulting in alkylation, e.g. Mukaiyama aldol addition and Michael reactions. Halogenation of silyl enol ethers gives haloketones. Acyloins form upon organic oxidation with an electrophilic source of oxygen such as an oxaziridine or mCPBA. In the Saegusa–Ito oxidation, certain silyl enol ethers are oxidized to enones with palladium acetate. Cyclic silyl enol ethers undergo regiocontrolled one-carbon ring contractions.
These reactions employ electron-deficient sulfonyl azides, which undergo chemoselective, uncatalyzed cycloaddition to the silyl enol ether, followed by loss of dinitrogen, alkyl migration to give ring-contracted products in good yield. These reactions may be directed by substrate stereochemistry, giving rise to stereoselective ring-contracted product formation. Ketene silyl acetals are related compounds formally derived from ketenes and acetals with general structure R-C=C
Resonance (chemistry)
In chemistry, resonance is a way of describing bonding in certain molecules or ions by the combination of several contributing structures into a resonance hybrid in valence bond theory. It has particular value for describing delocalized electrons within certain molecules or polyatomic ions where the bonding cannot be expressed by one single Lewis structure. Under the framework of valence bond theory, resonance is an extension of the idea that the bonding in a chemical species can be described by a Lewis structure. For many chemical species, a single Lewis structure, consisting of atoms obeying the octet rule bearing formal charges, connected by bonds of positive integer order, is sufficient for describing the chemical bonding and rationalizing experimentally determined molecular properties like bond lengths and dipole moment. However, in some cases, more than one Lewis structure could be drawn, experimental properties are inconsistent with any one structure. In order to address this type of situation, several contributing structures are considered together as an average, the molecule is said to be represented by a resonance hybrid in which several Lewis structures are used collectively to describe its true structure.
For instance, in NO2–, nitrite anion, the two N–O bond lengths are equal though no single Lewis structure has two N–O bonds with the same formal bond order. However, its measured structure is consistent with a description as a resonance hybrid of the two major contributing structures shown above: it has two equal N–O bonds of 125 pm, intermediate in length between a typical N–O single bond and N–O double bond. According to the contributing structures, each N–O bond is an average of a formal single and formal double bond, leading to a true bond order of 1.5. By virtue of this averaging, the Lewis description of the bonding in NO2– is reconciled with the experimental fact that the anion has equivalent N–O bonds; the resonance hybrid represents the actual molecule as the "average" of the contributing structures, with bond lengths and partial charges taking on intermediate values compared to those expected for the individual Lewis structures of the contributors, were they to exist as "real" chemical entities.
The contributing structures differ only in the formal apportionment of electrons to the atoms, not in the actual physically and chemically significant electron or spin density. While contributing structures may differ in formal bond orders and in formal charge assignments, all contributing structures must have the same number of valence electrons and the same spin multiplicity; because electron delocalization lowers the potential energy of a system, any species represented by a resonance hybrid is more stable than any of the contributing structures. The difference in potential energy between the actual species and the energy of the contributing structure with the lowest potential energy is called the resonance energy or delocalization energy; the magnitude of the resonance energy depends on assumptions made about the hypothetical "non-stabilized" species and the computational methods used and does not represent a measurable physical quantity, although comparisons of resonance energies computed under similar assumptions and conditions may be chemically meaningful.
Molecules with an extended π system such as linear polyenes and polyaromatic compounds are well described by resonance hybrids as well as by delocalised orbitals in molecular orbital theory. Resonance is to be distinguished from isomerism. Isomers are molecules with the same chemical formula but are distinct chemical species with different arrangements of atomic nuclei in space. Resonance contributors of a molecule, on the other hand, can only differ in the way electrons are formally assigned to atoms in the Lewis structure depictions of the molecule; when a molecular structure is said to be represented by a resonance hybrid, it does not mean that electrons of the molecule are "resonating" or shifting back and forth between several sets of positions, each one represented by a Lewis structure. Rather, it means that the set of contributing structures represents an intermediate structure, with a single, well-defined geometry and distribution of electrons, it is incorrect to regard resonance hybrids as interconverting isomers though the term "resonance" might evoke such an image.
Symbolically, the double headed arrow A ⟷ B is used to indicate that A and B are contributing forms of a single chemical species. A non-chemical analogy is illustrative: one can describe the characteristics of a real animal, the narwhal, in terms of the characteristics of two mythical creatures: the unicorn, a creature with a single horn on its head, the leviathan, a large, whale-like creature; the narwhal is not a creature that goes back and forth between being a unicorn and being a leviathan, nor do the unicorn and leviathan have any physical existence outside the collective human imagination. Describing the narwhal in terms of these imaginary creatures provides a reasonably good description of its physical characteristics. Due to confusion
Pyruvate kinase
Pyruvate kinase is the enzyme that catalyzes the final step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to adenosine diphosphate, yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of phosphoenolpyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues. There are four isozymes of pyruvate kinase in vertebrates: L, R, M1 and M2. R and L isozymes differ from M1 and M2 in that they are both allosterically and reversibly regulated. From a kinetic standpoint, the R and L isozymes of pyruvate kinase have two key conformation states; the R-state, characterized by high substrate affinity, serves as the activated form of pyruvate kinase and is stabilized by PEP and FBP, promoting the glycolytic pathway.
The T-state, characterized by low substrate affinity, serves as the inactivated form of pyruvate kinase and stabilized by ATP and alanine, causing phosphorylation of pyruvate kinase and the inhibition of glycolysis. Gene expression varies between the different isozymes. M1 and M2 isozymes are regulated by the gene PKM and R and L isozymes are regulated by the gene PKLR. In terms of structure, there is both a dimeric form of pyruvate kinase; the tetrameric form is the pyruvate kinase structure in its R-state conformation, namely with high binding affinity to PEP. In contrast, the dimeric form is its structure in T-state conformation, namely with a low binding affinity to PEP; as a result, gene expression can be regulated by converting the active tetrameric form of PKM2, which yields high PEP concentrations, into an inactive dimeric form, which yields a PEP concentration of nearly zero. The PKM gene consists of 11 introns. PKM1 and PKM2 are different splicing products of the M-gene and differ in 23 amino acids within a 56-amino acid stretch at their carboxy terminus.
The PKM gene is regulated through heterogenous ribonucleotide proteins like hnRNPA1 and hnRNPA2. Human PKM2 monomer is a single chain divided into A, B and C domains; the difference in amino acid sequence between PKM1 and PKM2 allows PKM2 to be allosterically regulated by FBP and for it to form dimers and tetramers while PKM1 can only form tetramers. Many Enterobacteriaceae, including E. coli, have two isoforms of pyruvate kinase, PykA and PykF, which are 37% identical in E. coli. They catalyze the same reaction as in eukaryotes, namely the generation of ATP from ADP and PEP, the last step in glycolysis, a step, irreversible under physiological conditions. PykF is allosterically regulated by fructose 1,6-bisphosphate which reflects the central position of PykF in cellular metabolism. PykF transcription in E. coli is regulated by Cra. PfkB was shown to be inhibited by MgATP at low concentrations of Fru-6P, this regulation is important for gluconeogenesis. There are two steps in the pyruvate kinase reaction in glycolysis.
First, PEP transfers a phosphate group to ADP, producing the enolate of pyruvate. Secondly, a proton must be added to the enolate of pyruvate to produce the functional form of pyruvate that the cell requires; because the substrate for pyruvate kinase is a simple phospho-sugar, the product is an ATP, pyruvate kinase is a possible foundation enzyme for the evolution of the glycolysis cycle, may be one of the most ancient enzymes in all earth-based life. In Archaean oceans, phospho-enolpyruvate may have been present abiotically. In yeast cells, the interaction of yeast pyruvate kinase with PEP and its allosteric effector Fructose 1,6-bisphosphate was found to be enhanced by the presence of Mg2+. Therefore, Mg2+ was isolated as an important component in the successful catalysis of PEP into pyruvate by pyruvate kinase. Furthermore, the metal ion Mn2+ was shown to have a similar, but stronger effect on the coupling free energy of YPK than Mg2+; the binding of metal ions to the metal binding sites on pyruvate kinase enhance the rate of this glycolytic reaction.
The glycolytic reaction catalyzed by pyruvate kinase is the final step of glycolysis. It is one of the three rate-affecting steps of the catabolic reaction cascade; the rate-affecting steps are the slower steps of a reaction and thus determines the rate of the overall reaction. In glycolysis, the rate-affecting steps are coupled with the hydrolysis of ATP or the phosphorylation of ADP to create the energetically favorable and irreversible reaction mechanism; this final step is regulated and deliberately irreversible because pyruvate is a crucial intermediate building block for further metabolic pathways. Once pyruvate kinase synthesizes pyruvate, pyruvate either enters the TCA cycle for further production of ATP under aerobic conditions, or is reduced to lactate under anaerobic conditions. Both of these secondary metabolic pathways are essential to the function of the metabolism. Pyruvate kinase serves as a regulatory enzyme for gluconeogenesis, a biochemical pathway in which the liver generates glucose from pyruvate and other substrates.
Gluconeogenesis utilizes noncarbohydrate sources to provide glucose to the brain and red blood cells in times of starvat
Alcohol
In chemistry, an alcohol is any organic compound in which the hydroxyl functional group is bound to a carbon. The term alcohol referred to the primary alcohol ethanol, used as a drug and is the main alcohol present in alcoholic beverages. An important class of alcohols, of which methanol and ethanol are the simplest members, includes all compounds for which the general formula is CnH2n+1OH, it is these simple monoalcohols. The suffix -ol appears in the IUPAC chemical name of all substances where the hydroxyl group is the functional group with the highest priority; when a higher priority group is present in the compound, the prefix hydroxy- is used in its IUPAC name. The suffix -ol in non-IUPAC names typically indicates that the substance is an alcohol. However, many substances that contain hydroxyl functional groups have names which include neither the suffix -ol, nor the prefix hydroxy-. Alcohol distillation originated in India. During 2000 BCE, people of India used. Alcohol distillation was known to Islamic chemists as early as the eighth century.
The Arab chemist, al-Kindi, unambiguously described the distillation of wine in a treatise titled as "The Book of the chemistry of Perfume and Distillations". The Persian physician, alchemist and philosopher Rhazes is credited with the discovery of ethanol; the word "alcohol" is from a powder used as an eyeliner. Al- is the Arabic definite article, equivalent to the in English. Alcohol was used for the fine powder produced by the sublimation of the natural mineral stibnite to form antimony trisulfide Sb2S3, it was considered to be the essence or "spirit" of this mineral. It was used as an antiseptic and cosmetic; the meaning of alcohol was extended to distilled substances in general, narrowed to ethanol, when "spirits" was a synonym for hard liquor. Bartholomew Traheron, in his 1543 translation of John of Vigo, introduces the word as a term used by "barbarous" authors for "fine powder." Vigo wrote: "the barbarous auctours use alcohol, or alcofoll, for moost fine poudre."The 1657 Lexicon Chymicum, by William Johnson glosses the word as "antimonium sive stibium."
By extension, the word came to refer to any fluid obtained by distillation, including "alcohol of wine," the distilled essence of wine. Libavius in Alchymia refers to "vini alcohol vel vinum alcalisatum". Johnson glosses alcohol vini as "quando omnis superfluitas vini a vino separatur, ita ut accensum ardeat donec totum consumatur, nihilque fæcum aut phlegmatis in fundo remaneat." The word's meaning became restricted to "spirit of wine" in the 18th century and was extended to the class of substances so-called as "alcohols" in modern chemistry after 1850. The term ethanol was invented 1892, combining the word ethane with the "-ol" ending of "alcohol". IUPAC nomenclature is used in scientific publications and where precise identification of the substance is important in cases where the relative complexity of the molecule does not make such a systematic name unwieldy. In naming simple alcohols, the name of the alkane chain loses the terminal e and adds the suffix -ol, e.g. as in "ethanol" from the alkane chain name "ethane".
When necessary, the position of the hydroxyl group is indicated by a number between the alkane name and the -ol: propan-1-ol for CH3CH2CH2OH, propan-2-ol for CH3CHCH3. If a higher priority group is present the prefix hydroxy-is used, e.g. as in 1-hydroxy-2-propanone. In cases where the OH functional group is bonded to an sp2 carbon on an aromatic ring the molecule is known as a phenol, is named using the IUPAC rules for naming phenols. In other less formal contexts, an alcohol is called with the name of the corresponding alkyl group followed by the word "alcohol", e.g. methyl alcohol, ethyl alcohol. Propyl alcohol may be n-propyl alcohol or isopropyl alcohol, depending on whether the hydroxyl group is bonded to the end or middle carbon on the straight propane chain; as described under systematic naming, if another group on the molecule takes priority, the alcohol moiety is indicated using the "hydroxy-" prefix. Alcohols are classified into primary and tertiary, based upon the number of carbon atoms connected to the carbon atom that bears the hydroxyl functional group.
The primary alcohols have general formulas RCH2OH. The simplest primary alcohol is methanol, for which R=H, the next is ethanol, for which R=CH3, the methyl group. Secondary alcohols are those of the form RR'CHOH, the simplest of, 2-propanol. For the tertiary alcohols the general form is RR'R"COH; the simplest example is tert-butanol, for which each of R, R', R" is CH3. In these shorthands, R, R', R" represent substituents, alkyl or other attached organic groups. In archaic nomenclature, alcohols can be named as derivatives of methanol using "-carbinol" as the ending. For instance, 3COH can be named trimethylcarbinol. Alcohols have a long history of myriad uses. For simple mono-alcohols, the focus on this article, the following are most important industrial alcohols: methanol for the production of formaldehyde and as a fuel additive ethanol for alcoholic beverages, fuel additive, solvent 1-propanol, 1-butanol, isobutyl alcohol for use as a solvent a
Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. The final product is a β-amino-carbonyl compound known as a Mannich base. Reactions between aldimines and α-methylene carbonyls are considered Mannich reactions because these imines form between amines and aldehydes; the reaction is named after chemist Carl Mannich. The Mannich reaction is an example of nucleophilic addition of an amine to a carbonyl group followed by dehydration to the Schiff base; the Schiff base is an electrophile which reacts in the second step in an electrophilic addition with a compound containing an acidic proton. The Mannich reaction is considered a condensation reaction. In the Mannich reaction, primary or secondary amines or ammonia, are employed for the activation of formaldehyde. Tertiary amines lack an N–H proton to form the intermediate enamine. Α-CH-acidic compounds include carbonyl compounds, acetylenes, aliphatic nitro compounds, α-alkyl-pyridines or imines.
It is possible to use activated phenyl groups and electron-rich heterocycles such as furan and thiophene. Indole is a active substrate; the mechanism of the Mannich reaction starts with the formation of an iminium ion from the amine and the formaldehyde. The compound with the carbonyl functional group can tautomerize to the enol form, after which it can attack the iminium ion. Progress has been made towards asymmetric Mannich reactions; when properly functionalized the newly formed ethylene bridge in the Mannich adduct has two prochiral centers giving rise to two diastereomeric pairs of enantiomers. The first asymmetric Mannich reaction with an unmodified aldehyde was carried with -proline as a occurring chiral catalyst; the reaction taking place is between a simple aldehyde, such as propionaldehyde, an imine derived from ethyl glyoxylate and p-methoxyaniline catalyzed by -proline in dioxane at room temperature. The reaction product is diastereoselective with a preference for the syn-Mannich reaction 3:1 when the alkyl substituent on the aldehyde is a methyl group or 19:1 when the alkyl group the much larger pentyl group.
Of the two possible syn adducts or the reaction is enantioselective with a preference for the adduct with enantiomeric excess larger than 99%. This stereoselectivity is explained in the scheme below. Proline enters a catalytic cycle by reacting with the aldehyde to form an enamine; the two reactants line up for the Mannich reaction with Si facial attack of the imine by the Si-face of the enamine-aldehyde. Relief of steric strain dictates that the alkyl residue R of the enamine and the imine group are antiperiplanar on approach which locks in the syn mode of addition; the enantioselectivity is further controlled by hydrogen bonding between the proline carboxylic acid group and the imine. The transition state for the addition is a nine-membered ring with chair conformation with partial single bonds and double bonds; the proline group is converted back to the aldehyde and a single isomer is formed. By modification of the proline catalyst to it is possible to obtain anti-Mannich adducts. An additional methyl group attached to proline forces a specific enamine approach and the transition state now is a 10-membered ring with addition in anti-mode.
The diastereoselectivity is at least anti:syn 95:5 regardless of alkyl group size and the enantiomer is preferred with at least 97% ee. The Mannich-Reaction is employed in the organic synthesis of numerous compounds. Examples include: alkyl amines peptides, nucleotides and alkaloids agrochemicals, such as plant growth regulators polymers catalysts formalin tissue crosslinking Pharmaceutical drugs soap and detergents; these compounds are used in a variety of cleaning applications, automotive fuel treatments, epoxy coatings polyetheramines from substituted branched chain alkyl ethers α,β-unsaturated ketones via the thermal degradation of Mannich reaction products Betti reaction Pictet–Spengler reaction Kabachnik–Fields reaction "Mechanism in Motion: Mannich reaction"
Keto-enediol tautomerizations. Enediol in the center; acyloin isomers at left and right. Ex. is hydroxyacetone, shown at right.
