Dakin Reaction
The Dakin Reaction allows the preparation of phenols from aryl aldehydes or aryl ketones via oxidation with hydrogen peroxide in the presence of base. The aryl formate or alkanoate formed as an intermediate is subsequently saponified to yield the substituted phenol product.
Ortho or para +M substituents (NH2, OH) favor this reaction.
Darzens Reaction
Darzens Condensation
The Darzens Reaction is the condensation of a carbonyl compound with an α-halo ester in the presence of a base to form an α,β-epoxy ester.
Mechanism of the Darzens Reaction
After deprotonation, the α-halo ester adds to the carbonyl compound to give syn and anti diastereomers:
In the subsequent step, an intramolecular SN2 reaction forms the epoxide:
Typically, the cis:trans ratio of the epoxide formation lies between 1:1 and 1:2.
In the past, Darzens methodology was primarily used for the synthesis of aldehydes and ketones, as a homologation reaction without any consideration of stereocontrol in the epoxide formation. For this sequence, saponification of the α,β-epoxy ester followed by decarboxylation gives the substituted carbonyl compound:
Darzens methodology for the construction of epoxides can also be used for α-halo carbonyl compounds, or similar compounds that can undergo deprotonation and bear electron-withdrawing groups. In addition, the reaction can be carried out with diazoacetate, where N2 is the leaving group, or with a sulphur ylide with SR2 as the leaving group (see Corey Chaykovsky).
In the following specific substitution pattern, the outcome of the reaction depends on the energy of the transition states of the addition, the rotation and the ring closure, as described by Aggarwal. Although explanations for the diastereoselectivity have been given, the enantioselectivity that is induced by the camphor-derived sulphonium group is not yet fully understood:
Darzens Reaction
Darzens Condensation
The Darzens Reaction is the condensation of a carbonyl compound with an α-halo ester in the presence of a base to form an α,β-epoxy ester.
Mechanism of the Darzens Reaction
After deprotonation, the α-halo ester adds to the carbonyl compound to give syn and anti diastereomers:In the subsequent step, an intramolecular SN2 reaction forms the epoxide:
Typically, the cis:trans ratio of the epoxide formation lies between 1:1 and 1:2.
In the past, Darzens methodology was primarily used for the synthesis of aldehydes and ketones, as a homologation reaction without any consideration of stereocontrol in the epoxide formation. For this sequence, saponification of the α,β-epoxy ester followed by decarboxylation gives the substituted carbonyl compound:
Darzens methodology for the construction of epoxides can also be used for α-halo carbonyl compounds, or similar compounds that can undergo deprotonation and bear electron-withdrawing groups. In addition, the reaction can be carried out with diazoacetate, where N2 is the leaving group, or with a sulphur ylide with SR2 as the leaving group (see Corey Chaykovsky).
In the following specific substitution pattern, the outcome of the reaction depends on the energy of the transition states of the addition, the rotation and the ring closure, as described by Aggarwal. Although explanations for the diastereoselectivity have been given, the enantioselectivity that is induced by the camphor-derived sulphonium group is not yet fully understood:
Delépine Reaction
The Delépine Reaction allows the synthesis of primary amines from alkyl halides by the reaction with hexamethylentetramine (urotropine) and subsequent acidic hydrolysis of the resulting quartenary ammonium salt.
Mechanism of the Delépine Reaction
An SN2 reaction leads to the hexamethylentetramine salt. In chloroform, the starting materials are soluble wheareas the products crystallize out. It is usually not possible to purify the salt:
Hexamethylenetetramine is formed in nearly quantitative yield from the condensation of ammonia and formaldehyde.
The compound is rather stable, although dihetero-substituted methylene groups are usually highly reactive. In neutral, aqueous solution, urotropine remains stable even at elevated temperatures. Urotropine decomposes in dilute aqueous acid, and the derived ammonium salts also decompose to form the amine hydrochloride and formaldehyde (and formaldehyde diethylacetal):
During acidic hydrolysis or ethanolysis, semiaminals are formed first; these further decompose to yield formaldehyde or the diethylacetal, ammonium salt and the amine hydrochloride:
For a review of the uses of hexamethylenetetramine, a versatile reagent in organic synthesis, please refer to Blažević
Dess-Martin Oxidation
The Dess-Martin Periodinane (DMP), a hypervalent iodine compound, offers selective and very mild oxidation of alcohols to aldehydes or ketones.
The oxidation is performed in dichloromethane or chloroform at room temperature, and is usually complete within 0.5 - 2 hours. Products are easily separated from the iodo-compound byproduct after basic work-up.
Mechanism of the Dess-Martin Oxidation
Diazotisation
The nitrosation of primary aromatic amines with nitrous acid (generated in situ from sodium nitrite and a strong acid, such as hydrochloric acid, sulfuric acid, or HBF4) leads to diazonium salts, which can be isolated if the counterion is non-nucleophilic.
Diazonium salts are important intermediates for the preparation of halides (Sandmeyer Reaction, Schiemann Reaction), and azo compounds. Diazonium salts can react as pseudohalide-type electrophiles, and can therefore be used in specific protocols for the Heck Reaction or Suzuki Coupling.
The intermediates resulting from the diazotization of primary, aliphatic amines are unstable; they are rapidly converted into carbocations after loss of nitrogen, and yield products derived from substitution, elimination or rearrangement processes.
Mechanism of Diazotisation
Dieckmann Condensation
The base-catalyzed intramolecular condensation of a diester. The Dieckmann Condensation works well to produce 5- or 6-membered cyclic ß-keto esters, and is usually effected with sodium alkoxide in alcoholic solvent.
The yields are good if the product has an enolizable proton; otherwise, the reverse reaction (cleavage with ring scission) can compete. See theClaisen Condensation.
Diels-Alder Reaction
The [4+2]-cycloaddition of a conjugated diene and a dienophile (an alkene or alkyne), an electrocyclic reaction that involves the 4 π-electrons of the diene and 2 π-electrons of the dienophile. The driving force of the reaction is the formation of new σ-bonds, which are energetically more stable than the π-bonds.
In the case of an alkynyl dienophile, the initial adduct can still react as a dienophile if not too sterically hindered. In addition, either the diene or the dienophile can be substituted with cumulated double bonds, such as substituted allenes.
With its broad scope and simplicity of operation, the Diels-Alder is the most powerful synthetic method for unsaturated six-membered rings.
A variant is the hetero-Diels-Alder, in which either the diene or the dienophile contains a heteroatom, most often nitrogen or oxygen. This alternative constitutes a powerful synthesis of six-membered ring heterocycles.
Mechanism of the Diels-Alder Reaction
Overlap of the molecular orbitals (MOs) is required:
Overlap between the highest occupied MO of the diene (HOMO) and the lowest unoccupied MO of the dienophile (LUMO) is thermally allowed in the Diels Alder Reaction, provided the orbitals are of similar energy. The reaction is facilitated by electron-withdrawing groups on the dienophile, since this will lower the energy of the LUMO. Good dienophiles often bear one or two of the following substituents: CHO, COR, COOR, CN, C=C, Ph, or halogen. The diene component should be as electron-rich as possible.
There are “inverse demand” Diels Alder Reactions that involve the overlap of the HOMO of the dienophile with the unoccupied MO of the diene. This alternative scenario for the reaction is favored by electron-donating groups on the dienophile and an electron-poor diene.
The reaction is diastereoselective.
Cyclic dienes give stereoisomeric products. The endo product is usually favored by kinetic control due to secondary orbital interactions.
Huisgen Cycloaddition
1,3-Dipolar Cycloaddition
The Huisgen Cycloaddition is the reaction of a dipolarophile with a 1,3-dipolar compound that leads to 5-membered (hetero)cycles. Examples of dipolarophiles are alkenes and alkynes and molecules that possess related heteroatom functional groups (such as carbonyls and nitriles). 1,3-Dipolar compounds contain one or more heteroatoms and can be described as having at least one mesomeric structure that represents a charged dipole.
Examples of linear, propargyl-allenyl-type dipoles
An example of an allyl-type dipole. See: Ozonolysis
Mechanism of the Huisgen 1,3-Dipolar Cycloaddition
2 π-electrons of the dipolarophile and 4 electrons of the dipolar compound participate in a concerted, pericyclic shift. The addition is stereoconservative (suprafacial), and the reaction is therefore a [2s+4s] cycloaddition similar to the Diels-Alder Reaction. Attention: many authors still use "[2+3] cycloaddition", which counts the number of involved atoms but does not follow IUPAC recommendations (link). IUPAC recommends the use of "(2+3)" for the number of involved atoms instead.
A condition for such a reaction to take place is a certain similarity of the interacting HOMO and LUMO orbitals, depending on the relative orbital energies of both the dipolarophile and the dipole. Electron-withdrawing groups on the dipolarophile normally favour an interaction of the LUMO of the dipolarophile with the HOMO of the dipole that leads to the formation of the new bonds, whereas electron donating groups on the dipolarophile normally favour the inverse of this interaction. Diazomethane as an electron-rich dipolar compound therefore rapidly reacts with electron-poor alkenes, such as acrylates. Relative reactivity patterns may be found in the literature (R. Huisgen, R. Grashey, J. Sauer in Chemistry of Alkenes, Interscience, New York, 1964, 806-877.).
The regioselectivity of the reaction depends on electronic and steric effects and is somewhat predictable. For example, the addition of alkynes to azides, which is an interesting reaction for the generation of 1,2,3-triazole libraries by the simple reaction of two molecules ("click chemistry"), leads to regioisomers:
V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596-2599.
The reaction has been modified to a more regioselective, copper-catalyzed stepwise process by the Sharpless group, which is no longer a classic Huisgen Cycloaddition (for a discussion of the nonconcerted mechanism see: click chemistry) . Another approach prefers the use of a directing electron withdrawing group, which is removable later:
D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo, E. Zunino, L. Vaccaro, J. Org. Chem. 2005, 70, 6526-6529.
In summary, the 1,3-dipolar cycloaddition allows the production of various 5-membered heterocycles. Many reactions can be performed with high regioselectivity and even enantioselective transformations of prochiral substrates have been published. Some interesting examples may be found in the recent literature
Directed ortho Metalation (DOM)
The reaction of an alkyllithium compound with an arene bearing a "Directed Metalation Group" (DMG) normally leads to an ortho-metalated intermediate. Good DMG's are strong complexing or chelating groups that have the effect of increasing the kinetic acidity of protons in the ortho-position.
The ortho-metalated intermediate can be reacted with a variety of electrophiles, after which the DMG can be retained if desired, converted to a different functional group, or in some cases removed.
Mechanism of Directed Ortho Metalation
The DMG does not necessarily have to be inert:
| strong DMGs: | -CON-R, -CONR2, | -N-COR, -N-CO2R |
 | -OCONR2, -OMOM | |
| -SO3R | ||
| -CH=NR | -SO2NR2 | |
| -CN | -SO2tBu | |
| moderate | -CF3 | -NR2 |
| -NC | ||
| -OMe | ||
| -F | ||
| -Cl | ||
| weak | -CH2O- | -O- |
-C C- | -S- | |
Ph
Knoevenagel Condensation
|
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