Reactive Intermediates and Rearrangement Reactions

Reactive Intermediates

• In chemistry, a reactive intermediate (or intermediate) is a short-lived, high-energy, highly reactive molecule.
• When generated in a chemical reaction, it quickly converts into a more stable molecule.
• Isolation and storage are rare, only occurring in exceptional cases (e.g., low temperatures, matrix isolation).
• The existence of reactive intermediates helps explain chemical reaction mechanisms.
• Carbon-based reactive intermediates include radicals, carbenes, carbocations, carbanions, arynes, and carbynes.
• Most chemical reactions involve multiple elementary steps, forming a reaction mechanism.
• Reactive intermediates differ from reactants, products, or simple reaction intermediates because they usually cannot be isolated and are observable only through fast spectroscopic methods.

Common Features of Reactive Intermediates

• Low concentration relative to reaction substrate and final product.
• With the exception of carbanions, these intermediates often do not obey the Lewis octet rule, contributing to their high reactivity.
• Often generated by chemical decomposition of a chemical compound.
• Their existence can often be proven by spectroscopic means.
• Cage effects must be considered.
• Stabilization often occurs through conjugation or resonance.
• Often difficult to distinguish from a transition state.
• Existence can be proven by chemical trapping.

Examples of Reaction Intermediates

Radicals

• Typically, electrons come in pairs, but radicals have unpaired electrons.
• Radicals prefer a greater degree of alkyl substitution and are even more stable in the allylic position.
• Hierarchy of radical intermediate stability:
  allylic > 3° > 2° > 1° > methyl

Carbocations

• A carbocation is an ion with a positively-charged carbon atom.
• Examples: methenium (CH3^+), methanium (CH5^+), and ethanium (C2H7^+).
• Carbocations serve as electrophiles in reactions, attracting electrons due to the electron deficiency of the carbon atom.
• Carbocations can undergo rearrangement to yield more stable structures, especially in the case of olefins.
• Carbocations prefer a greater degree of alkyl substitution, and are even more stable in the allylic position.
• Hierarchy of carbocation intermediate stability:
  allylic > 3° > 2° > 1° > methyl
• Example: Heating 3-pentanol with aqueous HCl initially forms a 3-pentyl carbocation that rearranges to a statistical mixture of 3-pentyl and 2-pentyl carbocations. These cations react with chloride ions to produce approximately 1/3 3-chloropentane and 2/3 2-chloropentane.

Carbanions

• A carbanion is an eight-electron intermediate with an sp^3 structure.
• Despite having a full octet, it is very reactive because carbon is not very electronegative.
• Although sp^3, it can participate in resonance because it can easily re-hybridize to an sp^2 structure.
• Carbanions serve as nucleophiles in reactions, donating electrons due to the excess of electrons on the carbon atom.
• Carbanions prefer a lesser degree of alkyl substitution and are more stable in the allylic position.
• Hierarchy of carbanion intermediate stability:
  allylic > methyl > 1° > 2° > 3°

Carbenes

• Carbenes were once thought of as short-lived intermediates.
• Carbenes are neutral and have six valence electrons, two of which are nonbonding.
• These electrons can either occupy the same sp^2 hybridized orbital to form a singlet carbene (paired electrons) or two different sp^2 orbitals to form a triplet carbene (unpaired electrons).
• The reactivity of singlet carbenes is concerted and similar to electrophilic or nucleophilic addition.
• The highly reactive nature of carbenes leads to very fast reactions, where the rate-determining step is generally carbene formation.

Preparation of Carbene

• The preparation of methylene starts with the yellow gas diazomethane, CH2N2.
• Diazomethane can be exposed to light, heat, or copper to facilitate the loss of nitrogen gas and the formation of the simplest carbene, methylene.
• The process is driven by the formation of nitrogen gas, which is a very stable molecule.
  H2CN2 ounderlight, heat, or copper H2C + N2

Carbene Reaction with Alkenes

• Carbenes such as methylene will react with an alkene, breaking the double bond and resulting in a cyclopropane.
  Alkene + H2C ounder light Cyclopropane + N2
• Cis-2-butene is converted to cis-1,2-dimethylcyclopropane and the trans-configuration is maintained; therefore the reaction is stereo-selective.
• Halogenated carbenes such as dichlorocarbene, Cl_2C:, are more stable than simple alkyl carbenes.
• Dichlorocarbene can be conveniently prepared from chloroform (CHCl3) with a base in the presence of a phase transfer catalyst. CHCl3 ounder aq. NaOH, phase-transfer catalyst :CCl_2
• These halogenated carbenes form cyclopropanes in the same manner as methylene.

Selected Rearrangement Reactions

• Examples: Beckmann, Baeyer-Villiger etc., illustrate various reaction mechanisms and types.
• High reactivity of the methylene group in a methylene compound prevents self-condensation of the aldehyde (Knoeveagel Condensation reaction).

Beckmann Rearrangement

• Named after the German chemist Ernst Otto Beckmann (1853-1923).
• It is a rearrangement of an oxime that can produce either nitriles or amides, depending on the starting material.
• Oximes from ketones develop into amides; oximes from aldehydes form into nitriles.
• The rearrangement has also been performed on haloimines and nitrones. Cyclic oximes and haloimines yield lactams.
• Example: Cyclohexanone + NH2OH ( ounderH2SO_4) yields cyclohexanoxime ( ounder rearrangement) yields caprolactam.
• Mechanism:

Baeyer-Villiger Oxidation

• An organic reaction that forms an ester from a ketone or a lactone from a cyclic ketone, using peroxyacids or peroxides as the oxidant.
• Rearrangement occurs such that an oxygen atom is inserted between one of the alkyl groups and the carbonyl carbon, giving an ester in the case of an acyclic ketone; cyclic ketones give lactones.
• Peroxytrifluoroacetic acid in a buffered system is generally the reagent of choice.
• Ketone + Peracid oreaction Ester + Carboxylic Acid
• Aldehyde + Peracid oreaction Carboxylic Acid
• The ability of the anion R"COO to split off as a leaving group determines the reactivity of the peracid. Electron-donating groups in the ketone and electron-deficient groups on the peracid accelerate the reaction.
• In the case of an asymmetric ketone, the more nucleophilic radical migrates preferentially. Where there is no steric hindrance, the order of migration preference is:
  Tert-alkyl > sec-alkyl > cyclohexyl > benzyl > phenyl > alkyl > methyl.
• Mechanism steps:
  1. Acid/base reaction: protonation of the carbonyl activates it while creating a more reactive nucleophile, the percarboxylate.
  2. Nucleophilic attack: the nucleophilic O attacks the carbonyl C with the electrons from the C=O \pi bond going to the positive O.
  3. Migration: electrons from the O come back (reforming the C=O bond), and the C-C electrons migrate to form a new C-O bond, displacing the carboxylate as a leaving group.
  4. Acid/base reaction: reveals the C=O and therefore the ester product.

Polycyclic Compounds

• Compounds with more than one ring of carbon atoms and whose rings share two or more of the same carbon atoms are known as polycyclic compounds; those with two rings are called bicyclic compounds.
• The rings may be fused as in Decalin or bridged as in norborane.

Nomenclature of Bicyclic Compounds

• They are named by prefixing bicycle- to the name of the parent hydrocarbon.
• The name of the parent hydrocarbon is obtained by counting the total number of carbon atoms in all the rings of the compound (as in norborane and decalin above).
• The carbon atoms attached to two rings are referred to as bridgehead carbons.
• The number of carbon atoms between the bridgehead carbons in the molecule is specified by counting from the bridgehead carbon and listing each of the numbers in brackets in decreasing order prior to the parent name of the hydrocarbon.
• Thus, norborane is named as bicyclo [2.2.1] heptane.
• Fused ring systems that share more than two atoms are called bicyclic molecules.
• Steps to name bicyclic alkanes:
  1. Count the total number of carbons in the entire molecule. This is the parent name (e.g., ten carbons in the system would be decane).
  2. Count the number of carbons between the bridgeheads, then place in brackets in descending order (e.g., [2,2,1]).
  3. Place the word bicyclo at the beginning of the name.

Naming Spiro Compounds

• Since both "bridgehead" positions are on the same carbon, we won't be able to use the same "bicyclo" nomenclature as before, but the process is very similar.
• We simply substitute "spiro" for "bicyclo", insert the two bridge lengths, and place the suffix as before. So the molecule is spiro [4.5]decane.

Numbering for Siprocyclic Compounds

• Numbering starts from the smaller ring, via shorter connection in the middle ring (including bridgeheads in numbering at their first appearance).