Mechanisms of organic reactions mirka.rovenska@lfmotol.cuni.cz

Types of organic reactions Substitution – an atom (group) of the molecule is replaced by another atom (group) Addition – π-bond of a compound serves to create two new covalent bonds that join the two reactants together Elimination – two atoms (groups) are removed from a molecule which is thus cleft into two products Rearrangement – atoms and bonds are rearranged within the molecule; thus, isomeric compound is formed

Mechanism A reaction can proceed by: homolytic mechanism – each fragment possesses one of the bonding electrons; thus, radicals are formed: A–B  A• + B• heterolytic mechanism – one of the fragments retains both the bonding electrons; thus, ions are formed: A–B  A+ + :B–

Agents Radical – possess an unpaired electron (Cl•) Ionic: A) nucleophilic – possess an electron pair that can be introduced into an electron-deficient substrate: i) anions (H–, OH–) ii) neutral molecules (NH3, HOH) B) electrophilic – electron-deficient  bind to substrate centres with a higher electron density: i) cations (Br+) ii) neutral molecules (for example Lewis acids: AlCl3)

Lewis acids and bases CH3–Cl + AlCl3  CH3+ + AlCl4- Lewis base: acts as an electron-pair donor; e.g. ammonia: NH3 Lewis acid: can accept a pair of electrons; e.g.: AlCl3, FeCl3, ZnCl2. These compounds – important catalysts: generate ions that can initiate a reaction: CH3–Cl + AlCl3  CH3+ + AlCl4- • •

Radical substitution - here: lipid peroxidation: 1. Initiation – formation of radicals: H2O  OH• + H• 2. Propagation – radicals attack neutral molecules generating new molecules and new radicals: CH3CH2R + •OH CH3CHR CH3C–O–O• 3. Termination – radicals react with each other, forming stable products; thus, the reaction is terminated (by depletion of radicals) H R O2 • – H2O fatty acid CH3CH2R CH3CHR + CH3C–OOH • H R

Electrophilic substitution An electron-deficient agent reacts with an electron-rich substrate; the substrate retains the bonding electron pair, a cation (proton) is removed: R–X + E+  R–E + X+ Typical of aromatic hydrocarbons: chlorination nitration etc.

Aromatic electrophilic substitution using Lewis acids Halogenation: Very often, electrophilic substitution is used to attach an alkyl to the benzene ring(Friedel-Crafts alkylation): benzene carbocation bromobenzene

Inductive effect Permanent shift of -bond electrons in the molecule composed of atoms with different electronegativity: – I effect is caused by atoms/groups with high electronegativity that withdraw electrons from the neighbouring atoms: – Cl, –C=O, –NO2: +I effect is caused by atoms/groups with low electronegativity that increase electron density in their vicinity: metals, alkyls: CH3 CH2 CH2 Cl δ+ < δ+ < δ+ δ- C H δ+ δ- C CH3

Mesomeric effects Permanent shift of electron density along the -bonds (i.e. in compounds with unsaturated bonds, most often in aromatic hydrocarbons) Positive mesomeric effect (+M) is caused by atoms/groups with lone electron pair(s) that donate π electrons to the system: –NH2, –OH, halogens Negative mesomeric effect (–M) is caused by atoms/groups that withdraw π electrons from the system: –NO2, –SO3H, –C=O

Activating/deactivating groups If inductive and mesomeric effects are contradictory, then the stronger one predominates Consequently, the group bound to the aromatic ring is: activating – donates electrons to the aromatic ring, thus facilitating the electrophilic substitution: a) +M > – I… –OH, –NH2 b) only +I…alkyls deactivating – withdraws electrons from the aromatic ring, thus making the electrophilic substitution slower: a) –M and –I… –C=O, –NO2 b) – I > +M…halogens

Electrophilic substitution & M, I-effects Substituents exhibiting the +M or +I effect (activating groups, halogens) attached to the benzene ring direct next substituent to the ortho, para positions: Substituents exhibiting the –M and – I effect (–CHO, –NO2) direct the next substituent to the meta position:

Nucleophilic substitution Electron-rich nucleophile introduces an electron pair into the substrate; the leaving atom/group retains the originally bonding electron pair: |Nu– + R–Y  Nu–R + |Y– This reaction is typical of haloalkanes: Nucleophiles: HS–, HO–, Cl– + alcohol is produced

Radical addition Again: initiation (creation of radicals), propagation (radicals attack neutral molecules, producing more and more radicals), termination (radicals react with each other, forming a stable product; the chain reaction is terminated) E.g.: polymerization of ethylene using dibenzoyl peroxide as an initiator:

Electrophilic addition An electrophile forms a covalent bond by attacking an electron-rich unsaturated C=C bond Typical of alkenes and alkynes Markovnikov´s rule: the more positive part of the agent (hydrogen in the example below) becomes attached to the carbon atom (of the double bond) with the greatest number of hydrogens:

Nucleophilic addition In compounds with polar unsaturated bonds, such as C=O: Nucleophiles – water, alcohols, carbanions – form a covalent bond with the carbon atom of the carbonyl group: – carbon atom carries + aldehyde/ketone used for synthesis of alcohols

Hemiacetals Addition of alcohol to the carbonyl group yields hemiacetal: As to biochemistry, hemiacetals are formed by monosaccharides: hemiacetal glucose hemiacetals

Elimination In most cases, the two atoms/groups are removed from the neighbouring carbon atoms and a double bond is formed (-elimination) Elimination of water = dehydration – used to prepare alkenes: In biochemistry – e.g. in glycolysis: – H2O 2-phospho- glycerate phosphoenol- pyruvate

Rearrangement In biochemistry: often migration of a hydrogen atom, changing the position of the double bond Keto-enol tautomerism of carbonyl compounds: equilibrium between a keto form and an enol form: E.g.: isomerisation of monosaccharides occurs via enol form: glucose (keto form) enol form fructose dihydroxyaceton- phosphate enol form glyceraldehyd- 3-phosphate