Mechanisms of organic reactions

Types of organic reactions Substitution – an atom (group) of the molecule is replaced by another Addition – atoms of a compound are being attached to a double (triple) bond, which is accompanied by reduction in bond multiplicity Elimination – two atoms (groups) are removed from the molecule Rearrangement – an atom (group) migrates from one atom of a molecule to another atom, most often of the same molecule

Mechanism Each of these types can proceed by: Homolytic mechanism – involves formation of radicals: A–B  A + B Heterolytic mechanism – involves formation of ions: A–B  A + + :B –

Agent Radical – possesses an unpaired electron (Cl ) Ionic: A) nucleophilic – possesses an electron pair that can be introduced into an electron-deficient substrate i) anions (H –, OH – ) ii) neutral molecules (NH 3, HOH) B) electrophilic – electron-deficient  accepts an electron pair when binding to a nucleophile: i) cations (Br + ) ii) neutral molecules (for example Lewis acids: AlCl 3 )

Lewis acids and bases Lewis base: acts as an electron-pair donor; for example ammonia: NH 3 Lewis acid: can accept a pair of electrons: AlCl 3, FeCl 3, ZnCl 2 – important in catalysis (form ions): CH 3 –Cl + AlCl 3  CH AlCl 4 -

Radical substitution 1. Initiation – formation of radicals: H 2 O  OH + H 2. Propagation – radicals attack substrates making new molecules and new radicals: CH 3 CH 2 R + OH CH 3 CHR  CH 3 C–O–O 3. Termination – radical recombines with another and the reaction is terminated H CH 3 CH 2 R - here: lipid peroxidation -H 2 O O2O2 CH 3 C–OOH R HR CH 3 CHR + fatty acid

Nitrotyrosine formation Nitrotyrosine is being formed in tissue damage caused by the reactive nitrogen species (RNS) RNS arise from NO, which is produced by nitric oxide synthase: arginine citrulline

RNS & nitrotyrosine

Electrophilic substitution Electron-deficient agent attacks the substrate with a higher electron density; the substrate retains the original bonding electron pair: R–X + E +  R–E + X + Typical for aromatic hydrocarbons Chlorination, nitration… :  -complex  -complex

Electrophilic substitution using Lewis acids Often used in order to incorporate an alkyl: C6H6C6H6 AlCl 3 + HCl +AlCl 4 -

Iodination of tyrosine in biochemistry - at the beginning of the synthesis of T 3, T 4 :

Mesomeric effects Permanent shift of  -bond electrons in compounds where a double bond neighbours upon an atom (group) with an electron pair or electron deficiency, respectively Positive mesomeric effect (+M) is caused by atoms/groups that „push“ electrons to neighbouring atoms: –NH 2, –OH, – SH Negative mesomeric effect (–M) is caused by atoms/groups that withdraw electrons of the neighbouring double/triple bond: –NO 2, –SO 3 H, –COOH

Electrophilic substitution & M effect Substituents exhibiting the +M effect: attached to the benzene ring, facilitate the subsequent substitution, favouring the ortho, para positions : Substituents exhibiting the –M effect slow down the subsequent substitution, favouring the meta position:

Inductive effect Permanent shift of  -bond electrons in the molecule comprising atoms with different electronegativity:  – I effect is caused by atoms/groups with high electronegativity that withdraw electrons of the neighbouring atoms: – Cl, – NO 2 :  +I effect is caused by atoms/groups with low electro- negativity that increase electron density in their neighbourhood; metals, alkyls:  + <  + <  +  -

Nucleophilic substitution Electron-rich nucleophile introduces an electron pair into the substrate; the leaving atom/group departs with an electron pair: |Nu – + R–Y  Nu–R + |Y – Nucleophiles: HS –, HO –, Cl – ++

Electrophilic addition Typical for alkenes and alkynes Markovnikov´s rule: the more positive part of the agent is attached to the carbon atom (of the double bond) with the greatest number of hydrogens: cis addition: both new bonds form on the same side of the alkene trans addition: new bonds are formed on opposite sides of the alkene

Nucleophilic addition In compounds with polar double bonds, such as C=O, where carbon carries  +: Nucleophiles: water, alcohols Addition of an alcohol to the carbonyl group yields a hemiacetal: hemiacetal

Hemiacetals in biochemistry: monosaccharides glucose

Elimination In most cases, the two atoms/groups are removed from the neighbouring carbon atoms and double bond is formed (  -elimination) Dehydration – elimination of water: 2

Dehydration in biochemistry (in glycolysis) 2-phosphoglycerate phosphoenolpyruvate

Rearrangement In biochemistry: often a migration of a hydrogen, changing the position of a double bond; isomers are formed Aldose-ketose isomerization in monosaccharides: aldose ketose in glycolysis (catabolism of glucose)