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

2. 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

3. 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 –

4. 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 (NH 3, HOH) B) electrophilic – electron-deficient  bind to substrate centres with a higher electron density: i) cations (Br + ) ii) neutral molecules (for example Lewis acids: AlCl 3 )

5. Lewis acids and bases Lewis base: acts as an electron-pair donor; e.g. ammonia: NH 3 Lewis acid: can accept a pair of electrons; e.g.: AlCl 3, FeCl 3, ZnCl 2. These compounds – important catalysts: generate ions that can initiate a reaction: CH 3 –Cl + AlCl 3  CH 3 + + AlCl 4 -

6. Radical substitution 1. Initiation – formation of radicals: H 2 O  OH + H 2. Propagation – radicals attack neutral molecules generating new molecules and new radicals: CH 3 CH 2 R + OH CH 3 CHR CH 3 C–O–O 3. Termination – radicals react with each other, forming stable products; thus, the reaction is terminated (by depletion of radicals) H CH 3 CH 2 R - here: lipid peroxidation: – H 2 O O2O2 CH 3 C–OOH R HR CH 3 CHR + fatty acid

7. 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.

8. 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

9. 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, –NO 2 : +I effect is caused by atoms/groups with low electronegativity that increase electron density in their vicinity: metals, alkyls: CH δ+δ+ δ-δ- H δ+δ+ H δ+δ+ C CH 3 CH 3 CH 2 CH 2 Cl δ+ < δ+ < δ+ δ-

10. 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: –NH 2, –OH, halogens Negative mesomeric effect (–M) is caused by atoms/groups that withdraw π electrons from the system: –NO 2, –SO 3 H, –C=O

11. 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, –NH 2 b) only +I…alkyls deactivating – withdraws electrons from the aromatic ring, thus making the electrophilic substitution slower: a) –M and –I… –C=O, –NO 2 b) – I > +M…halogens

12. 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, –NO 2 ) direct the next substituent to the meta position:

13. 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

14. 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:

15. 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:

16. 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: used for synthesis of alcohols – carbon atom carries  + aldehyde/ketone

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

18. 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: 2-phospho- glycerate phosphoenol- pyruvate – H 2 O

19. 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 glyceraldehyd- 3-phosphate enol form