Mechanisms of organic reactions

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 (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)

5. Lewis acids and bases • 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- ••

6. Radical substitution - here: lipid peroxidation: • 1. Initiation – formation of radicals: H2O  OH• + H• • 2. Propagation – radicals attack neutral moleculesgenerating 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 CH3C–OOH CH3CHR + • H R

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 usedto attach an alkyl to the benzene ring(Friedel-Crafts alkylation): benzene carbocation bromobenzene

9. δ+ <δ+ <δ+ δ- CH3 CH2 CH2 Cl δ+ H CH3 δ+ δ- H C CH3 C δ+ H CH3 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:

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: –NH2, –OH, halogens • Negative mesomeric effect (–M) is caused by atoms/groups that withdraw π electrons from the system: –NO2, –SO3H, –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, –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

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, –NO2) 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. aldehyde/ketone 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 + used for synthesisof alcohols

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

18. 2-phospho-glycerate phosphoenol-pyruvate 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

19. glucose(keto form) enol form fructose 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: dihydroxyaceton- phosphate glyceraldehyd- 3-phosphate enol form