Mechanisms of organic reactions mirka rovenskalfmotol cuni cz

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 (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: Al. Cl 3)

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. : Al. Cl 3, Fe. Cl 3, Zn. Cl 2. These compounds – important catalysts: generate ions that can initiate a reaction: CH 3–Cl + Al. Cl 3 CH 3+ + Al. Cl 4 -

Radical substitution - here: lipid peroxidation: 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 fatty acid – H 2 O CH 3 CHR O 2 • H R CH 3 C–O–O • CH 3 CH 2 R CH 3 CHR • + CH 3 C–OOH H R 3. Termination – radicals react with each other, forming stable products; thus, the reaction is terminated (by depletion of radicals)

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

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: δ+ < CH 3 δ+ CH 2 < δ+ δ- CH 2 Cl +I effect is caused by atoms/groups with low electronegativity that increase electron density in their vicinity: metals, alkyls: H δ+ δ+ H C δ- H δ+ CH 3 C

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

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

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:

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: + alcohol is produced Nucleophiles: HS–, HO–, Cl–

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: – carbon atom carries + Nucleophiles – water, alcohols, carbanions – form a covalent bond with the carbon atom of the carbonyl group: aldehyde/ketone used for synthesis of alcohols

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

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: – H 2 O In biochemistry – e. g. in glycolysis: 2 -phosphoglycerate phosphoenolpyruvate

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 dihydroxyacetonphosphate enol form glyceraldehyd 3 -phosphate