REACTIVE INTERMEDIATES IN SYNTHETIC ORGANIC CHEMISTRY Carbon atoms in stable - hence relatively unreactive - carbon compounds have the following characteristics: (1) Closed (i.e. octet) valence shells - 8 electrons in the carbon valence shell - 4 covalent bonds - hence no vacant or singly-filled low energy orbital to allow attack by electron-donors. (2) Neutral, i.e. no overall charge - hence no very strong electrostatic driving force for attack by nucleophiles or electrophiles. (3) Bond angles appropriate for the hybridisation involved - i.e. ca. 109° 28' for sp3, ca. 120° for sp2 and 180° for sp - hence no serious bond-strain. Moderate deviations from these criteria lead to compounds with greaterthan-normal reactivity: H2 C H2C CH2 3 109º 28' (sp ) H2C CH2 Raney Ni > 200° No reaction C H2 H2 C 60º (sp3) H2C H2 C CH2 Raney Ni 120° H3C CH3 Species with large deviations from these criteria - such as carbanions, R–, or carbocations, R+, are usually too unstable to allow isolation but may show synthetically useful reactivity when generated as shortlived reactive intermediates in chemical reactions. The three reactive intermediates studied in this course are: Free radicals Carbenes and Arynes. ORGANIC FREE RADICALS: Organic Free Radicals: organic compounds which contain at least one unpaired electron. In the simplest cases an atom in the compound has only seven electrons in its valence shell and the unpaired electron is localised on either a carbon atom or on a heteroatom. Note the characteristic 'yl' termination of the systematic names for free radicals and the representation of the unpaired electron by a dot at the appropriate atom: CH4 CH3CH2CH3 (CH3)3CH (CH3)3C CH3 CH3• Methane n-Propane t-Butane OH t-Butanol SH Methanethiol CH3CH2CH2• (CH3)3C• Methyl n-Propyl t-Butyl (CH3)3C O• t-Butoxyl CH3 S• Methanethiy l Optimum geometry - planar - sp2 hybridised: C The norbornyl radical has considerably increased reactivity because ring-strain prevents the bridge-head carbon attaining the optimum planar geometry: • Preparation of Free Radicals: (1) Homolytic cleavage of weak single covalent bonds. or h R E E R R E• + •E R E = N, O, S, Halogen, etc. Note the use of 'fish-hook' single-headed curved arrows, i.e. indicate the movement of a single electron. Thermal cleavage: N-N, O-O, S-S, Cl-Cl, Br-Br, C-N, N-Cl, O-Cl, O-Br to ca. 130° O O O• 2 Di-t-Butyl peroxide Half-life at 150° ca. 1 h t-Butoxyl radical Ph O 2 Ph • O Benzoyl radical Ph O O 60-100° O O Di-Benzoyl peroxide Half-life at 100° ca. 30 min NC N N CN 60-100° Azobis(isobutyronitrile) 'AIBN' Half-life at 100° ca. 5 min 2 NC Ph• + CO2 Phenyl radical • + N N 2-Cyanoprop-2-yl radical Photolytic cleavage - compounds with low-energy electronic absorptions only: h Cl-Cl Ph Ph O O O h 2 Cl• 2 Ph O CH3 O C h CH3 R O N O R O Cl O • O O CH3 C• + Ph• + CO2 CH3• h R O• + NO• h R O• + Cl• (2) Redox reactions of non-radical precursors: Reduction. _• + Na CH3 O C CH3 + Na Na+ Naphthalide radical anion _ O Ketyl radical + • C Na anion CH3 CH3 Oxidation: Ar3N: + AgPF6 • 0 + [Ar3N•] [PF6]- + Ag Amminium radical cation Detection of Free Radicals: (1) Electron Spin Resonance (ESR) Spectroscopy. The degeneracy of spin of an unpaired electron is lifted in a strong magnetic field. E corresponds to microwave radiation. Hyperfine splitting due to electron-proton spin coupling aids structural interpretation. CH3• Quartet resonance _• Septet resonance • • etc. Octet resonance (2) Matrix Isolation: Free radicals generated and trapped in a radiation-transparent solid argon matrix at very low temperature may be studied spectroscopically: CH3 O O O CH3 O h Solid Argon 5-10 oK O H3C O + CH3 + CO2 Stability of Free Radicals: allylic ≈ benzylic > 3° alkyl > 2° alkyl > 1° alkyl Substitution effect - radical centres are electron-deficient, hence stabilised by attached electron releasing alkyl groups. Resonance effect: H2 C H C CH2• •H2C •CH2 H C CH2 CH2 • etc. The combination of electronic and steric effects can result in very stable - and, in suitable circumstances, even isolable - free radicals: H O• O 2,4,6-Tri-t-butylphenoxyl O• Galvinoxyl Characteristic Reaction Pathways of Free Radicals: (1) Dimerisation: R• + R• R R Leads to non-radical products - termination steps in radical chainreactions. (2) Radical abstraction: R• E C R—E + •C Ease of abstraction = I ≈ Br > H > Cl This can be a chain transfer process in radical mechanisms. (3) Disproportionation - one radical is oxidised by another: 2 CH3CH2CH2 H3C H2 C CH3CH2CH3 + CH3CH=CH2 CH2 CH2 + H CH CH3 H3C H2 C CH3 + CH2 H C CH3 Hydrogen abstraction from one n-propyl radical by the other results in the radical accepting hydrogen being reduced to an alkane. The radical losing hydrogen is simultaneously oxidised to an alkene. This leads to non-radical products - i.e. is a termination step in radical chain-reactions. (4) Radical addition to unsaturated structures: R H2 R C CH2 + CH2=CH2 This is a chain propagation step in radical chain-reactions. (5) Rearrangement: Despite what we might expect, simple free radicals do not normally undergo rearrangement: H + CH3 C CH 2 CH3 1° + C Very rapid CH3 CH3 - H migration 2e in migration system 3° H • CH3 C CH 2 CH3 1° • C H• migration CH2H CH3 CH3 CH2H 3° 3e in migration system The transition states for both rearrangements are very similar: * H CH3 CH3 CH2 * = + or • Consider the orbitals involved in the transition state: H 1s and 2 C 2p. 1s 2p 2p Combination of the H 1s and 2 C 2p atomic orbitals gives three molecular orbitals: (A) (B) (C) (A) is bonding for the hydrogen atom and both carbon atoms. (B) is bonding for the two C atoms but antibonding for the C2-H interaction. (C) is antibonding for the two C atoms. In addition there is no net interaction between the hydrogen atom and the two carbon atoms. (A) is the lowest energy orbital while (B) and (C) are approximately equivalent in energy. (B) (C) (A) Carbocation - 2e Favourable T.S. Rapid rearrangement (B) (C) (A) Radical - 3e Unfavourable T.S. No rearrangement -Unsaturated free radicals will undergo rearrangement with migration of the unsaturated group: • CH2 CH2 CH2 HC CH • CH C C • CH3 CH 3 CH2 CH2 CH3 C CH2 CH3 CH3 CH3 1° 3° Stable intermediate (6) Fragmentation: O Ar Ar• C + CO2 O• FREE RADICALS IN ORGANIC SYNTHESIS (1) Free Radical Substitution of Hydrogen by Other Atoms. (a) Photochemical halogenation of saturated hydrocarbons Cl2 h 2 Cl• CH3CH2CH3 + Cl• • CH3CHCH3 + HCl • CH3CHCH3 + Cl2 CH3CHClCH3 + Cl• • CH3CHCH3 + Cl• Initiation Propagation by chain transfer Termination