Chemistry of C-C π-bonds. Lectures 5-8: Aromatic Chemistry

Transcription

1 Chemistry of C-C π-bonds Lectures 5-8: Aromatic Chemistry I was sitting writing on my textbook, but the work did not progress; my thoughts were elsewhere. I turned my chair to the fire and dozed. Again the atoms were gamboling before my eyes. This time the smaller groups kept modestly in the background. My mental eye, rendered more acute by the repeated visions of the kind, fitted together all twining and twisting in snake-like motion. But look! What was that? ne of the snakes had seized hold of its own tail, and the form whirled mockingly before my eyes. As if by a flash of lightning I awoke; and this time also I spent the rest of the night in working out the consequences of the hypothesis. Let us learn to dream, gentlemen, then perhaps we shall find the truth... But let us beware of publishing our dreams till they have been tested by waking understanding andout 2 Dr Martin Smith ffice: CRL 1 st floor Telephone: (2) martin.smith@chem.ox.ac.uk

2 The Chemistry of C-C π bonds Aromatic Chemistry Benzene Preparation and general reactivity profile What is aromaticity? Resonance and molecular orbital explanations Reactivity Typical reactivity electrophilic aromatic substitution Mechanisms of electrophilic substitution bromination as a worked example itration, Sulfonation riedel Crafts Alkylation and Acylation Reminder: cation stability through hyperconjugation and delocalization Gatterman-Koch ormylation Monosubstituted Benzenes Phenol acidity Benzoic acid preparation and acidity Aniline preparation and basicity Reactions of Monosubstituted Benzenes Electrophilic Aromatic substution: ortho-, meta- and para- Substituent effects: (i) ortho- and para- directing and ACTIVATIG Energy Profiles and the ammond Postulate (ii) ortho- and para- directing and DEACTIVATIG inductive effects (iii) meta- directing and DEACTIVATIG Reactions of Monosubstituted and Polysubstituted Arenes Substituents affect both rate and orientation Designing synthetic routes The ordering of synthetic steps is important Multiple substitutions: effects of orientation (which group dominates?) Transforming functional groups in aromatic chemistry Diazonium salts Generation and Stability The S 1 reaction for aromatic compounds

3 Books The Chemistry of C-C π bonds Introducing Iodine (via a radical mechanism) Introducing luorine (the Balz-Scheimann reaction) The Sandmeyer reaction (introduction of C, and ) Replacement with (not as pointless as it appears!) ucleophilic Aromatic Substitution Mechanistic considerations An addition-elimination process (compare with conjugate addition-substitution) Evidence for anionic intermediates Substituent effects (which groups work and which ones don t?). Real Examples: Synthesis of luoxetine (Prozac) Synthesis of Vancomycin Textbooks: [1]. rganic Chemistry, ayden, Greeves, Wothers and Warren, UP, Chapter 22 [2]. Aromatic Chemistry by Malcolm Sainsbury, xford Chemistry Primers, UP, Comments, questions and queries welcome.

4 The Chemistry of C-C π bonds Aromatic Chemistry Benzene Typical reaction: Electrophilic Aromatic Substitution: E + E Example: alogenation + e 3 + Compare reactivity of benzene with the reactivity of an isolated alkene in a bromination reaction: + - Conclusion: benzene is less reactive than an isolated (cyclic) alkene (why?)

5 The Chemistry of C-C π bonds Benzene contains [4n+2] π electrons and is aromatic also drawn as: a continuous system through overlap of 6 p-orbitals The formation of a continuous π system through the overlap of 6 p-orbitals is a stabilizing interaction ow much is this aromatic stability worth? Examine hydrogenation an exothermic reaction (as the products are thermodynamically more stable than the starting materials) Conclusion:

6 The Chemistry of C-C π bonds omination gives a substitution rather than an addition product Mechanism? - e 3 + Stabilization of the cationic intermediate by delocalization (sometimes called resonance ) Evidence for the cationic intermediate [for reference, δ C (benzene) = 128.5] 13 C MR: o, p- carbons very deshielded

7 The Chemistry of C-C π bonds Reaction Energy Profile TS 1 TS 2 E + Starting materials Products reaction progress Reminder: An intermediate can be directly observed (and often isolated!) We cannot directly look at the TS, so we make assumptions about what the TS looks like based on the ammond Postulate: If two states, as for example a transition state and an unstable intermediate, occur consecutively during a reaction process and have nearly the same energy content, their interconversion will only involve a small reorganisation of molecular structure. This is an elegant way of saying: the transition state (probably) looks like an intermediate close to it in energy

8 The Chemistry of C-C π bonds ther common electrophilic substitution reactions: itration (E = 2 ) Electrophile is 2 + S 2 ther common electrophilic substitution reactions: Sulfonation (E = S 3 ) S S S 2 S S S

9 The Chemistry of C-C π bonds At high temperatures sulfonation is reversible S 3 2 S C S 3 ther common electrophilic substitution reactions: riedel Crafts Alkylation (R = alkyl) R Al 3 R Al 3 R R Rearrangement and polysubstitution Al 3 catalytic Al 3

10 The Chemistry of C-C π bonds Alkyl groups are electron-donating through hyperconjugation (so the starting materials are more reactive than the products) 'hyperconjugation' or σ-conjugation - one of the C- bonds interacts with the π system [C- must be perpendicular to the plane of the ring for the C- σ orbital to overlap with the π system] this means that alkyl groups are electron donating and means that alkyl substituted benzenes are MRE reactive than unsubstituted benzenes Cation stability a reminder 1. yperconjugation Planar Structure C 3 empty p orbital π-conjugation - [ resonance is a shorthand way of describing how the molecular orbitals overlap leading to delocalization] also drawn as: remember: the bonds are not 'moving' the cation is delocalized over these three atoms

11 The Chemistry of C-C π bonds riedel-crafts acylation Al Acylium Cation R R Al 3 R R R anhydride R R ow to introduce alkyl groups on an aromatic ring (if C alkylation does not work): Use riedel-crafts acylation and reduce the ketone functional group Target: Problem with C alkylation: Al 3 plus other products of rearrangement and polyalkylation Al K, heat Wolff-Kishner reaction

12 The Chemistry of C-C π bonds Gatterman-Koch formylation (a special riedel-crafts type reaction): Al 3 C Cu C C Monsubstituted Benzenes So far: Y Y = alogen, 2, S 3, Alkyl, acyl (aldehyde, ketone) Phenol (Y = ) Phenol an extremely stable enol Acidity: compare with non aromatic alcohol: pka = pka = A reminder (and brief aside): pka is a measure of the position of the equilibrium between an acid and its conjugate base A (aq) + 2 (l) 3 + (aq) +A - (aq)

13 The Chemistry of C-C π bonds Most important factor in acid strength is the stability of the conjugate base A - So for a strong acid, the conjugate base A - is stable, the equilibrium lies over to the RS and the pka is low. The stronger the acid, the lower the pka A few representative examples: 3 C 2 pka Et 12 Et C Acidity of Phenol vs cyclohexanol Most important to consider the stabilities of the anions 1. Delocalization The lone pair in a p-orbital on oxgen, which is perpendicular to the plane of the ring, can interact with the pi system.

14 The Chemistry of C-C π bonds Delocalization (continued) we can draw this as: [Remember the charge is not actually moving around the ring] 2. An inductive effect The aromatic substituent is sp 2 hybridized (vs sp 3 hybridized in cyclohexanol) and hence has more s character. The higher proportion of s character means that the electrons see more effective nuclear charge [cf radial probability functions]. Y = C 2 (benzoic acids) Prepared by: (i) oxidation of toluene C 2 C 2 (ii) Grignard reaction with C 2 Mg C C 2 then +

15 The Chemistry of C-C π bonds Benzoic acid pka = 4.2 (compare with acetic acid C 3 C 2, pka 4.8) C 2 C 2 Y = 2 (anilines) Prepared by: Reduction of nitro compounds Basicity: Aniline is less basic than cyclohexylamine pka = 10.7 pka = 4.6 Two effects: Delocalization Inductive effect 2 2 2

16 The Chemistry of C-C π bonds Reactions Electrophilic aromatic substitution. ow do substituents affect reactivity? Y E+ Y Y Y E E E The nature of Y affects both orientation (o- vs m- vs p-) and rate of reaction 1. rtho- and para- directing, and ACTIVATIG groups Typically: Y = alkyl, 2, R 2 (R = alkyl), CR,, R, CR) Me Me Me Me The Me group is ACTIVATIG (the reaction goes 10 9 times faster than it does with benzene) why? [activation energy is effectively the energy required to overcome the barrier to reaction]

17 The Chemistry of C-C π bonds TS 1 TS 2 Activation energy Intermediate E Y Starting materials Y Products E o, m, p reaction progress To predict reactivity we need to look at the nature of the TS - We can do this using the ammond Postulate: The transition state looks like an intermediate close to it in energy Therefore: consider intermediates in this reaction rtho-: Me Me Me Me -+ Me

18 The Chemistry of C-C π bonds Meta: Me Me Me Me -+ Me Para: Me Me Me Me -+ Me Relating this to the TS energy :

19 The Chemistry of C-C π bonds benzene higher in energy TS 1 m- higher in energy TS 2 E o-, p- similar in energy Intermediate Starting materials Products reaction progress Therefore: more stable intermediate formed faster, and ortho- and para- products predominate 2. rtho- and para- directing, and DEACTIVATIG groups Typically: Y =,,, I (these groups withdraw and donate electrons) e 3 alogens withdraw electrons via an inductive effect (this affects the rate) and donate through the unsaturated system (this affects orientation and is sometimes called a mesomeric effect).

20 The Chemistry of C-C π bonds Consider ortho- e 3 -+ TS 1 m- higher in energy TS 2 E o-, p- similar in energy Intermediate benzene lower in energy Starting materials Products reaction progress Conclusions:

21 The Chemistry of C-C π bonds Meta- directing, and DEACTIVATIG groups Typically: 2, S 3, almost all carbonyl compounds (C 2, C 2 R, C, CR) C 2 Me C 2 Me C 2 Me C 2 Me S Consider ortho- and meta- C 2 Me C 2 Me2 C 2 Me C 2 Me o-, p- higher in energy TS 1 TS 2 E m- lower in energy benzene lower in energy Intermediate Starting materials Products reaction progress

22 The Chemistry of C-C π bonds Designing a simple synthetic route: substituent effects are important for selectivity and efficiency C 2 2 C 2 2 or or 2 All cheap and readily available Which is the best starting material? Consider monosubstituted starting materials: C 2 2 Me group activating o, p - directing Choice of starting material: 3 2 S % para- 59% ortho-

23 The Chemistry of C-C π bonds The order of reactions in a synthetic sequence can be important C 2 RUTE 1 C 3 group o- & p- directing 2 C 2 Which route is best? group m-directing RUTE RUTE 1 : xidation then nitration C 2 C 2 C 2 KMn S Conclusion:

24 The Chemistry of C-C π bonds RUTE 2: itration then oxidation 3 2 KMn4 C S Conclusion: What about arenes with two or more groups? Which effects dominate? Examine the effects of individual substituents: electronically first, then consider steric effect (i) substituents direct to the same position Me Me Me C 2 Me 2

25 The Chemistry of C-C π bonds (i) substituents direct to conflicting positions oadly categorize substituents into 3 classes of decreasing effect 1. STRGLY activating and ortho- & para- directing (, R, 2 and R 2 groups) 2. Alkyl groups and halogens 3. All other meta- directors If substituents are in different classes, then the higher numbered class dominates. Me Me 2 3 C Me Me Me If substituents are in the same class then it is to be expected that mixtures will be produced (and hence that this is maybe not a good route to the proposed compound!) C 2 Me C 2 Me Important to remember that we can extend and modify these effects through functional group interconversion reactions: 2 2, Pd 2 a 2 (or Sn/) (aq.), 0 C

26 The Chemistry of C-C π bonds Diazonium salts: 2 2, Pd 2 a 2 (or Sn/) (aq.), 0 C Mechanism for generation: a a Effectively the S 1 mechanism for aromatic compounds (note: cation is not stable) Compare with S Ar reaction in the next lecture 2 sp 2 cation not stabilized by delocalization A useful reaction there is not a reagent for +

27 The Chemistry of C-C π bonds ther substituents may be introduced in this fashion: (i) iodine (probably a radical, rather than an ionic mechanism). Remember: single headed ('fish-hook') arrows indicate the movement of a single electron one electron two electrons I KI 2 I - I I I I - I I I I I 2 I I chain process continues (ii) luorine (the Balz-Schiemann reaction) 2 B 4 - a 2, B 3

28 The Chemistry of C-C π bonds (iii) The Sandmeyer reaction (to introduce, C) 2 - X a 2 aq. Cu X X =,, C Mechanism another radical reaction X Cu - X Cu(I) X Cu X Cu(II) X Recycle - catalytic in Cu Cu X Cu(I) inally: replacement by (not a good way to make benzene, but useful for directing other groups, though an outdated way to achieve this better methods available) - 2 P a 2-2 (g) 2 C aq. 2 C 2 C 2 C 2 used to direct orientation of bromination

29 The Chemistry of C-C π bonds ucleophilic Aromatic Substitution: S Ar (substitution nucleophilic aromatic) + + verall: substitution on an aromatic ring what is the mechanism? Mechanistic considerations: I. Cannot be S S 2 requires access to σ* orbital of C- bond (which is buried inside the aromatic ring) Therefore nucleophile ( - ) cannot get anti to the requisite C- bond Mechanistic considerations: II. Unlikely to be S 1 (compare with diazo compounds!) + S 1 X + Carbocation would be in an sp 2 orbital (and would not be stabilized by the aromatic ring) Compare with other cations we have seen: Cation not stabilized by delocalization

30 The Chemistry of C-C π bonds Mechanism: an addition-elimination reaction Remember: S 2 reactions at sp 2 centres (including aromatic rings) are very rare ur shorthand structures indicate that the charge is delocalized around the ring but is centred on the ortho and para positions is there evidence for this? or Anion (often called a Meisenheimer complex) 2 13 C MR: o, p- carbons very shielded In both cases the ionic charge is localized almost exclusively to the ortho and para positions Implication: groups to stabilize the anionic intermediates in S Ar reactions MUST be on these carbons

31 The Chemistry of C-C π bonds Compare with other addition-eliminations: (i) conjugate substitution of an amine [written as Ar 2 ] Et Et + heat Et Et Et 2 Amine nucleophiles prefer 1,4 addition Ar 2 -Et Et Et Ac Ar 2 Et Et Et verall addition-elimination mechanism (ii) conjugate substitution of an alcohol Me Ph Me Ph - Me proton transfer Me Ph Ph verall addition-elimination mechanism

32 The Chemistry of C-C π bonds Example of S Ar: RS Base SR - - SR nly the ortho chlorine is lost the meta one is retained urther confirmation: isolation of an intermediate (!) Me Me Me A stable molecule (structure confirmed by X-ray crystallography) Which (EWG) groups can accelerate nucleophilic aromatic substitution? So far we have seen the 2 group but other groups can also function in this regard u u u - So any group that can stabilize the negative charge in the intermediate can facilitate the reaction so carbonyl groups are effective too

33 The Chemistry of C-C π bonds ucleophilic aromatic substitution is generally fastest when the leaving group is fluoride. SLW AST u - RDS [breaks aromaticity] u [restores aromaticity] u Rate > > > I [compare with S 2: Rate I > > > ] The rate-determining step is attack of the nucleophile on the aromatic ring as this breaks the aromaticity. The second step, involving loss of the leaving group and restoration of aromaticity, is fast. Electronegative polarizes σ-bond and inductively withdraws electron density from the high energy anionic intermediate ote that the reaction is bimolecular in the RDS and therefore: Synthesis of luoxetine - serotonin uptake inhibitor for treatment of depression (marketed as Prozac ) 3 C + Ph Me a Me 2 Ac 3 C Ph Me a Me Me 3 C Ph 3 C Ph

34 The Chemistry of C-C π bonds Example of S Ar in the synthesis of a complex molecule: Synthesis of Vancomycin sugar Me 2 C C R R R a 2 C 3 2 C 2 R R R Me Me Me Me Me Me AST R R SLW R R 2 Regiochemistry in S Ar reaction: attacks at the centre substituted with the fluorine