1. Prof M Wills1 Organic Chemistry year 1 2008-2009 Professor Martin Wills Email: m.wills@warwick.ac.uk Office: C504m.wills@warwick.ac.uk CONTENT OF LECTURES Substitution reactions at saturated carbon atoms: ‘S N 2 and S N 1’. Mechanisms of substitution reactions, intermediates, orbital structures, implications for stereochemistry, inversion and racemisation. Clayden et al, Chapter 17. Formation and reactions of alkenes: ‘E2 and E1’. Methods for making alkenes, structure and selectivity. Reactions of alkenes with electrophiles and nucleophiles. Oxidation and reduction reactions. Clayden et al. Chapters 19 and 20.

2. Prof M Wills2 What you should know – what you will learn What you should know by now: -Hybridisation (sp, sp 2, sp 3 ) of carbon atoms. -Orbital structure of C-C and C=C bonds. -E/Z and R/S definition and how to assign configuration. -Electronegativity and formal charge. -Organic reaction mechanisms – ‘arrow pushing’. -Factor which influence the stability of cations and anions. -Free energy and reaction profiles. What you will learn in this part of the course: -The detailed mechanisms of substitution reactions at saturated carbon atoms (S N 2 and S N 1 mechanisms). -Factors which influence the mechanisms of substitution reactions. -Methods for the formation of alkenes (E2 and E1 mechanisms ). -Reactions of alkenes. -Reduction and oxidation reactions of alkenes.

3. Prof M Wills3 Nucleophilic substitution reactions – overview: Why these reactions are important and some examples: What mechanisms could there be for this reaction? Can you define; the nucleophile, the electrophile, the leaving group. What is the role of the solvent? What solvents could be used? What about the counterion? Solvent

4. Prof M Wills4 Substitution reactions – some definitions. What is the significance of the ‘saturated carbon atom’. What ‘shape’ do the groups around this atom define? Which leaving groups can be used – what ‘drives’ the reaction? Key point: Good leaving groups are halides (Cl, Br, I), OSO 2 R, other groups which stabilise a negative charge.

5. Prof M Wills5 Mechanisms of substitutions reactions: S N 2 There are two major mechanisms of substitution reactions. The first is called the S N 2 mechanism – Substitution, Nucleophilic, Bimolecular: What do these three terms mean? It is a single step mechanism; the nucleophilic adds and the leaving group is simultaneously displaced in the same step. A concerted mechanism. Rate = k [nBuBr][nPrO - ] What happens if I double the concentration of bromide? What if I double the rate of bromide and of propoxide? Reaction co-ordinate. Energy Bromide (starting material) Ether (product)

6. Prof M Wills6 Mechanisms of substitutions reactions: S N 1 The second is called the S N 1 mechanism – Substitution, Nucleophilic, Unimolecular: What do these three terms mean? It is a two step mechanism; the leaving group leaves in the first step to form a cationic intermediate and the nucleophilic adds in the second step Rate = k [C 6 H 13 Br] i.e. [acetate (nucleophile)] is not featured What happens if I double the concentration of bromide? What if I double the rate of bromide and of propoxide? Energy Bromide (starting material) Acetate (product) Cation (intermediate)

7. Prof M Wills7 The transition state for S N 2 reactions: The S N 2 mechanism – structure of the transition state. What ‘shape’ do the groups around this atom define? *** Key point of nomenclature; it’s S N 2 not SN 2 *** This is important *** What is the hybridisation at this C atom? What does this symbol mean? Note partial bonds to nucleophile and leaving group. Nucleophile adds electron density to  * antibonding orbital.

8. Prof M Wills8 Stereochemical consquences of S N 2 reactions: The S N 2 mechanism – What happens at chiral centres: *** Key point of nomenclature; INVERSION *** This is important *** Key concept – inversion of configuration.

9. Prof M Wills9 *** Key point of nomenclature; RACEMISATION *** This is important *** Why are there two products now? What happened to the square brackets? What is the ratio of the products? Stereochemical consquences of S N 1 reactions:

10. Prof M Wills10 Nucleophilic substitution reactions: Summary. S N 1 and S N 2 The ‘1’ and ‘2’ refer to the molecularity of the reaction (the number of species in the rate Expression). S N 1 is a two step reaction. S N 2 is a one step reaction. S N 2 mechanisms go with inversion of configuration, S N 1 with racemisation. Make sure you understand the difference between an intermediate and a transition state. Other substitution mechanisms include the S N 2’ :

11. Prof M Wills11 Factors which influence S N 2 and S N 1 reactions: ‘If I do a substitution reaction, will it go through an S N 2 or S N 1 mechanism?’ i) Substrate structure. Steric hindrance and cation stability. E2 Competes? A primary halide is more likely to undergo S N 2, a tertiary S N 1. A secondary halide may do both.

12. Prof M Wills12 Other factors that increase cation stability. Cation stability can also be increased by an adjacent double bond or aromatic ring: However an adjacent benzyl or allyl group can also increase the rate of S N 2 reactions, by stabilising the transition state:

13. Prof M Wills13 ii) Effect of the solvent. Solvents which stabilise cations will tend to favour S N 1. For example dipolar aprotic solvents such as dimethylformamide (DMF) and dimethylsulfoxide (DMSO). iii) Effect of the nucleophile. In general, more reactive nucleophiles favour the S N 2 reaction. This is fairly logical. Factors which influence S N 2 and S N 1 reactions cont: iv) Effect of the leaving group; good leaving groups are needed for both mechanisms.

14. Prof M Wills14 S N 2 vs S N 1 – all aspects must be considered:

15. Prof M Wills15 Formation and use of the OTs leaving group (very common in synthesis): What is the mechanism, and why go to all this trouble, i.e. why is OH a poor leaving group? How else can it be Made into a good leaving group? Key point; Learn what a OTs (tosyl group) is – it will come up again!

16. Prof M Wills16 Examples of substitution mechanisms, and applications. Mitsunobu reaction – a modern reaction. Real life examples and applications in synthesis? How to make an unsymmetrical ether? More on epoxides in Dr Clark’s lectures. S N 2 reactions are generally more synthetically useful.

17. Prof M Wills17 Alkenes– reminder of structure and formation: Already discussed in Prof M. Shipman’s lectures: In the case of a carbon atom attached to three other groups (by two single bonds and one double bond) the single 2s and two2p orbitals mix (rehybridise) to form three sp 2 orbitals. These are all arranged at mutual 120 degree angles to each other and define a trigonal shape, the remaining p orbital projects out of the plane of the three sp 2 orbitals and overlaps with an identical orbital on an adjacent atom to form the double bond: The resulting structure is rigid and cannot rotate about the C=C bond without breakage of the bond between the p-orbitals (the  bond). The can be separated into E and Z configuration isomers. The  bond is much more reactive than the  bond – the bonds are not equivalent to each other.

18. Prof M Wills18 Alkynes – reminder of structure and formation: In the case of a carbon atom attached to two other groups (by one single bonds and one triple bond) the single 2s and one 2p orbitals mix (rehybridise) to form two sp orbitals. These are all arranged at mutual 180 degree angles to each other and define a linear shape, the remaining p orbitals projecting out from the sp orbital to overlap with identical orbitals on an adjacent atom to form the triple bond: Both  bonds in an alkyne are much more reactive than the  bond.

19. Prof M Wills19 Alkenes – formation: Most (but not all) alkene formation reactions involve an ELIMINATION reaction. Alkyne reduction is also important (see later). Key point – H from one carbon atom and a leaving group (typically a halide) from the adjacent carbon atom. Recap on alkene structure. Do you recall the orbital structure of an alkene? Can you use the Cahn-Ingold-Prelog rules to determine the configuration?

20. Prof M Wills20 Mechanisms for the formation of alkenes: E1 and E2: Most elimination reactions, to form alkenes, involve an E2 or E1 elimination. E2 = Elimination, bimolecular. It is a one-step reaction. A strong base is needed - why is this? Reaction co-ordinate. Energy Bromide (starting material) Alkene (product) Rate = k [Cyclohexylbromide][MeO-]

21. Prof M Wills21 E2 elimination – stereochemical implications: The ‘anti periplanar’ requirement. E2 reactions require correct orbital alignment in order to work. The optimal arrangement is ‘anti periplanar’, where the ‘H’ and ‘Br’ (in an alkyl bromide) are anti to each other. Which base would you use?

22. Prof M Wills22 E2 elimination – stereochemical implications: orbital alignment: Orbital alignment in E2 elimination reactions: The alignment of  and  * orbitals in the substrate leads to a smooth transition to a  bond in the product. Which is the most likely product?

23. Prof M Wills23 The E1 elimination mechanism: E1 = Elimination, unimolecular. It is a two-step reaction. It proceeds via a cationic intermediate. Reaction co-ordinate. Energy Bromide (starting material) Alkene (product) Rate = k [Methylcyclohexylbromide] Cation (intermediate) Why does the substrate now have an extra methyl group? Why was a weak base used in this reaction? Triethylamine (Et 3 N) is a weak base.

24. Prof M Wills24 Nature of the intermediate in an E1 reaction: E1 reactions proceed through a ‘flat’, i.e. trigonal, cation (like S N 1 reactions). Sometimes multiple products are formed (irrespective of mechanism)– What products would you predict from this reaction (more than one is possible)?

25. Prof M Wills25 Formation of alkenes by elimination of alcohols: See if you can write the mechanism for the following (E1) reaction: Why is acid needed when the alcohol is the leaving group – why can’t we rely on a base? What other alkene product can be formed, and how? What would be the effect of using a base and an acid in the following? E1 cb ‘conjugate base’ is less common mechanism, but important.

26. Prof M Wills26 Some alternatives to ‘simple’ elimination – the Wittig reaction: The Wittig reaction is one of a number of reaction that provide a means for controlling where the double bond ends up. Key point: this is important – learn it

27. Prof M Wills27 Some alternatives to ‘simple’ elimination – the Wittig reaction (this is important – learn it) Here is the mechanism of the Wittig reaction (you need to complete it). You sometimes see an alternative mechanism:

28. Prof M Wills28 Substitution vs elimination, base vs nucleophile: Sometimes a particular substrate can undergo a substitution or an elimination reaction. The outcome depends on all the factors involved in the reaction; The ‘is an alkoxide a nucleophile or a base?’ question. Answer - depends what it does:. The most important factor is probably the substrate structure – deprotonation may outpace nucleophilic addition when a substrate is very hindered. Certain substrates cannot undergo elimination reactions.

29. Prof M Wills29 Reactions of alkenes with electrophilic reagents - bromine: Alkenes are electron rich (in the  system) and react with electrophilic reagents: The mechanism is as follows, the intermediate is a bromonium ion:

30. Prof M Wills30 Further additions of electrophiles to double bonds - HBr: Hydrogen halides (HCl, HBr) also add across double bonds. The mechanism involves the addition of a proton first (with the electron-rich alkene), then the bromide. This is logical, because the alkene is electron rich.

31. Prof M Wills31 Regioselectivity of electrophilic additions to alkenes: Addition of HCl and HBr (and other acids) across unsymmetric alkenes results in formation of the more substituted halide (via the more substituted cation). The mechanism involves the addition of a proton first, as before, but in this case the unsymmetrical intermediate has a larger density of positive charge at one end.

32. Prof M Wills32 Acid catalysed hydration (addition of water) to alkenes: Acid catalysed hydration (addition of water) is a very important reaction of alkenes: The mechanism involves the addition of a proton first, as before, followed by addition of water, the regioselectivity is the same as for addition of HCl: This mode of addition of H 2 O is referred to as ‘Markonikov’ selectivity (i.e. formation of the MOST substituted alcohol via the MOST substituted cation.

33. Prof M Wills33 Oxymercuration of alkenes with Hg(OAc) 2 gives Markovnikov product. Mechanism…

34. Prof M Wills34 Radical reactions of alkenes: HBr in diethylether containing peroxides. Mechanism (Clayden et al p 1033-1035)

35. Prof M Wills35 Radical reactions of alkenes - intramolecular radical cyclisation reactions: Intramolecular radical reactions :

36. Prof M Wills36 Nucleophilic additions to C=C bonds – require nearby electron withdrawing groups (‘ewg’). The polar effects of C=O bonds can be transmitted through adjacent C=C bonds, e.g. The oxygen atom drives the reaction- it is more likely to gain a negative charge because it is more electronegative than adjacent atoms. An enone: (a compound with a directly linked C=C and C=O double bond) can react with a nucleophile at either the C of the C=O bond or at the C at the end of the C=C bond. This is called conjugate addition, 1,4-addition and/or ‘Michael’ addition. More on this from Prof Challis later in course.

37. Prof M Wills37 Polymerisation of alkenes/reactions of alkynes. Alkenes/Alkynes Another important reaction of alkenes is polymerisation, which is often radical-initiated: Alkynes are capable of many of the same reactions as alkenes, but twice if enough reagent is used, e.g. addition of bromine: More on polymerisation later in the course (Professor Haddleton).

38. Prof M Wills38 Cycloaddition reactions of alkenes: The Diels-Alder reaction. Complete the diagram below: Stereochemistry: Bonds are formed on one face of the alkene, hence there is a high degree of stereocontrol.

39. Prof M Wills39 Alkene hydroboration reaction (important)!

40. Prof M Wills40 Hydroboration mechanism – to be completed in lecture:

41. Prof M Wills41 Reduction reactions of alkenes: and alkynes, stereochemistry – formation of cis alkenes by hydrogenation. The reduction takes place on a surface, and the hydrogen is transferred to one side of the alkyne.

42. Prof M Wills42 trans Alkenes can also be formed from alkynes: This is commonly known as ‘reducing metal’ reduction. It works by a mechanism in which ‘electrons’ are generated from the metal. Li, K and Mg are also sometimes used. Here is the mechanism: tBuOH is often used as a source of protons.

43. Prof M Wills43 Reduction of alkenes to alkanes – hydrogenation most commonly used: Commonly used Metals: Commonly used Supports: Stereochemistry: Why use a support, how does the reaction work?

44. Prof M Wills44 Hydrogenation of alkenes to make margarine: Saturated fats have high melting points because they pack more efficiently. Polyunsaturated fats are regarded as healthier than saturated ones but tend to be liquids so They are partially hydrogenated to make margarine – solid but still with double bonds in..

45. Prof M Wills45 Alkene oxidation reactions: Alkene oxidation reactions can give epoxides, diols, or even ketones from complete cleavage of the alkene. What is the structure of ozone? Why might these products be useful?

46. Prof M Wills46 Epoxidation of alkenes using peracids: This is one of the best mechanisms!

47. Prof M Wills47 Ozonolysis of alkenes cleaves the double bond:

48. Prof M Wills48 Alkene dihydroxylation: Note – OsO 4 is expensive and very toxic. Better to use it catalytically (how would you do this?).

49. Prof M Wills49 The Wacker Oxidation: This is a commercial reaction used on a large scale in industry. The CuCl 2 and O 2 reoxidise the PdCl 2 (Pd is expensive).

50. Prof M Wills50 What you should understand and know: MECHANISM OF REACTIONS AT SATURATED CARBON ATOMS The mechanisms and stereochemical implications of S N 2 and S N 1 reactions. Inversion with S N 2, racemisation with S N 1. Factors which determine the likely pathway. Alternative leaving groups. Examples of applications in synthesis. SYNTHESIS AND REACTIONS OF ALKENES (C=C) E1 and E2 elimination mechanisms. Stereoselective alkene synthesis from alkynes by hydrogenation and dissolving metal reduction; Wittig reaction including ylid formation and mechanism; hydrogenation of alkenes; epoxidation, dihydroxylation and ozonolysis of alkenes; hydration and hydroboration of alkenes; Wacker oxidation; Diels-Alder cycloaddition.