2. Part 3iii CHM1C3 Substitution Reactions: Structure of Substrate

3. Content of Part 3iii The Effect of  -Substituents on the Rate of S N 2 Reactions The Effect of  -Substituents on S N 2 Structural Changes leading from S N 2 to S N 1 Mechanism The Trityl Carbocation The Alkyl and Allyl Cation: S N 1 Reactions Alkyl Halides and Vinyl Halides Comparison Bridge Headed Structures: The Carbocation Structure

4. After completing PART 4iii of this course you should have an understanding of, and be able to demonstrate, the following terms, ideas and methods. (i)Understand how reactions that proceed via an S N 2 mechanism have rates that decrease as the number and size of substituents increase on the  and  -positions, (ii)Understand that structurally homologous series of substrates under the same experimental conditions (temperature and solvent) can undergo different substitution reaction mechanisms, (iii)Understand that any structural factors that stabilise the carbocation (+I inductive or resonance) will promote S N 1 reaction mechanisms, (iv)Understand the structure of the trityl cation, (v)Understand the structure of the allyl cation relative to the alkyl cation, (vi) Understand the structure of the vinyl cation relative to the alkyl and allyl cations. (vii) Understand why the allylic halides are much more reactive toward nucleophiles than alkyl halides, and – Learning Objectives Part 3iii – Substitution Reactions: Structure CHM1C3 – Introduction to Chemical Reactivity of Organic Compounds–

5. Effect of Substituent Changes on the Substrate Changing the substituent on a substrate can (i) Affect the reaction rate (ii) Result in a change in reaction mechanism

6. The Effect of  -Substituents on the Rate of S N 2 Reactions Solvent: EtOH Nucleophile: Br: - Rel. Rate 0.000022 Rel. Rate 1 Rel. Rate 0.027 Rel. Rate 0.00049 All Rates = k[R-Cl][Br - ] 

7. S N 2 Rate decreases Steric Argument The Electrophilic carbon centre becomes more hindered to attack by the nucleophile as the H’s are replaced by Me’s (or alternative way of understanding is to consider the pentavalent transition states becoming higher in energy as they become sterically more crowded). Electronic Argument The partial positive charge decreases on the electrophilic carbon as the number of +I Me inductive groups increases, thus the electrophilic carbon becomes less reactive towards nucleophiles.

8. Rate = [R-Br][OEt - ] 1 0.28 0.03 0.0000042    The Effect of  -Substituents on S N 2 Relative Rate

10. S N 2 to S N 1 Mechanism Solvent: EtOH/H 2 O Nucleophile: OH: - ~Rel. Rate 1000 ~Rel. Rate 100 ~Rel. Rate 10 ~Rel. Rate 1

11. Log Rate SN2SN2SN1SN1 Rate = k[R-Br][OH - ]Rate = k[R-Br]

12. Sterically the most accessible carbon centre. Thus, the nucleophile can attack unhindered + I inductive effect of the Me group results in lower partial positive charge character on the substituting carbon. Thus, less reactive carbon S N 2 Rate Decreases Steric Argument Electronic Argument

13. S N 1 Rate Increases Only 2 +I inductive Me groups stabilising the carbocation 3 +I inductive Me groups stabilising the carbocation, therefore forms the fastest

14. SN2SN2SN1SN1 Rate = k[R-Cl][H 2 O]Rate = k[R-Br] S N 2/S N 1 Mixed Rate S N 2 to S N 1 Mechanism CH 3 C(O)CH 3 /H 2 O Solvent System H 2 O is the nucleophile

15. Why is the transition from S N 2 to S N 1 Earlier? Benzyl Cation The positive charge can delocalised into the aromatic ring via conjugation of the p-orbitals. The cation stabilising effect of a Ph group must be greater than the stabilising effect of a Me group, as the S N 2 to S N 1 transition is earlier.

16. The Trityl Carbocation Stereoelectronic Stability Arguments The trityl cation is very stable because the positive charge can be delocalised over all three rings through 10 different resonance structure, placing the + charge on the circled atoms. Steric Argument Electronic Argument These pairs of H’s would occupy the same position in space if the structure was perfectly planar. Thus, rings have to twist out of plane to give a propeller 3D structure. This limits the amount of delocalisation of the central p-orbital. Therefore, a trityl cation is not three times as more stable as a benzyl cation!

18. The Alkyl and Allyl Cation: S N 1 Reactions Rel Rate 1 <<< 1

19. Alkyl Cation Allyl Cation 1 + I inductive effect stabilising the cation Cation stabilised by conjugation over three atoms Inductive effects weaker than resonance effects Revise Reactive Intermediates notes wrt Carbocations

20. A key point to take away from this part of the course is that you have to start to examine both steric, and electronic arguments when you consider chemical reactions. KEY POINT: Steric and Electronic Considerations And to appreciate that in many instances they predict differing outcomes!

21. – Summary Sheet Part 3iii – Substitution Reactions: Structure CHM1C3 – Introduction to Chemical Reactivity of Organic Compounds– Detailed analysis and correlation of the structure of substrates which undergo nucleophilic substitution reactions and the reaction mechanism type (S N 1 or SN 2 ) enables a deeper understanding of these proposed reaction mechanism types. It is found that when experimental conditions only permit S N 2 reactions (low dielectric solvents) the reaction rate decreases as the size and number of the substituents increases on the  - and  - positions to the leaving group. The reason for this decrease in rate is due to the hindrance these substituents cause at the electrophilic carbon centre, inhibiting the nucleophile from attacking it. Alternatively, one can consider that the energy of the transition state will increase as the number and size of the  - and  -substituents increase: the pentavalent transition state will become increasingly sterically crowded, and therefore raised in energy In the above paragraph, only steric arguments were considered (i.e. the size and number of groups), however, electronic effects are also very important. For example, substituents that are able to stabilise carbocations, such as alky groups via there +I inductive effects or aromatic group via charge delocalistion through resonance, will promote S N 1 reaction types. It is interesting to compare and contrast the reactions of alkyl and allyl with nucleophiles. Allyl halides react more easily than do alkyl halides. To understand such differences in reactivity requires a detailed understanding of the electronic structure and hybridisation of the electrophilic carbon centres. The allyl halide very readily undergoes heterolytic cleavage of the C-Hal bond as the resulting carbocation (the allyl cation) is resonance stabilised. The alkyl halides do not have such resonance stabilised carbocations, thus reaction conditions which promote S N 1 reaction types are slow for these substrates.

22. Exercise 1: Substitution Reactions 12 Rationalise why compound 1 undergoes substitution reaction with nucleophiles readily, whereas compound 2 is inert.

23. Answer 1: Substitution Reactions 12 Rationalise why compound 1 undergoes substitution reaction with nucleophiles readily, whereas compound 2 is inert. S N 2 Conditions: Nucleophile attack trajectory from behind the C-Br bond is possible in 1, but is impossible in 2, as result of the bridging carbon atom. S N 1 Conditions: The planar carbocation structure is obtainable with compound 1 (indeed the charge can be stabilised into the three rings through resonance). However, the carbocation resulting from the heterolysis of the C-Br bond in 2 is not able to attain the sp 2 hybridised structure which will lead to delocalistion of the charge. Blocked Rigid structure does not allow planarisation to an sp 2 hybridised carbocation The p-orbital is at 90 o to the  -orbitals, therefore no resonance stabilistion

24. The alkyl chlorides D, E and F undergo nucleophilic substitution reactions in which the rate equation is only dependent on the concentration of alkyl bromide. Alkyl bromide E reacts the fastest and alkyl bromide F reacts the slowest. Rationalise these observations. Exercise 2: Substitution Reactions

25. The alkyl chlorides D, E and F undergo nucleophilic substitution reactions in which the rate equation is only dependent on the concentration of alkyl bromide. Alkyl bromide E reacts the fastest and alkyl bromide F reacts the slowest. Rationalise these observations. Rate equation indicates that the reaction mechanism is S N 1 in nature, i.e. all go by a carbocationic reactive intermediate. 2 o alkyl cation 3 o alkyl cation Both can attain planar sp 2 geometry. 2 o alkyl cation less stable than 3 o alkyl cation, based on the number of +I alkyl inductive groups. Therefore, E reacts faster than D Can not attain planar sp 2 geometry easily because of bridging ethylene group. Thus, it forms very slowly. Therefore, F reacts the slowest despite being a 3 o alkyl cation. Answer 2: Substitution Reactions

26. Bridge Headed Structures: The Carbocation Structure 1 0.000001 0.00000000000001 Rel. Rate Rate = k[RBr] SN1SN1 Solvent: EtOH/H 2 O (80:20) Nucleophile: H 2 O Temp: 25 o C

27. Becomes increasingly difficult to attain the PLANAR sp 2 hybridised carbocation