2. Part 3ii Substitution Reactions: Solvent MeOH DMSO

3. Content of Part 3ii Solvent polarity and its effect on the S N 1 reaction mechanism Solvent polarity and its effect on the S N 2 reaction mechanism Protic and non-protic solvents and their effect on the S N 2 mechanism Protic and polar non-protic solvents and change of mechanism from S N 1 to S N 2 Increasing solvent polarity and change of mechanism from S N 2 to S N 1

4. After completing PART 5ii of this course you should have an understanding of, and be able to demonstrate, the following terms, ideas and methods. (i)Understand how changes in the polarity of the solvent can change the rate of reaction in both S N 2 and S N 1 reaction mechanisms, (ii)Understand what is meant by the dielectric constant of a solvent, (iii)Understand what is meant by protic and non-protic solvents, (iv)Understand what a hydrogen bond is, (v)Understand how protic solvents reduce the rate of reaction of nucleophiles with substrates, and (vi)Understand how increasing the polarity of the solvent can change the mechanism of substitution from S N 2 to S N 1. – Learning Objectives Part 3ii – Substitution Reactions: Solvent CHM1C3 – Introduction to Chemical Reactivity of Organic Compounds–

5. Effect of Solvent Changing the solvent in which a reaction is carried out in can (i) Effect the reaction rate (ii) Result in a change in reaction mechanism

6. Solvent Polarity and S N 1 Reactions Solvent: H 2 O Solvent: H 2 O/EtOH Rate = k[R-Br] Relative Rate SN1SN1 SN1SN1 1 30 000 Why is reaction much faster in water alone?

7. Both reactions must involve the sp 2 hybridised carbocation.  (H 2 O) = 78  (EtOH) = 30 The carbocation is obviously a very polar species. Polar species are most stable in polar solvents. The dielectric constant (  ) of a solvent is a measure of the polarity of a solvent. The larger the  the more polar the solvent. Thus, higher  solvent solvate and stabilise the carbocation more easily than lower  solvents. Thus, cations are generated more rapidly in higher  solvents.

8. Solvent Polarity and S N 2 Reactions Increasing solvent polarity on substrates that undergo S N 2 substitution reactions has a much less dramatic effect. As there is no cation formed there is nothing to stabilise. However, it is found that there is usually a slight decrease in rate with increasing polarity, especially when the nucleophile is charged, i.e. an anion. In much the same way as a carbocation is stabilised by higher polarity solvents, so are anions. Thus, in higher polarity solvents the nucleophile is more solvated and more stable, and therefore less reactive and the rate drops in higher polarity solvents.

9. Protic Solvents and Nucleophile Interaction A protic solvent is one in which there is hydrogen capable of forming a hydrogen bond to the nucleophile, i.e. a hydrogen attached to an electronegative heteroatom (O and N). e.g. H 2 O, MeOH, EtOH This results in a highly solvated and stable nucleophile, and therefore relative unreactive.

10. Non-Protic Solvents and the Nucleophile Interaction A non-protic solvent is one in which there is no hydrogen capable of forming a hydrogen bond to the nucleophile. This then results in the nucleophile being poorly solvated and relatively more reactive. DMSO DMF MeCN Acetone Ethylacetate Chloroform Dichloromethane Ether Alkanes

11. Protic Solvent MeOH Non-Protic Solvent DMF Rate = k[R-I][N 3 - ] SN2SN2 SN2SN2 1 45 000 Rel. Rate It should be noted MeOH and DMF have similar  values, 33 and 37 respectively. Thus, any rate differences are not a result of solvating ability alone.

12. ++ -- Hydrogen Bond None of the Hs are attached to electronegative atoms, therefore no H-bond donors, as above. Therefore, lone pairs on N 3 - are available for attaching the electrophilic centre DMF Polar Protic Solvent Lone pairs are rendered less effective in attacking the electrophilic centre Polar Non-Protic Solvent

13. Protic and Polar Non-Protic Solvents and Change of Mechanism from S N 1 to S N 2 Rate = k[R-Cl] SN1SN1 MeOH  = 33 Rate = k[R-I][N 3 - ] SN2SN2 DMSO  = 46

14. MeOH hydrogen bonds to CN - very efficiently, thus making the CN - a relatively poor nucleophile, under these conditions. The C-Cl bond then has time to fragment to generate the carbocation and Cl -. Therefore, reaction proceeds via S N 1 mechanism DMSO There are no strong hydrogen bonding interactions between the cyanide and the DMSO. Thus, the cyanide anion lone pairs are ‘naked’ and, therefore is a relatively good nuclephile. MeOH:Protic,  = 33 DMSO:Non-Protic,  = 47 Reactive Unreactive i.e. the cyanide can react with R-Cl before the C-Cl bond fragments. Thus, reaction proceeds via an S N 2 mechanism

15. Increasing Solvent Polarity and Change of Mechanism from S N 2 to S N 1 This is fairly simple to conceptualise: If your start with a alkyl halide in a low dielectric solvent then the carbocation will not be formed as the dielectric of the solvent will not support the polar carbocation. Thus, S N 2 reaction mechanism will predominate at low . As the polarity of the solvent increases it becomes increasingly easier to support a carbocation, and the I - is hydrogen bonded as is a poor nuclephile. Thus, S N 1 reaction mechanism will predominate at high . Rate = k[I - ][R-Br] SN2SN2 Rate = k[R-Br] SN1SN1 Solvent: EtOEt  = 3 IBr - Br I-I- Solvent: H 2 O  = 78 I Br - Br I-I-

16. http://www.asiinstruments.com/technical.asp Solvent H 2 O MeOH EtOH 1-PrOH 1-BuOH 1 PeOH HCO 2 H CH 3 CO 2 H Dielectric Constant 80 33 24 20 18 15 58 6 Solvent CH 2 Cl 2 CHCl 3 CCl 4 Dielectric Constant 9 5 2 Solvent HCONMe 2 DMF MeCOMe acetone MeCOEt MeCO 2 Et Dielectric Constant 38 21 18 6 n-Octane n-Hexane n-Pentane Benzene 22222222 THF tetrahydrofuran Et 2 O CCl 4 932932 MeS(O)Me DMSO MeNO 2 nitromethane MeCN acetonitrile 47 39 37 Polar Protic Polar Non-ProticNon-Polar Non-Protic Polar? All values rounded to nearest integer Polar?

17. High  solvents: Cation formation promoted (if Nu is poor, i.e. attacks slowly) S N 1 Promoted Low  solvents: Cation formation prevented S N 2 Promoted Polar Protic solvents: Hydrogen bond to Nu, Ineffective Nu, R-X is able to cleave, before Nu attacks S N 1 Promoted Polar Non-protic solvents Nu lone pair not hydrogen bonded Effective Nu, and attacks before R-X cleaves S N 2 Promoted

18. – Summary Sheet Part 3ii – Substitution Reactions: Solvent If one considers an S N 1 reaction in which a carbocation is formed, then increasing the polarity of the solvent will lead to better solvation of the carbocation, and therefore greater stability. Thus, increasing the solvent polarity from, for example EtOH (  = 30) to H 2 O (  = 78), the rate of reaction increases by several orders of magnitude as the stability of the carbocation is so much greater in H 2 O than EtOH. Indeed, a reaction in a low dielectric solvent may go via an S N 2 reaction (i.e. no requirement for stabilisation of a carbocation), but when transferred to a higher dielectric solvent may change mechanism to S N 1. Not only is the stabilisation of the carbocation important by the solvent, but also the interaction of the nucleophile with the solvent. Nucleophiles have by definition a lone pair of electrons for donation to electrophilic centres, i.e. the carbon attached to the leaving group. However, if the solvent has a hydrogen atom attached to a electronegative heteroatom (O, S, N, such as an alcohol, amine or thiol) then this hydrogen atom will carry a partial positive charge and interact as hydrogen bond acceptor with the lone pair of electrons on the nucleophile. Thus, the lone pair of electrons will now be less effective in a nucleophilic sense. Thus, S N 2 mechanisms might be slowed down on transferring to protic solvents, or even change to S N 1 if the media is even just slight more polar due to the increased time available for scission of the C-leaving group bond. CHM1C3 – Introduction to Chemical Reactivity of Organic Compounds–

19. Identify the ethers B and C, and rationalise the difference in reaction outcomes. Exercise 1: Substitution Reactions

20. SN1SN1 SN2SN2 Identify the ethers D and E, and rationalise the difference in reaction outcomes. EtOH hydrogen bonds to the EtO -, making EtO - a poor nucleophile. Thus, C-Br bond cleaves before attack of EtO -. DE Answer 1: Substitution Reactions carbocationic reactive intermediate DMSO does not hydrogen bond to the EtO - lone pairs, making EtO - a good nucleophile. Thus, EtO - attacks electrophilic centre before C-Br bond cleave.