2. Part 3 CHM1C3 Substitution Reactions R 1 R 2 R 3 Cl Nu R 1 R 2 R 3 Nu Inversion of Configuration Racemisation of Configuration R 1 R 2 R 3 Nu R 1 R 2 R 3 Nu Rate =k[R-Cl][Nu] S N 2 Rate =k[R-Cl] S N 1

3. Content of Part 3 Part 3i. The Role of Kinetics and Chirality in Determining Mechanisms of the Substitution Reaction Part 3ii. Effect of Solvent on the Substitution Reaction Part 3iii.Effect of Structure on the Substitution Reaction Part 3iv. Nature of the Attacking Nucleophile Part 3v.Nature of the Leaving Group

4. Part 5i Substitution Reactions: Mechanisms Bimolecular substitution (S N 2) (and elimination (E2)) reactions and transition states Unimolecular substitution (S N 1) (and elimination (E1)) reactions and reactive intermediates

5. Content of Part 5i The S N 2 Reaction Mechanism The S N 1 Reaction Mechanism Reaction Rates/Chirality in Determining the Mechanism Transition States Reactive Intermediates

6. After completing PART 4i of this course you should have an understanding of, and be able to demonstrate, the following terms, ideas and methods. (i) Understand how by considering both the reaction kinetics and the stereochemical outcome of substitution reactions the S N 2 and S N 1 mechanisms were devised, (ii)Understand the difference in timings of the arrow-pushing in the mechanisms of the S N 2 and S N 1 reaction, (iii)Understand the terms bimolecular and unimolecular, (iv)Understand the reaction energy profile for a reaction in which a transition state leads to the formation of the products – a S N 2 reaction, and (vi)Understand the reaction energy profile for a reaction in which a reactive intermediate leads to the formation of the products – a S N 1 reaction. – Learning Objectives Part 5i – Substitution Reactions: Mechanisms CHM1C3 – Introduction to Chemical Reactivity of Organic Compounds–

8. Nucleophililic Substitution Reactions at sp 3 Carbons It is found that there are two possible stereochemical outcomes, each described by a different rate equation, and different stereochemical outcomes. DescriptorRate EquationStereochemical Outcome S N 2rate = k[R-Hal][Nu]Inversion S N 1rate = k[R-Hal]Racemisation Stereochemistry Rate Equation

9. Clearly, two different reaction mechanisms must be in operation. It is the job of the chemists to fit the experimental data to any proposed mechanism

10. Reaction Mechanisms The mechanism of a reaction consists of everything that happens as the starting materials are converted into products. In principle, therefore, writing (or drawing) the mechanism means describing everything that happens in the course of the reaction. However, providing an exact description of a reaction on paper is an impossible goal. Instead, a proposal for the mechanism of a reaction should include certain types of information about the course of the reaction. Thus, the reaction mechanism should: [1]Account for the number of reaction steps as indicated by the rate equation [2]Account for reactive intermediates or transition states [3]Account for any stereochemical relationships between starting materials and products

12. SN2SN2

13. The S N 2 Reaction Mechanism Nucleophile attacks from behind the C-Cl  -bond. This is where the  *-antibonding orbital of the C-Cl bond is situated. Rate =k[R-Hal][Nu] R 1 R 2 R 3 Cl Nu sp 3 Bimolecular Process Rate Determinig Step

14. http://chemistry.boisestate.edu/rbanks/organic/sn2.gif

15. http://www.personal.psu.edu/faculty/t/h/the1/sn2.htm

16. http://www.bluffton.edu/~bergerd/classes/CEM221/sn-e/SN2-1.html

17. Transition States: See S N 2 and E2 Reaction Mechanisms A transition state is the point of highest energy in a reaction or in each step of a reaction involving more than one step. The nature of the transition state will determine whether the reaction is a difficult one, requiring a high activation enthalpy (  G ‡ ), or an easy one. Transition states are always energy maxima, I.e. at the top of the energy hill, and therefore, can never be isolated. A transition states structure is difficult to identify accurately. It involves partial bond cleavage and partial bond formation.

18. Transition States Rate = k[A][B] See S N 2 and E2 Reaction Mechanisms

20. SN1SN1

21. The S N 1 Reaction Mechanism Nucleophile attacks from either side of the carbocationic intermediate.

22. Reactive Intermediates: See S N 1 and E1 Reaction Mechanisms Reactive intermediates are energy minima, i.e. at the bottom of the energy hill, and therefore, can be isolated. A reactive intermediate structure is much easier to identify and in certain cases these high energy species can be isolated and structurally characterised.

23. Reactive Intermediates Rate = k[A] See S N 1 and E1 Reaction Mechanisms And Radical Chain Reaction

25. – Summary Sheet Part 3i – Substitution Reactions: Mechanisms The difference in electronegativity between the carbon and chlorine atoms in the C-Cl sigma (  ) bond result in a polarised bond, such that there is a partial positive charge (  + ) on the carbon atom and a slight negative charge (  - ) on the halogen atom. Thus, we can consider the carbon atom to be electron deficient, and therefore electrophilic in nature (i.e. electron liking). Thus, if we react haloalkanes with nucleophiles (chemical species which have polarisable lone pairs of electrons, which attack electrophilic species), the nucleophile will substitute the halogen atom. The difference in electronegativity between the carbon and chlorine atoms in the C-Cl sigma (  ) bond result in a polarised bond, such that there is a partial positive charge (  + ) on the  -carbon atom and a slight negative charge (  - ) on the halogen atom, which in turn is transmitted to the  -carbon atom and the protons associated with it. Thus, the hydrogen atoms on the  -carbon atom are slightly acidic. Thus, if we react haloalkanes with bases (chemical species which react with acids), the base will abstract the proton atom, leading to carbon-carbon double bond being formed with cleavage of the C-Cl bond. Substitution (and elimination) reactions can be described by two extreme types of mechanism. One mechanism is a concerted and relies on the starting materials interacting to form a transition state, and the other is a step-wise process in which one of the starting material s is converted into a reactive intermediate, which then reacts with the other reagent. Discussions of transition states and reactive intermediates in the course of a reaction is very useful when proposing an organic reaction mechanism, which takes into account the experimental evidence for a reaction, such as rate equations and stereochemical outcomes. CHM1C3 – Introduction to Chemical Reactivity of Organic Compounds–

27. Exercise 1: Substitution Reactions cis-1-Bromo, 3-methylcyclopentane reacts with NaSMe (MeS — is an excellent nucleophile) to afford a product with molecular formulae C 7 H 14 S. The rate of the reaction was found to be dependent on both the bromoalkane and the NaSMe. (i)Identify the product, and (ii)propose an arrow pushing mechanism to account for the product formation.

28. Answer 1: Substitution Reactions cis-1-Bromo, 3-methylcyclopentane reacts with NaSMe (MeS — is an excellent nucleophile) to afford a product with molecular formulae C 7 H 14 S. The rate of the reaction was found to be dependent on both the bromoalkane and the NaSMe. (i)Identify the product(s), and (ii)propose an arrow pushing mechanism to account for the product formation. Starting material molecular formula = C 6 H 11 Br Product molecular formula = C 7 H 14 S Lost Br, Gained SMe, Substitution Reaction Rate equation indicates bimolecular process, S N 2 Envelope Conformation of Cyclopentane

29. Exercise 2: Substitution Reactions Compounds A and B when treated with a weak base are deprotonated to form the carboxylate anion. One of these carboxylate anions then reacts further to afford the lactone P, whilst the other carboxylate anion is does not lead to P. Identify the carboxylate anion which affords P, and rationalise its formation with an arrow pushing mechanism, as well as rationalising why the other carboxylate anion does not afford P. ABP

30. Answer 2: Substitution Reactions Compounds A and B when treated with a weak base are deprotonated to form the carboxylate anion. One of these carboxylate anions then reacts further to afford the lactone P, whilst the other carboxylate anion is unaffected. Identify the carboxylate anion which affords P, and rationalise its formation with an arrow pushing mechanism, as well as rationalising why the other carboxylate anion does not afford P.  * orbital of C-I bond ABPReaction must be S N 2 type, because if it was S N 1 like the carbocation below would be generated from both S1 and S2. Therefore both S1 and S2 would afford P