ASR Further Organic Mechanisms Notes

2025/ASRJC/Chemistry 1 ANDERSON SERANGOON JUNIOR COLLEGE 2025 H3 CHEMISTRY FURTHER ORGANIC MECHANISMS Learning Outcomes Nucleophilic Substitution Students should be able to: (a) explain how the relative rate of nucleophilic substitution is affected by the nature of the (i) nucleophile (ii) leaving group (iii) substituents (b) describe and compare the mechanisms and kinetics of SN1 and SN2 reactions, in terms of (i) the energy profile and rate law, including steady state approximation in S N1 [mathematical treatment of steady state is not required] (ii) stereochemistry, including ion pair interactions in SN1 (iii) substituents effects (c) explain the factors affecting competition between S N1 and S N2 mechanisms [solvent effects are not required] Elimination Students should be able to: (a) understand and apply the following concepts to the study of elimination reactions: (i) syn– and anti– elimination; and its effect on stereoselectivity (ii) regioselectivity: Zaitsev (thermodynamic) and Hofmann (kinetic) product(s) (b) describe and compare the mechanisms and kinetics of E1 and E2 reactions, in terms of (i) the energy profile and rate law (ii) regioselectivity (c) explain the E2/SN2 competition, in terms of (i) substrate effects (ii) base effects References 1. Organic Chemistry, 7th edition, McMurry J (2008) 2. Organic Chemistry, J Clayden 3. Organic Chemistry as a Second Language, David R. Klein 4. ChemgaPedia

2025/ASRJC/Chemistry 2 1. Nucleophilic substitution of halogenoalkanes C+−X– covalent bond is polar in halogenoalkane, thus the carbon is electron –deficient and attracts nucleophiles to undergo two main types of reactions: either substitution of the halogen or undergo base–induced elimination to yield an alkene. Nucleophilic substitution C XNu - +  - CNu + X - Elimination H X Nu Nu H X Depending on the substrates and conditions used, a mixture of both substitution and elimination products can form. Reagents and conditions: NaOH(aq), heat under reflux + OH- RCH2 OH + Br- substrate leaving group nucleophile RCH2 Br 1.1 SN2 mechanism This is a one–step reaction mechanism. The nucleophile, OH –, approaches the substrate, RCH2CH2Br, from a direction opposite the leaving group, in this case Br. The C–O bond is partially formed and the C –Br bond is partially broken in the transition state. The transition state contains a pentavalent carbon atom. OH-  - + - C R H R1 HO Br C R H R1 HO transition state + Br - nucleophile substrate leaving group C R H R1 Br polar bond A transition state is an unstable species that has very short lifetime and thus cannot be isolated. It lies in an energy maximum.

2025/ASRJC/Chemistry 3 energy progress of reaction OH - Br R1 H R Br - + R1 H R OH BrOH R1H R reactants products transition state - Since it is a bimolecular, one– step reaction, one nucleophile (OH– ion) and one substrate molecule (RCH 2Br) are involved in the rate– determining step . Thus the rate equation is: rate = k [Nu][substrate] This nucleophilic substitution is known as SN2 (Bimolecular Nucleophilic substitution). Should the bromoalkane be an enantiopure sample, say R isomer only, the product formed will be the S isomer or vice versa. In other words, there will be an inversion of configuration. Thus from the products, we can also deduce whether this is a SN2 reaction. CH BrOH- C CH3 H CH2CH3 HO + Br - CH3CH2 + CH3 (R)-2-bromobutane (S)-butan-2-ol 1.2 SN1 mechanism C R H R1 Br OH-  - + C R H R1 HO + Br -slow C R H R1 C R H R1 fast (planar) carbocation intermediatesubstrate leaving group polar bond nucleophile This is a two–step reaction mechanism with a carbocation intermediate formed. Here it involves breaking a C–Br bond thus requires a high activation energy  slow step

2025/ASRJC/Chemistry 4 An intermediate can be a molecule, ion or free radical that is formed in one step of a reaction mechanism and consumed in a subsequent step. Like transition states, intermediates are unstable. However, intermediates can be observ ed with special instruments. An intermediate is more stable than a transition states and thus lies in a shallow “trough” between two transition states, a local energy minima. energy progress of reaction reactants products - intermediate transition state (1) transition state (2) HH R C + OH R1 H RBr R1 H R Only one RCH 2Br substrate molecule is involved in the rate–determining step. Thus, the rate equation is: rate = k [substrate] This nucleophilic substitution is known as SN1 (Unimolecular Nucleophilic substitution). Since a planar carbocation is formed in the intermediate, there are two possible approaches the nucleophile can “attack”, forming two stereochemically different isomers. C R H R1 OH- (a) (b) C R H R1 HO formed via route (a) + C R H R1 OH formed via route (b) Br- Should the bromoalkane be an enantiopure sample, say R isomer only, the product formed will be a mixture of both R and S isomers.

2025/ASRJC/Chemistry 5 Steady State Approximation What is Steady Sate Approximation? One or more intermediates can be formed in multi –step reaction. An intermediate does not appear in the rate equation, as its concentration cannot be measured. Hence, it is necessary to express the concentration of intermediates in terms of concentration of species that can be measured. If the concentrations of the intermediates is a lot smaller than that of the reactants, the rate of change of concentration of the intermediates will also be very small, and that can be assumed to be zero. In other words, the concentration of an intermediate remains low (but not zero) and constant for most of the reaction as shown by the following graph: Steady State Approximation in SN1 The steady state approximation can be applied to S N1 mechanism. The carbocation concentration is low because it is consumed in the second step as quickly as it is generated. The first step in S N1 is the slow step with a high activation energy. The second step has a lower activation energy as it involves the collision of two oppositely charged particles. The nucleophile (OH–) is also in a much higher concentration than the carbocation and hence it is able to react immediately with the carbocation formed. It is also assumed that the rate of the backward reaction in Step 1 is a lot slower than that between the carbocation and OH– as (1) OH– is a better nucleophile (2) [OH–] >> [Br–] Energetically, the C–Br bond broken is also weaker than the C–O bond formed. [int] time Steady state zone [int] 0d dt =

2025/ASRJC/Chemistry 6 SN1 Mechanism: C CH3 CH3 H3C Br C CH3 CH3 H3C + Br- k1 k-1 C CH3 CH3 H3C OH- k2 fast slow C CH3 CH3 H3C OH Applying steady state approximation, 1 2 1 [] 0 [ ] [ ][ ] [ ][ ] 0 d carbocation dt k RX k carbocation OH k carbocation Br−− − = − − = Rearranging, 1 2 1 1 21 [ ] [ ][ ] [ ][ ] [][] [ ] [ ] k RX k carbocation OH k carbocation Br k RXcarbocation k OH k Br −− − −− − =+ = + Assuming that k2[OH–] >> k–1[Br–] 1 2 2 1 2 2 1 [][] [] Rate of formation of product [ ][ ] [] [][] [] k RXcarbocation k OH k carboca