Molecular Orbitals for Alkyl Halide Electrophiles To build molecular orbitals, first recall that the energy of the ‘starting’ atomic orbitals depends the electronegativity of the element, which you can get from the periodic table... So therefore: more electronegative element therefore lower energy atomic orbital 1 Chemistry 335 Supplemental Slides: Chapter 2

Molecular Orbitals for Alkyl Halide Electrophiles The energy stabilization (or destabilization) that results from bonding (or antibonding) depends on energy difference and the ability of the orbitals to mix! higher energy LUMO – therefore worse electrophile! far in energy but good orbital overlap close in energy but poor orbital overlap better bond – harder to break! As we move down the periodic table, the orbitals become more diffuse and therefore have poorer overlap with first row elements like carbon. 2 Chemistry 335 Supplemental Slides: Chapter 2

poor base / good nucleophile good base / poor nucleophile 2.6 Predicting Substitution vs. Elimination Remember that anything with a pair of electrons can in principle act as a base or a nucleophile. Determining whether a substitution or elimination is most likely requires evaluation of the structure of the starting material (e.g. 1o, 2o, 3o, etc.), the quality of the leaving group (e.g. I > Br > Cl) and the properties of the nucleophile/base (e.g stabilized vs. unstabilized, light vs. heavy, etc.). poor base / good nucleophile good base / poor nucleophile Me or Bn 1o 2o 3o SN2 SN2 SN2 or no reaction SN2 E2 SN2 E2 E2, SRN1 or no rxn E2 E2 A. Recall that methyl halides and benzyl halides can’t undergo elimination, since they have no a-hydrogens. Similarly, 3o alkyl halides can’t participate in SN2 reactions because they’re too hindered. So quite a few of the scenarios imagined by this table are trivial to assign. B. A methyl (or benzyl) alkyl halide that is presented with a poor nucleophile will either react very slowly or else not react at all. Similarly, a 3o alkyl halide that is presented with a poor base could either react very slowly, not react at all, or undergo substitution by a different mechanism (which we’ll talk about later). C. Electron-rich species that are good nucleophiles and poor bases will prefer to react via substitution; electron-rich species that are good bases and poor nucleophiles will prefer to react via elimination. 3 Chemistry 335 Supplemental Slides: Chapter 2

poor base / good nucleophile good base / poor nucleophile 2.6 Predicting Substitution vs. Elimination Remember that anything with a pair of electrons can in principle act as a base or a nucleophile. Determining whether a substitution or elimination is most likely requires evaluation of the structure of the starting material (e.g. 1o, 2o, 3o, etc.), the quality of the leaving group (e.g. I > Br > Cl) and the properties of the nucleophile/base (e.g stabilized vs. unstabilized, light vs. heavy, etc.). poor base / good nucleophile good base / poor nucleophile Me or Bn 1o 2o 3o SN2 SN2 SN2 or no reaction SN2 SN2 E2 SN2 E2 > SN2 E2 E2, SRN1 or no rxn E2 E2 D. Substitution is favoured for 1o alkyl halides since they are relatively unhindered, and since the competing elimination pathway would deliver a relatively unsubstituted (and therefore less stabilized) alkene. E. 2o alkyl halides can go either way. Elimination tends to predominate for many ‘typical’ 2o alkyl halides but: - exact product ratios vary with solvent, temperature, specific substrate geometry, etc. - SN2 predominates for allylic, benzylic and propargylic 2o alkyl halides - SN2 will be favoured by using a polar aprotic solvent or by reducing the basicity of the nucleophile - E2 elimination is more likely for cyclic 2o alkyl halides - Elimination is more likely for homoallylic and homopropargylic substrates (due to the possibility to create increased conjugation in the product) 4 Chemistry 335 Supplemental Slides: Chapter 2

2.10 Roundup of Aldol-Like Reactions 5 Chemistry 335 Supplemental Slides: Chapter 2

2.10 Roundup of Aldol-Like Reactions 6 Chemistry 335 Supplemental Slides: Chapter 2

2.10 Roundup of Aldol-Like Reactions 7 Chemistry 335 Supplemental Slides: Chapter 2

2.10 Roundup of Aldol-Like Reactions Alert: Aldol and Claisen condensations are reversible. The reverse reaction in each case is often non-obvious and usually undesired. Retro-aldol and retro-Claisen reactions are generally driven by relief of strain energy. Consider the following synthetic route: only observed product not observed Huh? What happened?!? 8 Chemistry 335 Supplemental Slides: Chapter 2

2.10 Roundup of Aldol-Like Reactions Alert: Aldol and Claisen condensations are reversible. The reverse reaction in each case is often non-obvious and usually undesired. Retro-aldol and retro-Claisen reactions are generally driven by relief of strain energy. Consider the following synthetic route: only observed product not observed Huh? What happened?!? 9 Chemistry 335 Supplemental Slides: Chapter 2

2.12 Summary of Carbonyl Substitution Reactions 10 Chemistry 335 Supplemental Slides: Chapter 2

2.21 Carbenes & a-Eliminations Carbenes can be singlets or triplets triplet singlet • Whether singlet or triplet is the ground state depends on the separation in energy between the sp2 and p orbitals... • For simple alkyl or H substituents, triplet carbenes are lower in energy: • But donor substituents stabilize the empty p-orbital and thus stabilize the triplet state: 11 Chemistry 335 Supplemental Slides: Chapter 2

• Includes all sections from Chapter 2 except: End of Chapter Wrap-Up Term Test Number 2: • Wednesday, March 1st • Includes all sections from Chapter 2 except: • 2.5 Base-Promoted Rearrangements (covered with other rearrangements) • 2.6.1 Swern Oxidation (covered with other oxidations)  Read these sections anyway, since they will be covered in Term Test 3 and on the Final Exam. • Cutoff for material on the test is Friday, February 24th. • Expect the following sections in the test: • Short reaction questions (fill in reactants, reagents or product) • Molecular shape and stereochemistry (diastereomers, enantiomers, etc.) • Reaction mechanism (tougher than in Term Test 1) • Synthesis proposal (fairly easy since this is your first one) • To prepare: • Read all of Chapter 2 – pay attention to the details. • Do all the in-chapter problems, and all end-of-chapter problems. • For further practice, try to propose mechanisms for the reactions in problem #4 of Chapter 1 (p. 46). These are tough, but you have the tools. • When you’re ready, try the practice test posted on the course website. 12 Chemistry 335 Supplemental Slides: Chapter 2