PHARMACEUTICAL ORGANIC CHEMISTRY

1. PHARMACEUTICAL ORGANIC CHEMISTRY ALKYL HALIDES SATHEESH KUMAR G

2. Alkyl Halides • Alkyl halides are organic molecules containing a halogen atom bonded to an sp3 hybridized carbon atom. • Alkyl halides are classified as primary (1°), secondary (2°), or tertiary (3°), depending on the number of carbons bonded to the carbon with the halogen atom. • The halogen atom in halides is often denoted by the symbol “X”.

3. Types of Alkyl Halides • Other types of organic alkyl halides include: • Allylic halides have X bonded to the carbon atom adjacent to a C-C double bond. • Benzylic halides have X bonded to the carbon atom adjacent to a benzene ring. • NOT ALKYL HALIDES • Vinyl halides have a halogen atom (X) bonded to a C-C double bond. • Aryl halides have a halogen atom bonded to a aromatic ring.

4. The Polar Carbon-Halogen Bond • The electronegative halogen atom in alkyl halides creates a polar C-X bond, making the carbon atom electron deficient. • Electrostatic potential maps of four simple alkyl halides illustrate this point. • This electron deficient carbon is a key site in the reactivity of alkyl halides.

5. Reaction Types for Alkyl Halides

6. The BimolecularNucleophilic Substitution (SN2) Reaction • Recall that an SN2 reaction takes place in a single step. • The Nu–C bond forms at the same time the C–L bond breaks.

7. The UnimolecularNucleophilic Substitution (SN1) Reaction • A nucleophilic substitution reaction taking place in two steps is an example of a unimolecular nucleophilic substitution (SN1)mechanism.

8. The Bimolecular Elimination(E2) Reaction • Recall that an E2 reaction takes place in a single step. • The B–H s bond and the C=C p bond form at the same time the H–C s bond and the C–L s bond break.

9. The Unimolecular Elimination(E1) Reaction • Elimination reactions can also take place in two steps, via a unimolecular elimination.

10. SN2: Substitution, Nucleophilic, Bimolecular • SN2 reaction takes place in a single step – “concerted” • The Nu–C bond forms at the same time the C–L bond breaks.

11. SN2: Substitution, Nucleophilic, Bimolecular • SN2 free energy diagram - maps change in energy as reaction progress DE -DH only means the reaction is spontaneous; it does not indicate whether or not it will occur or how fast reaction progress

12. SN2: Substitution, Nucleophilic, Bimolecular • SN2 free energy diagram - maps change in energy as reaction progress The EA is the energy required to get the reaction going. The lower the EA, the faster the reaction DE reaction progress

13. SN2: Substitution, Nucleophilic, Bimolecular • SN2 free energy diagram - maps change in energy as reaction progress EA depends on the energy of ‡. Lower its energy—i.e. stabilize it—the faster the reaction will proceed DE reaction progress

14. Hammond Postulate • Thermodynamics is the study of energy states and the changes that occur during a reaction. • Just because a reaction is thermodynamically possible, does not indicate whether it will occur or at what rate • Kinetics is the study of reaction rates. • Just because a reaction is fast does not indicate anything about DH or DS (or by extension DG).

15. SN2: Substitution, Nucleophilic, Bimolecular • For SN2 the ‡ resembles the reactants There are two species involved in the rate limiting (only) step Rate (SN2) = k[Nu][R-X] DE reaction progress

16. SN2: Substitution, Nucleophilic, Bimolecular • For SN2 the ‡ resembles the reactants To increase the rate of SN2, increase the energy of the Nu: and/or choose the substrate so the ‡ has the lowest energy DE reaction progress

17. Factor 1: Structure of R-X/LG • Empirical evidence: As alkyl substitution increases on the sp3-carbon center for substitution, the rate decreases

18. Factor 1: Structure of R-X/LG • With each additional alkyl group bonded to the carbon, steric hindrance of the nucleophile increases, which slows the reaction

19. Factor 1: Structure of R-X/LG • Increasing the number of R groups on the carbon with the leaving group also increases crowding in the transition state, thereby decreasing the reaction rate. • The SN2 reaction is fastest with unhindered halides.

20. Factor 2: Strength of the Nu: • A nucleophile is a species that seeks positive charge centers—literally “nucleus loving” • In general, nucleophiles are electron pair donors, or Lewis bases in structure via a lone pair or p-bond • Nucleophiles can be negatively charged or neutral • Counter-ions are often omitted for negatively charged nucleophiles

21. Factor 2: Strength of the Nu: Although nucleophilicity and basicity are interrelated, they are fundamentally different. • Basicity is a measure of how stable a species becomes after it has accepted a proton • It is characterized by an equilibrium constant, KA in an acid-base reaction, making it a thermodynamic property • Nucleophilicityis a measure of how rapidly an atom donates its electron pair to other atoms to form bonds. • It is characterized by a rate constant, k, making it a kinetic property.

22. Factor 2: Strength of the Nu: Hammond Postulate and SN2 : • A stronger Nu: is closer in energy to the ‡, which lowers the EA giving a faster SN2 reaction. • A weaker Nu: is farther in energy to the ‡, which raises the EA giving a slower SN2 reaction. ‡ closer to raised energy of reactants Lower EA Stronger Nu: Weaker Nu:

23. Factor 2: Strength of the Nu: Nucleophilicity parallels basicity in three instances: • For two nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile. • The relative nucleophilicity of HO¯ and CH3COO¯, is determined by comparing the pKa values of their conjugate acids (H2O = 15.7, and CH3COOH = 4.8). • HO¯ is a stronger base and stronger nucleophile than CH3COO¯. • HO¯ is a stronger base and stronger nucleophile than H2O.

24. Factor 2: Strength of the Nu: Nucleophilicity parallels basicity in three instances: • A negatively charged nucleophile is always a stronger nucleophile than its conjugate acid. • Right-to-left across a row of the periodic table, nucleophilicity increases as basicity increases:

25. Factor 2: Strength of the Nu: • Common nucleophiles for an SN2 reaction:

26. Factor 2: Strength of the Nu: Steric Effects on Nucleophile Strength • Nucleophilicity does not parallel basicity when steric hindrance becomes important. • Steric hindrance is a decrease in reactivity resulting from the presence of bulky groups at the site of a reaction. • Steric hindrance decreases nucleophilicity but not basicity. • Sterically hindered bases that are poor nucleophiles are called non-nucleophilic bases.

27. Factor 3: Leaving Group Ability • A leaving group must leave in the rate-determining step of an SN2, SN1, E2, or E1 reaction. • The identity of the leaving group has an effect on the rate of each reaction. • A good leaving group is necessary for the reaction to be exothermic (and spontaneous) via a -DH

28. Factor 3: Leaving Group Ability Experimental Data: Never LGs Good LGs

29. Factor 4: Solvent Effects • There are two types of solvent in which SN2, SN1, E2, and E1 reactions can take place: polar protic solvents and polar aprotic solvents.

30. Factor 4: Solvent Effects Review: Polar protic solvents bear -OH groups; good H-bond donors Polar aprotic have strong dipoles, but cannot donate in H-bonding

31. Factor 4: Solvent Effects Nucleophilicity can be affected by the nature of the solvent! If the solvent stabilizes the Nu: too strongly, its energy will be reduced and by the Hammond postulate the reaction will slow Stronger Nu: Weaker Nu:

32. Factor 4: Solvent Effects • Polar protic solvents solvate both cations and anions well. • If the salt NaBr is used as a source of the nucleophile Br¯ in H2O: • Na+ is solvated by ion-dipole interactions with H2O molecules. • Br¯ is solvated by strong hydrogen bonding interactions. H-bonds have reduced the ability of Br- to act as a Nu:

33. Factor 4: Solvent Effects • Polar aprotic solvents solvate cations by ion-dipole interactions. • Anions are not well solvated because the solvent cannot hydrogen bond to them. • These anions are said to be “naked” and therefore, more reactive.

34. Factor 4: Solvent Effects • Since it is the anion (nucleophile) that matters in SN2, solvents that do not stabilize negative charge give faster reactions. • In aprotic solvents, ion–dipole interactions are much weaker because the positive end of the net dipole is typically buried inside the solvent molecule.

35. Factor 4: Solvent Effects • Since it is the anion (nucleophile) that matters in SN2, solvents that do not stabilize negative charge give faster reactions. • In aprotic solvents, ion–dipole interactions are much weaker because the positive end of the net dipole is typically buried inside the solvent molecule.

36. Factor 4: Solvent Effects Solvent effects can cause reversal of nucleophilicity trends: • In polar proticsolvents, nucleophilicity increases down a column of the periodic table as the size of the anion increases-opposite of basicity! • In polar aprotic solvents, nucleophilicity parallels basicity, and the stronger base is the stronger nucleophile.

37. Factor 4: Solvent Effects More empirical evidence; note how in a polar protic solvent, the larger, less basic nucleophiles give faster reactions:

38. Factor 5: Heat • When substitution and elimination reactions are both favored under a specific set of conditions, it is often possible to influence the outcome by changing the temperature under which the reactions take place. • All of these reactions have an EA that needs to be surmounted. • Heat will accelerate the rate of all reactions; the object is not to overheat to allow higher EA reaction pathways to compete

39. Factor 5: Heat • As the energy barrier increases, the percentage of molecules decreases. • As the temperature increases, the percentage of molecules increases. • In general a 10o rise in temperature will double the rate of a reaction. • At a particular temperature, only a certain percentage of molecules possess enough energy to surmount an energy barrier.

40. Factor 6: Stereospecificity of SN2

41. Factor 6: Stereospecificity of SN2 • The backside attack requires the remaining three groups of the substrate to “flip over” to the other side. • This is known as a Walden inversion. • In general R usually becomes S and vice-versa, but be careful as the product may have a different set of priority numbers!