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PHARMACEUTICAL ORGANIC CHEMISTRY. ALKYL HALIDES SATHEESH KUMAR G. Alkyl Halides. Alkyl halides are organic molecules containing a halogen atom bonded to an sp 3 hybridized carbon atom.
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PHARMACEUTICAL ORGANIC CHEMISTRY ALKYL HALIDES SATHEESH KUMAR G
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”.
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.
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.
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.
The UnimolecularNucleophilic Substitution (SN1) Reaction • A nucleophilic substitution reaction taking place in two steps is an example of a unimolecular nucleophilic substitution (SN1)mechanism.
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.
The Unimolecular Elimination(E1) Reaction • Elimination reactions can also take place in two steps, via a unimolecular elimination.
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.
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
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
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
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).
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
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
Factor 1: Structure of R-X/LG • Empirical evidence: As alkyl substitution increases on the sp3-carbon center for substitution, the rate decreases
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
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.
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
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.
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:
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.
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:
Factor 2: Strength of the Nu: • Common nucleophiles for an SN2 reaction:
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.
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
Factor 3: Leaving Group Ability Experimental Data: Never LGs Good LGs
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.
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
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:
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:
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.
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.
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.
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.
Factor 4: Solvent Effects More empirical evidence; note how in a polar protic solvent, the larger, less basic nucleophiles give faster reactions:
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
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.
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!