Alkyl Halides and Nucleophilic Substitution Notes ch 7

Alkyl Halides and Nucleophilic Substitution

Introduction to Alkyl Halides

• Alkyl halides are organic molecules with a halogen atom bonded to an sp^3 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”.
• There are other types of organic halides: vinyl halides, aryl halides, allylic halides, and benzylic halides.
  • Vinyl halides have a halogen atom (X) bonded to a C=C double bond.
  • Aryl halides have a halogen atom bonded to a benzene ring.
  • 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.

Nomenclature

• Common names are often used for simple alkyl halides.
  • Name all the carbon atoms of the molecule as a single alkyl group.
  • Name the halogen bonded to the alkyl group.
  • Combine the names of the alkyl group and halide, separating the words with a space.

Physical Properties

• Alkyl halides are weak polar molecules.
• They exhibit dipole-dipole interactions because of their polar C—X bond, but they cannot participate in intermolecular hydrogen bonding because the rest of the molecule contains only C—C and C—H bonds.
• Alkyl halides have higher boiling points (bp) and melting points (mp) than alkanes with the same number of carbons.
  • Example: Ethane (CH3CH3, bp = -89 °C) vs. Bromoethane (CH3CH2Br, bp = 39 °C).
• Boiling points and melting points increase as the size of the R group increases due to larger surface area.
  • Example: Ethyl chloride (CH3CH2Cl, mp = -136 °C, bp = 12°C) vs. Propyl chloride (CH3CH2CH2Cl, mp = -123 °C, bp = 47°C).
• Boiling points and melting points increase as the size of X increases due to increased polarizability of the halogen.
  • Example: Ethyl chloride (CH3CH2Cl, mp = -136 °C, bp = 12°C) vs. Ethyl bromide (CH3CH2Br, mp = -119 °C, bp = 39 °C).
• Alkyl halides are soluble in organic solvents but insoluble in water.

Interesting Alkyl Halides

• Chloromethane (CH3Cl) is produced by giant kelp and algae and is found in emissions from volcanoes. Most atmospheric chloromethane comes from these natural sources.
• Dichloromethane (or methylene chloride, CH2Cl2) is an important solvent previously used to decaffeinate coffee. Supercritical CO2 is now used due to concerns about residual CH2Cl2.
• Halothane (CF3CHClBr) is a safe general anesthetic that replaced other anesthetics like CHCl3 (causes liver and kidney damage) and CH3CH2OCH2CH3 (diethyl ether, which is very flammable).
• Other notable halogenated compounds include Teflon, poly(vinyl chloride) (PVC), Freon 11 (CFC13), and DDT.

The Polar Carbon-Halogen Bond

• The electronegative halogen atom in alkyl halides creates a polar C—X bond, making the carbon atom electron deficient.

General Features of Nucleophilic Substitution

• Three components are necessary in any substitution reaction: a substrate, a nucleophile, and a leaving group.
• Negatively charged nucleophiles like HO^− and HS^− are used as salts with Li^+, Na^+, or K^+ counterions to balance the charge. Since the identity of the counterion is usually inconsequential, it is often omitted from the chemical equation.
• To draw any nucleophilic substitution product:
  • Find the sp^3 hybridized carbon with the leaving group.
  • Identify the nucleophile, the species with a lone pair or \pi bond.
  • Substitute the nucleophile for the leaving group and assign charges (if necessary) to any atom that is involved in bond breaking or bond formation.

The Leaving Group

• In a nucleophilic substitution reaction of R—X, the C—X bond is heterolytically cleaved, and the leaving group departs with the electron pair in that bond, forming X^- .
• The more stable the leaving group X^- , the better able it is to accept an electron pair.
• For example, H2O is a better leaving group than HO^- because H2O is a weaker base.

The Nucleophile

• Nucleophiles and bases are structurally similar: both have a lone pair or a \pi bond. They differ in what they attack.
• Basicity is a measure of how readily an atom donates its electron pair to a proton. It is characterized by an equilibrium constant, K_a in an acid-base reaction, making it a thermodynamic property.
• Nucleophilicity is a measure of how readily an atom donates its electron pair to other atoms. It is characterized by a rate constant, k, making it a kinetic property.
• Nucleophilicity parallels basicity in three instances:
  1. For two nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile. For example, HO^- is a stronger base and stronger nucleophile than CH_3COO^-.
  2. A negatively charged nucleophile is always a stronger nucleophile than its conjugate acid. HO^- is a stronger base and stronger nucleophile than H_2O.
  3. Right-to-left-across a row of the periodic table, nucleophilicity increases as basicity increases
• Steric hindrance decreases nucleophilicity but not basicity.
• Sterically hindered bases that are poor nucleophiles are called nonnucleophilic bases.
• If the salt NaBr is used as a source of the nucleophile Br^- in H2O, the Na^+ cations are solvated by ion-dipole interactions with H2O molecules, and the Br^- anions are solvated by strong hydrogen bonding interactions.
• In polar protic solvents, nucleophilicity increases down a column of the periodic table as the size of the anion increases. This is the opposite of basicity.

Polar Protic and Aprotic Solvents

• Polar protic solvents exhibit dipole-dipole interactions and have O—H or N—H bonds, allowing them to participate in hydrogen bonding. Examples include water and alcohols.
• Polar aprotic solvents also exhibit dipole—dipole interactions, but they have no O—H or N—H bonds. Thus, they are incapable of hydrogen bonding. Examples include DMSO, acetone, and DMF.
• Polar aprotic solvents solvate cations by ion—dipole interactions, but anions are not well solvated because the solvent cannot hydrogen bond to them. These anions are said to be “naked”.
• In polar aprotic solvents, nucleophilicity parallels basicity, and the stronger base is the stronger nucleophile.
• Because basicity decreases as size increases down a column, nucleophilicity decreases as well.

Mechanisms of Nucleophilic Substitution

• In a nucleophilic substitution, bond making and bond breaking can occur in different orders.
  1. Bond making and bond breaking occur at the same time (SN2). The mechanism is comprised of one step.
  2. Bond breaking occurs before bond making (SN1). The mechanism has two steps, and a carbocation is formed as an intermediate.
  3. Bond making occurs before bond breaking. This mechanism has an inherent problem. The intermediate generated in the first step has 10 electrons around carbon, violating the octet rule.
• SN2 (substitution nucleophilic bimolecular) mechanism involves a one-step bimolecular reaction where the rate depends on the concentration of both reactants (second order).
• SN1 (substitution nucleophilic unimolecular) mechanism involves a two-step mechanism where the rate depends on the concentration of only the alkyl halide (first order).
• All SN2 reactions proceed with backside attack of the nucleophile, resulting in inversion of configuration at a stereogenic center.
• Methyl and 1° alkyl halides undergo SN2 reactions with ease.
• 2° Alkyl halides react more slowly.
• 3° Alkyl halides do not undergo SN2 reactions. This order of reactivity can be explained by steric effects.

SN2 Reaction

• Steric hindrance caused by bulky R groups makes nucleophilic attack from the backside more difficult, slowing the reaction rate.
• Increasing the number of R groups on the carbon with the leaving group increases crowding in the transition state, thereby decreasing the reaction rate.
• The SN2 reaction is fastest with unhindered halides.
• The SN2 reaction is a key step in the laboratory synthesis of many important drugs.
• Nucleophilic substitution reactions are important in biological systems as well.

SN1 Reaction

• The mechanism of an SN1 reaction has two steps, and carbocations are formed as reactive intermediates.
• Loss of the leaving group in Step [1] generates a planar carbocation that is achiral. In Step [2], attack of the nucleophile can occur on either side to afford two products which are a pair of enantiomers.
• Because there is no preference for nucleophilic attack from either direction, an equal amount of the two enantiomers is formed—a racemic mixture. We say that racemization has occurred.
• The rate of an SN1 reaction is affected by the type of alkyl halide involved.
• 3° Alkyl halides undergo SN1 reactions with ease.
• 2° Alkyl halides react more slowly.
• Methyl and 1° alkyl halides do not undergo SN1 reactions.
• This trend is exactly opposite to that observed in SN2 reactions.

Carbocation Stability

• Carbocations are classified as primary (1°), secondary (2°), or tertiary (3°), based on the number of R groups bonded to the charged carbon atom.
• As the number of R groups increases, carbocation stability increases: 3° > 2° > 1° > methyl.
• The order of carbocation stability can be rationalized through inductive effects and hyperconjugation.

Inductive Effects and Hyperconjugation

• Inductive effects are electronic effects that occur through \sigma bonds.
  • Specifically, the inductive effect is the pull of electron density through \sigma bonds caused by electronegativity differences between atoms.
• Alkyl groups are electron donating groups that stabilize a positive charge.
  • Since an alkyl group has several \sigma bonds, each containing electron density, it is more polarizable than a hydrogen atom and better able to donate electron density.
• In general, the greater the number of alkyl groups attached to a carbon with a positive charge, the more stable will be the cation.
• Hyperconjugation is the spreading out of charge by the overlap of an empty p orbital with an adjacent \sigma bond.
  • This overlap (hyperconjugation) delocalizes the positive charge on the carbocation, spreading it over a larger volume, and this stabilizes the carbocation.
• Example: CH3^+ cannot be stabilized by hyperconjugation, but (CH3)_2CH^+ can.

The Hammond Postulate

• The Hammond postulate relates reaction rate to stability. It provides a quantitative estimate of the energy of a transition state.
• The Hammond postulate states that the transition state of a reaction resembles the structure of the species (reactant or product) to which it is closer in energy.
• In an endothermic reaction, the transition state resembles the products more than the reactants, so anything that stabilizes the product stabilizes the transition state as well.
  • Thus, lowering the energy of the transition state decreases E_a, which increases the reaction rate.
• In the case of an exothermic reaction, the transition state resembles the reactants more than the products.
  • Thus, lowering the energy of the products has little or no effect on the energy of the transition state.
• According to the Hammond postulate, the stability of the carbocation determines the rate of its formation.

SN1 Reactions, Nitrosamines, and Cancer

• SN1 reactions are thought to play a role in how nitrosamines, compounds having the general structure R_2NN=O, act as toxins and carcinogens.

Predicting the Likely Mechanism of a Substitution Reaction

• Four factors are relevant in predicting whether a given reaction is likely to proceed by an SN1 or an SN2 reaction:
  1. The most important is the identity of the alkyl halide.
  2. The nature of the nucleophile is another factor.
  3. A better leaving group increases the rate of both SN1 and SN2 reactions.
  4. The nature of the solvent is a fourth factor.
• Strong nucleophiles (which usually bear a negative charge) present in high concentrations favor SN2 reactions.
• Weak nucleophiles, such as H_2O and ROH, favor SN1 reactions by decreasing the rate of any competing SN2 reaction.
• Polar protic solvents like H_2O and ROH favor SN1 reactions because the ionic intermediates (both cations and anions) are stabilized by solvation.
• Polar aprotic solvents favor SN2 reactions because nucleophiles are not well solvated and, therefore, are more nucleophilic.

Vinyl Halides and Aryl Halides

• Vinyl and aryl halides do not undergo SN1 or SN2 reactions because heterolysis of the C—X bond would form a highly unstable vinyl or aryl cation.
• Backside attack of the nucleophile is not possible in vinyl halides.
• Heterolysis of the C-X bond forms a very unstable carbocation, making the rate-determining step very slow in vinyl halides.

Nucleophilic Substitution and Organic Synthesis

• To carry out the synthesis of a particular compound, we must think backwards and ask ourselves the question: What starting material and reagents are needed to make it?
• If we are using nucleophilic substitution, we must determine what alkyl halide and what nucleophile can be used to form a specific product.
• To determine the two components needed for synthesis, remember that the carbon atoms come from the organic starting material, in this case, a 1° alkyl halide. The functional group comes from the nucleophile, HO^-$$ in this case.