Chapter 12: Organohalides: Nucleophilic Substitutions and Eliminations

Alkyl Halides

Introduction to Organohalides

• Organohalides, also known as alkyl halides or haloalkanes, are compounds featuring a halogen atom bonded to an $sp^3$-hybridized carbon atom.

• While not frequently part of biochemical pathways in terrestrial organisms, the reactions they undergo (nucleophilic substitutions and eliminations) are common.

• Alkyl halide chemistry serves as a simple model for mechanistically similar reactions in more complex biomolecules.

Naming Alkyl Halides

• Alkyl halides are named by treating the halogen as a substituent on a parent alkane chain.

• Step 1: Identify the longest chain and name it as the parent chain; include any double or triple bonds.

• Step 2: Number the parent chain carbons, starting nearest the first substituent (alkyl or halo).

  • Assign a number to each substituent based on its position on the chain.

  • If multiple halogens are present, number and list them alphabetically when naming.

• Step 3: If the parent chain can be numbered from either end according to Step 2, begin at the end nearer the substituent with alphabetical precedence.

• Simple alkyl halides are named by identifying the alkyl group first, then the halogen (e.g., methyl iodide for $CH_3I$).

Properties of Alkyl Halides

• Halogen size increases down the periodic table, leading to increased carbon-halogen bond lengths.

• Carbon-halogen bond strengths decrease down the periodic table.

• The carbon-halogen bond is polarized, with the carbon having a partial positive charge ($\delta$+) and the halogen having a partial negative charge ($\delta$−).

• The carbon atom in the C-X bond behaves as an electrophile in polar reactions.

Preparing Alkyl Halides from Alkenes

• Alkyl halides can be prepared using electrophilic addition reactions with HX and $X_2$ with alkenes.

  • Hydrogen halides (HCl, HBr, HI) react with alkenes via a polar mechanism, resulting in Markovnikov addition.

  • Bromine and chlorine undergo anti-addition through a halonium ion intermediate, forming 1,2-dihalogenated products.

Allylic Bromination

• Alkyl halides can be synthesized from alkenes via reaction with N-bromosuccinimide (NBS) in the presence of light.

• Bromine substitutes for hydrogen at the allylic position (next to the double bond).

Mechanism of Allylic Bromination

• A bromine radical abstracts an allylic hydrogen atom from the alkene, forming an allylic radical plus HBr.

• The allylic radical then reacts with $Br_2$ to form the product and a bromine radical that propagates the chain reaction.

• $Br_2$ is produced from the reaction between NBS and HBr formed in the first step.

Stability of Allylic Radicals

• Allylic radicals are more stable than alkyl radicals (by ~40 kJ/mol or 9 kcal/mol) and vinylic radicals (by ~85 kJ/mol or 19 kcal/mol).

• According to the Hammond postulate, allylic radicals form faster.

• Allylic radicals are stable due to resonance.

• Allylic bromination of unsymmetrical alkenes can yield a mixture of products because the intermediate allylic radical is not always symmetrical, leading to unequal reaction probabilities at different ends.

• Products from allylic bromination can be converted into conjugated dienes through dehydrohalogenation with a base.

Preparing Alkyl Halides from Alcohols

• Alcohols can be transformed into alkyl halides using various methods:

  • Treating the alcohol with HCl, HBr, or HI (works best with tertiary alcohols $R_3COH$; primary and secondary alcohols react slowly and at higher temperatures).

  • Reaction with HX is rapid for tertiary alcohols and can be carried out by bubbling HCl or HBr gas into a cold ether solution of the alcohol.

  • Primary and secondary alcohols react with thionyl chloride ($SOCl<em>2$) or phosphorus tribromide ($PBr</em>3$) under mild conditions; these reactions are less acidic and less prone to acid-catalyzed rearrangements than the HX method.

  • Alkyl fluorides can be prepared from alcohols using reagents like diethylaminosulfur trifluoride ($(CH<em>3CH</em>2)<em>2NSF</em>3$) and HF in pyridine solvent.

Reactions of Alkyl Halides: Grignard Reagents

Grignard Reagents

• Named after Victor Grignard.

• Alkylmagnesium halides (RMgX) are formed from the reaction of alkyl halides (RX) with magnesium metal in ether or tetrahydrofuran (THF) solvent.

• Grignard reagents are examples of organometallic compounds (contain a carbon-metal bond).

• They can also be made from alkenyl (vinylic) and aryl (aromatic) halides.

• The carbon-magnesium bond in the Grignard reagent is polarized, making the carbon atom both nucleophilic and basic.

• Grignard reagents are magnesium salts ($R<em>3C^- +MgX$) of carbon acids ($R</em>3C-H$).

• They react with weak acids (e.g., $H<em>2O$, ROH, $RCO</em>2H$, $RNH_2$) to abstract a proton and form hydrocarbons.

• Hydrocarbons are weak acids (pKa’s 44-60), so carbon anions are strong bases.

• Grignard reagents do not play a role in the biochemistry of living organisms.

• They are useful carbon-based nucleophiles in laboratory reactions and act as models for more complex carbon-based nucleophiles important in biological chemistry.

Organometallic Coupling Reactions

Alkyllithium Reagents

• Alkyllithium reagents (RLi) can be prepared through the reaction of an alkyl halide with lithium metal.

• Alkyllithiums are both nucleophiles and strong bases, exhibiting similar chemistry to alkylmagnesium halides.

Gilman Reagents

• Alkyllithiums react with copper(I) iodide in diethyl ether to form lithium diorganocopper compounds ($R_2CuLi$), also known as Gilman reagents.

• Gilman reagents participate in coupling reactions with organochlorides, bromides, and iodides (but not fluorides).

• Organometallic coupling reactions create carbon-carbon bonds, enabling the synthesis of larger molecules from smaller ones.

Mechanism of Gilman Coupling Reaction

• The mechanism involves the initial formation of a triorganocopper intermediate, followed by coupling and loss of RCu.

Suzuki-Miyaura Reaction

• Organopalladium compounds are utilized in organocoupling reactions.

• The Suzuki-Miyaura reaction involves reacting an aromatic or vinyl-substituted boronic acid [$R-B(OH)_2$] with an aromatic or vinyl-substituted organohalide.

• The Suzuki-Miyaura reaction does not work with alkyl substrates.

• The Suzuki-Miyaura reaction is used for the preparation of biaryl compounds.

• The Suzuki-Miyaura reaction requires only a catalytic amount of metal and palladium compounds are less toxic.

• The Suzuki-Miyaura reaction is used in the synthesis of drug candidates like Valsartan (Diovan).

Mechanism of the Suzuki-Miyaura Coupling Reaction

• The mechanism involves the reaction of an aromatic halide (ArX) with a catalyst to generate an organopalladium intermediate.

• The organopalladium intermediate then reacts with an aromatic boronic acid.

• The diarylpalladium intermediate decomposes to yield the biaryl product.

Discovery of the Nucleophilic Substitution Reaction

• Alkyl halides act as electrophiles, reacting with nucleophiles/bases through substitution or elimination.

  • Substitution: the nucleophile replaces the X group.

  • Elimination: HX is removed, forming an alkene.

• In 1896, Paul Walden discovered that enantiomers of malic acids could be interconverted via substitution reactions, with some reactions causing an inversion of configuration at the chirality center.

• Nucleophilic substitution reactions are common and versatile in organic chemistry.

• These reactions explain the transformations in Walden’s cycle, where one nucleophile (e.g., $Cl^−$ or $HO^−$) is replaced by another.

• Investigations in the 1920s and 1930s aimed to clarify the mechanism of nucleophilic substitution reactions and understand how inversions of configuration occur.

• In the Walden cycle interconverting enantiomers of 1-phenylpropan-2-ol, at least one step must involve inversion of configuration at the chirality center.

• Nucleophilic substitution of a primary or secondary alkyl halide or tosylate always proceeds with inversion of configuration.

The SN2 Reaction

Kinetics

• Kinetics studies reaction rates.

• There is a direct relationship between the reaction rate and the concentrations of reactants.

• For a simple nucleophilic substitution, the reaction rate depends on the concentration of each reactant.

• If the concentration of $OH^−$ doubles, the reaction rate doubles.

• If the concentration of $CH_3Br$ doubles, the reaction rate doubles.

Second-Order Reaction

• In a second-order reaction, the rate is linearly dependent on the concentrations of two species.

• The rate equation is: Reaction rate = k [$CH_3Br$] [$^−OH$]

  • [$CH<em>3Br$] = concentration of $CH</em>3Br$ in molarity

  • [$^−OH$] = concentration of $^−OH$ in molarity

  • k = rate constant

SN2 Mechanism

• $S_N2$ stands for substitution, nucleophilic, bimolecular.

• Proposed by E. D. Hughes and Christopher Ingold in 1937.

• The reaction takes place in a single step without intermediates.

• The incoming nucleophile reacts with the alkyl halide or tosylate (substrate) from the opposite direction of the leaving group.

• Inversion of stereochemistry at carbon.

• The nucleophile approaches from 180º away from the leaving halide ion, inverting stereochemistry at carbon.

• During the reaction, an electron pair on the nucleophile ($Nu:^−$) forces out the leaving group ($X:^−$), which takes the electron pair from the C-X bond.

• The transition state of an $S_N2$ reaction has a planar arrangement of the carbon atom and the remaining three groups.

Characteristics of the SN2 Reaction

• The rate of a chemical reaction is determined by $\Delta G^{\ddagger}$, the energy difference between the reactant ground state and transition state.

• Higher reactant energy decreases the activation energy, decreasing $\Delta G^{\ddagger}$ and increasing the reaction rate; higher transition-state energy increases $\Delta G^{\ddagger}$ and decreases the reaction rate.

Substrate: Steric Effects

• The $S_N2$ transition state involves partial bond formation between the incoming nucleophile and the alkyl halide carbon atom.

• Bromomethane is readily accessible, resulting in a fast $S_N2$ reaction.

• $S_N2$ reactions occur only at relatively unhindered sites. Relative reactivities for different substrates follow the order: methyl > primary > secondary >> tertiary.

• Vinylic halides ($R<em>2C=CRX$) and aryl halides are unreactive toward $S</em>N2$ reactions.

The nucleophile

• A Lewis base.

• Any species, either neutral or negatively charged, that has an unshared pair of electrons.

• If negatively charged, the product is neutral; if neutral, the product is positively charged.

• Nucleophilicity roughly parallels basicity when comparing nucleophiles with the same reacting atom.

• $OH^−$ is more basic and nucleophilic than acetate ion ($CH<em>3CO</em>2^−$), which is more basic and nucleophilic than $H_2O$.

• Nucleophilicity is the affinity of a Lewis base for a carbon atom in the $S_N2$ reaction, while basicity is the affinity of a base for a proton.

• Nucleophilicity usually increases going down a column of the periodic table.

• $HS^−$ is more nucleophilic than $HO^−$.

• Halide reactivity order is I^− > Br^− > Cl^−.

• Negatively charged nucleophiles are more reactive than neutral ones.

• $S_N2$ reactions are often carried out under basic conditions rather than neutral or acidic conditions.

The Leaving Group

• Best leaving groups stabilize the negative charge in the transition state.

• The greater the charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction.

• Weak bases (e.g., $Cl^−$ and tosylate ion) make good leaving groups, while strong bases (e.g., $OH^−$ and $NH_2^−$) make poor leaving groups.

• Alkyl fluorides, alcohols, ethers, and amines do not typically undergo $S_N2$ reactions.

• To carry out an $S_N2$ reaction with an alcohol, the $HO^−$ group must be converted into a better leaving group.

• A primary or secondary alcohol is converted into an alkyl chloride by reaction with $SOCl<em>2$ or an alkyl bromide by reaction with $PBr</em>3$.

• An alcohol can be made more reactive toward nucleophilic substitution by treating it with p-toluenesulfonyl chloride to form a tosylate.

Epoxides

• Epoxides are three-membered cyclic ethers.

• Epoxides are more reactive than other ethers due to angle strain in the three-membered ring.

• Epoxides react with aqueous acid to give 1,2-diols and readily with many other nucleophiles.

• Propene oxide reacts with HCl to give 1-chloropropan-2-ol by $S_N2$ backside attack on the less hindered primary carbon atom.

The Solvent

• Protic solvents (those with –OH or –NH groups) are generally unfavorable for $S_N2$ reactions.

• Protic solvents decrease the rates of $S_N2$ reactions by lowering the ground-state energy of the nucleophile.

• Methanol and ethanol slow down $S_N2$ reactions by solvation of the reactant nucleophile.

• Solvent molecules hydrogen bond to the nucleophile and form a cage around it.

• Polar aprotic solvents (polar but without –OH or –NH groups) are the best solvents for $S_N2$ reactions.

• Polar aprotic solvents increase the rates of $S_N2$ reactions by raising the ground-state energy of the nucleophile.

• These solvents dissolve many salts due to their high polarity, but they solvate metal cations rather than nucleophilic anions.

• Bare, unsolvated anions have greater nucleophilicity, and $S_N2$ reactions occur at correspondingly faster rates.

Summary of SN2 Reaction Characteristics

• Substrate

  • Steric hindrance raises the energy of the $S_N2$ transition state, increasing $\Delta G^{\ddagger}$ and decreasing the reaction rate.

  • $S_N2$ reactions are best for methyl and primary substrates.

• Nucleophile

  • Basic, negatively charged nucleophiles are less stable and have a higher ground-state energy than neutral ones, decreasing $\Delta G^{\ddagger}$ and increasing $S_N2$ reaction rate.

• Leaving Group

  • Good leaving groups (more stable anions) lower the energy of the transition state, decreasing $\Delta G^{\ddagger}$ and increasing $S_N2$ reaction rate.

• Solvent

  • Protic solvents solvate the nucleophile, lowering its ground-state energy, increasing $\Delta G^{\ddagger}$, and decreasing $S_N2$ reaction rate.

  • Polar aprotic solvents surround the cation but not the nucleophilic anion, raising the nucleophile's ground-state energy, decreasing $\Delta G^{\ddagger}$, and increasing $S_N2$ reaction rate.

SN1 Reaction

SN1 Characteristics

• The $S_N1$ reaction is a unimolecular nucleophilic substitution reaction.

• The rate of reaction depends only on the alkyl halide concentration, and is independent of the $H_2O$ concentration, making it a first-order process.

• The nucleophile concentration does not appear in the rate equation (rate-limiting step).

• The mechanism involves three steps:

  1. Spontaneous dissociation of the alkyl bromide occurs in a slow, rate-limiting step, creating a carbocation intermediate and bromide ion.

  2. The carbocation intermediate reacts with water (nucleophile) in a fast step to yield protonated alcohol.

  3. Loss of a proton from the protonated alcohol intermediate generates the neutral alcohol product.

• The $S_N1$ reaction's rate-limiting step is a spontaneous dissociation of the alkyl halide, yielding a carbocation intermediate.

• If an $S_N1$ reaction is carried out on one enantiomer of a chiral reactant and proceeds through an achiral carbocation intermediate, the product will be optically inactive.

• The symmetrical intermediate carbocation can react with a nucleophile equally well from either side, leading to a racemic (50:50) mixture of enantiomers.

• $S<em>N1$ reactions on enantiomerically pure substrates do not occur with complete racemization. Most give a minor (0-20%) excess of inversion. E.g., the reaction of (R)-6-chloro-2,6-dimethyloctane with $H</em>2O$ yields approximately 80% racemization and 20% inversion.

• The leaving group shields one side of the carbocation intermediate from reaction with the nucleophile, leading to some net inversion of configuration rather than complete racemization.

• Factors that lower $\Delta G^{\ddagger}$, either by lowering the energy level of the transition state or by raising the energy level of the ground state, favor faster $S<em>N1$ reactions. The more stable the carbocation intermediate, the faster the $S</em>N1$ reaction.

• Carbocation stability: 3° > 2° > 1° > –$CH_3$. Allylic and benzylic cations are also favored.

• Primary allylic and benzylic carbocations are about as stable as secondary alkyl carbocations. Secondary allylic and benzylic carbocations are about as stable as tertiary alkyl carbocations.

• Allylic and benzylic substrates are particularly reactive in $S<em>N2$ and $S</em>N1$ reactions.

• The leaving group reactivity order is identical to the order for $S_N2$ reactions.

• For $S_N1$ reactions carried out under acidic conditions, neutral water can be the leaving group.

• The nucleophile does not affect the $S<em>N1$ reaction rate because the $S</em>N1$ reaction occurs through a rate-limiting step.

• Solvent effects in the $S_N1$ reaction are due largely to stabilization or destabilization of the transition state.

• Any factor that stabilizes the intermediate carbocation should increase the rate of an $S_N1$ reaction (Hammond postulate).

• Carbocation solvation: the electron-rich oxygen atoms of solvent molecules orient around the positively charged carbocation and thereby stabilize it.

• $S_N1$ reactions take place much more rapidly in polar solvents like water and methanol than in nonpolar solvents like ether and chloroform.

Summary of SN1 Reaction Characteristics

• Substrate: Best substrates yield the most stable carbocations (tertiary, allylic, benzylic halides).

• Leaving Group: Good leaving groups increase the reaction rate by lowering the energy level of the transition state.

• Nucleophile: The nucleophile does not affect the reaction rate.

• Solvent: Polar solvents stabilize the carbocation intermediate by solvation, thereby increasing the reaction rate.

Biological Substitution Reactions

• $S<em>N1$ and $S</em>N2$ reactions are known in biological chemistry.

• Pathways for biosynthesis of the many thousands of terpenes.

• The substrate in a biological substitution reaction is often an organodiphosphate rather than an alkyl halide.

• The leaving group is the diphosphate ion, $PP_i$, rather than a halide ion.

• A fragrant alcohol found in roses and used in perfumery.

• Two $S_N1$ reactions occur, both with diphosphate ion as the leaving group.

• $S<em>N2$ reactions are involved in almost all biological methylations, which transfer a –$CH</em>3$ group from an electrophilic donor to a nucleophile.

• The –$CH_3$ donor is S-adenosylmethionine (SAM), which contains a positively charged sulfur (a sulfonium ion).

• The leaving group is the neutral S-adenosylhomocysteine molecule.

Elimination Reactions: Zaitsev’s Rule

• When a nucleophile/Lewis base reacts with an alkyl halide, two kinds of reactions can occur:

  • Substitution, where a nucleophile reacts at carbon to substitute for the halide

  • Elimination, where a nucleophile reacts at a neighboring hydrogen to cause elimination of HX

• Elimination reactions almost always give mixtures of alkene products.

• Zaitsev’s rule states that in the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates.

  • Formulated in 1875 by Alexander Zaitsev, a Russian chemist.

• Elimination reactions can take place by different mechanisms: E1, E2, and E1cB reactions.

  • Differ in the timing of C-H and C-X bond breaking.

  • All three mechanisms occur in the laboratory.

  • E1cB predominates in biological pathways.

E2 Reaction

• C-H and C-X bonds break simultaneously, giving the alkene in a single step without intermediates.

E1cB Reaction

• C-H bond breaks first, giving a carbanion intermediate that loses X to form the alkene.

The E2 Reaction and the Deuterium Isotope Effect

• The E2 reaction is the most common pathway for elimination in the laboratory.

• The E2 reaction occurs when an alkyl halide is treated with a strong base, such as hydroxide ion or alkoxide ion ($R-O^−$).

• The reaction takes place in a single step through a transition state in which the double bond begins to form as the H and X groups are leaving.

• E2 reactions show second-order kinetics and follow the rate law:

• Both base and alkyl halide take part in the rate-limiting step.

• Deuterium isotope effect (supporting evidence for E2 mechanism):

  • A carbon-hydrogen bond is weaker than a carbon-deuterium bond.

  • A C-H bond is more easily broken than an equivalent C-D bond.

  • The rate of C-H bond cleavage is faster.

• E2 reactions occur with periplanar geometry.

  • All four reacting atoms—the hydrogen, the two carbons, and the leaving group—lie in the same plane.

  • Anti periplanar geometry occurs when the H and the X are on opposite sides of the molecule.

  • Syn periplanar geometry occurs when the H and the X are on the same side of the molecule.

• The $sp^3$ orbitals in the reactant C-H and C-X bonds must overlap and become p orbitals in the alkene product.

  • They must overlap in the transition state.

  • Occurs most easily if all orbitals are periplanar.

• Anti periplanar geometry for E2 eliminations has specific stereochemical consequences.

  • Meso-1,2-dibromo-1,2-diphenylethane undergoes E2 elimination on treatment with base to give only the E alkene.

  • No Z alkene is formed because the transition state leading to the Z alkene would have to have syn periplanar geometry and thus be higher in energy.

• Anti periplanar geometry is also particularly important in cyclohexane rings, where chair geometry forces a rigid relationship between substituents on adjacent carbon atoms.

  • Only if the hydrogen and the leaving group are trans diaxial can an E2 reaction occur.

The E1 and E1cB Reactions

• The E1 reaction is a unimolecular elimination reaction in which the C-X bond breaks before the C-H bond, giving a carbocation intermediate.

  • Analogous to the $S_N1$ reaction.

  • Two steps are involved, with the first as rate-limiting.

  • Carbocation intermediate is present.

• E1 elimination begins with the same unimolecular dissociation as in the $S_N1$ reaction.

  • Dissociation is followed by loss of H+ from the adjacent carbon rather than by substitution.

• Best E1 substrates are also the best $S_N1$ substrates (mixtures of substitution and elimination products usually result).

• E1 mechanisms are supported by evidence.

  • E1 reactions show first-order kinetics, consistent with a rate-limiting, unimolecular dissociation process.

  • E1 reactions show no deuterium isotope effect.

  • Rupture of the C-H (or C-D) bond occurs after the rate-limiting step rather than during it.

  • There is no geometric requirement on the E1 reaction.

  • The halide and the hydrogen are lost in separate steps.

E1cB Reaction

• The E1cB reaction is a unimolecular elimination reaction in which the C-H bond breaks before the C-X bond, giving a carbanion intermediate.

  • The anion formed expels a leaving group on the adjacent carbon.

  • Common in substrates that have a poor leaving group (e.g., –OH) that is two carbons removed from a carbonyl group (HO-C-CH-C=O).

  • The carbonyl group makes the adjacent hydrogen unusually acidic by resonance stabilization of the anion intermediate.

Biological Elimination Reactions

• All three elimination reactions—E1, E1cB, and E2—occur in various biological pathways, with the E1cB mechanism is particularly common.

• 3-hydroxy carbonyl compounds are frequently converted to conjugated unsaturated carbonyl compounds by elimination reactions.

• The substrate is usually an alcohol, and the H atom is usually adjacent to a carbonyl group, just as in the laboratory.

• Biosynthesis of fats where a 3-hydroxybutyryl thioester is dehydrated to the corresponding unsaturated (crotonyl) thioester by elimination reactions.

A Summary of Reactivity: SN1, SN2, E1, E1cB, and E2

• Recognizing trends and making generalizations aids in predicting reaction outcomes.

• Primary Alkyl Halides

  • $S_N2$ substitution occurs if a good nucleophile is used.

  • E2 elimination occurs if a strong base is used.

  • E1cB elimination occurs if the leaving group is two carbons away from a carbonyl group.

• Secondary Alkyl Halides:

  • $S_N2$ substitution occurs if a weakly basic nucleophile is used in a polar aprotic solvent.

  • E2 elimination predominates if a strong base is used.

  • E1cB elimination takes place if the leaving group is two carbons away from a carbonyl group.

  • $S_N1$ and E1 reactions occur if a weakly basic nucleophile is used in a protic solvent.

• Tertiary Alkyl Halides:

  • E2 elimination occurs when a base is used.

  • $S_N1$ substitution and E1 elimination occur together under neutral conditions, such as in pure ethanol or water.

  • E1cB elimination takes place if the leaving group is two carbons away from a carbonyl group.