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 (SOCl2) or phosphorus tribromide (PBr3) 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 ((CH3CH2)2NSF3) 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 (R3C^- +MgX) of carbon acids (R3C-H).
They react with weak acids (e.g., H2O, ROH, RCO2H, 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]
[CH3Br] = concentration of CH3Br 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 (R2C=CRX) and aryl halides are unreactive toward SN2 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 (CH3CO2^−), 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 SOCl2 or an alkyl bromide by reaction with PBr3.
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:
Spontaneous dissociation of the alkyl bromide occurs in a slow, rate-limiting step, creating a carbocation intermediate and bromide ion.
The carbocation intermediate reacts with water (nucleophile) in a fast step to yield protonated alcohol.
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.
SN1 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 H2O 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 SN1 reactions. The more stable the carbocation intermediate, the faster the SN1 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 SN2 and SN1 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 SN1 reaction rate because the SN1 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
SN1 and SN2 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.
SN2 reactions are involved in almost all biological methylations, which transfer a –CH3 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.