Alkene Addition Reaction Practice prediction of major products Attention to regioselectivity and stereochemistry Attempt synthesis by using all addition reactions Master mechanisms for Halohydrogenation Hydration (with possible Rearrangement) Halogenation

Addition Reaction Addition is the opposite of elimination A π bond is converted to a s bond

Addition Reaction as Lewis Acid/Base Rxn. A pi bond will often act as a Lewis base (as a nucleophile or as a Brønsted-Lowry base). Cation as Lewis acid.

Addition / Elimination Equilibria Because an addition is the reverse of an elimination, often the processes are at equilibrium An equilibrium is dynamic process The sign of ΔG (the free energy) dictates which side the equilibrium will favor

Energy/Entropy for Addition Rxn Bonds broken – bonds formed = 166 kcal/mol – 185 kcal/mol = –19 kcal/mol Typical addition reactions: ΔH < 0, ΔS < 0.

Low Temperature Favor Addition Since To favor addition, a –ΔG is needed The entropy term needs to be small (including negative) to favor addition. Since –TΔS is always positive, lower Temperature would help addition Conversely, high temperature favors elimination.

I. Hydrohalogenation (+ HX) Note the low temperature used in this addition reaction Symmetrical alkene gives single addition product unless rearrangement occurs For asymmetrical alkenes, multiple products may arise yet addition rxn may show preference (selectivity, regiochemistry)

Selectivity in Hydrohalogenation When HX added to Asymmetrical alkene: Markovnikov (1869) showed that in general, H atoms tend to add to the carbon already bearing more H atoms

Markovnikov’s rule for Hydrohalogenation Or, in general, halogen atoms tend to add to the carbon that is more substituted with other carbon groups Regioselective reaction: One constitutional isomer is formed in greater quantity than another The structure of the minor product for the above?

Mechanism for Addition Reaction The rate law of Markovnikov rxn : rate = k[alkene][HX] Thus a two step mechanism: Protonation of C=C bond by HX, followed by nucleophilic attack by halide

Carbocation as rxn intermediate

Hydrohalogenation via Carbocation The stability of carbocation dictate the Markovnikov regioselectivity

Stable carbocation has lower activation energy

Addition Products as Racemic Mixture Although chirality centers are formed, addition of halide on carbocation gives racemic mixture (equal mix) Carbocation (sp2) allows addition from both sides

Rearrangements on Carbocation Rearrangements (hydride or methyl shifts) occur for the carbocation if the shift makes it more stable. Mechanism:

Rearrangement gives more product Significant diversity of products limits synthetic utility 

Regioselectivity depends on Reagents/Solvent/Catalyst used! Anti-Markovnikov addition: Addition in the presence of peroxides such as H2O2 The different regioselectivities are the result of different Reaction mechanism.

Predict Addition Product and Mechanism Predict the major product(s) and Mechanism for B

II: Acid Catalyzed Hydration The components of water (-H and –OH) are added across a C=C double bond The acid catalyst is often shown over the arrow, because it is regenerated rather than being a reactant

Rate of Hydration Rxn Acid catalyzed hydration shows preference of more substituted alkene

Hydration Mechanism: Carbocation

Hydration Thermodynamics Similar to Hydrohalogenation, hydration reactions are also reversible Exothermic, entropy decrease process Thus low temperature could help Hydration Addition Elimination

Hydration Elimination Equilibrium Note the concentrated sulfuric acid strongly absorbs/removes water from reaction to help elimination (Châtelier’s principle)

Hydration: Stereochemistry Similar to Hydrohalogenation, the stereochemistry of hydration reactions is controlled by the geometry of the carbocation, yielding a racemic mixture

Application of Hydration Industrial production of ethanol utilizes hydration reaction of ethylene (ethene) In general, the presence of carbocation intermediate allows rearrangement, thus only limited application for synthesis 

III: Oxymercuration-Demercuration In carbocation mechanism, rearrangements often produce a mixture of products, the synthetic utility of Markovnikov hydration reactions is somewhat limited Oxymercuration-demercuration is an alternative process to synthesize alcohol (Markovnikov products) without the possibility of rearrangement

Mercuric cation (HgOAc+) Oxymercuration begins with mercuric acetate Mercuric cation As an electrophile (positive charge) As a Lewis acid Alkene is a nucleophile

Mercuration & Nucleophilic Attack Nucleophile water attacks the carbon with more substituents (eventually leading to Markovnikov alcohol)

Demercuration NaBH4 is generally used to replace the –HgOAc group with a –H group via a free radical mechanism.

IV. Hydroboration-Oxidation To achieve anti-Markovnikov hydration, Hydroboration-Oxidation is often used THF for tetrahydrofuran, an ether Note that the process occurs in two steps

Hydroboration-Oxidation: Syn Addition Hydroboration-Oxidation reactions achieve syn addition Anti addition is NOT observed

BH3 , B2H6, BH3•THF BH3 : similar to a carbocation, electrophile Dimerization of borane forms more stable diborane (B2H6). BH3•THF is stabilized, used as hydroboration agent

Hydroboration: Addition of Borane C=C as nucleophile/Lewis base attacks borane Two more cycles gives R3B. Boron attacks Carbon with fewer substituents.

Oxidation with H2O2 forms alcohol

Hydroboration forming One chiral center When ONE chirality center is formed, a racemic mixture results, similar to carbocation addition. Borane can add to alkene from both sides of the C=C bond, leading to both R and S products. Anti-Markovnikov alcohol

Stereochemistry involving TWO chiral centers SYN addition of B-H bond on C=C bond: When TWO chirality centers are formed, a racemic mixture results. The syn addition of H and OH. Two stereoisomers: (3S, 4R) and (3R, 4S) only, No (3S, 4S) nor (3R, 4R) products formed. Concerted addition of B-H bond!

Predict Hydration Product

III. Catalytic Hydrogenation The addition of H2 across a C=C double bond Stereochemistry: If a chirality center is formed, syn addition is observed

Catalytic Hydrogenation: Energy diagram Without catalyst: Exothermic reaction with high activation energy Typical catalysts include Pt, Pd, and Ni

Catalytic Hydrogenation: Mechanism The metal catalyst is believed to both adsorb the H atoms and coordinate the alkene The H atoms add to the same side of the alkene pi system

IV. Halogenation: Add X-X Halogenation involves adding two halogen atoms across a C=C double bond Halogenation is a key step in the production of PVC

Halogenation: Energetics and Stereochemistry Exothermic: Halogenation with Cl2 and Br2 is generally effective, but halogenation with I2 is too slow and halogenation with F2 is too violent Halogenation occurs with anti addition

Polarizibility of X2 Allows Nuc: Attack Halogen molecules (Br2. Cl2 ) is nonpolar, but polarizable (Br+ -Br-) Nucleophile (such as alkene) attacks positive charge of Br2 During nucleophilic attack, bromide ion as leaving group

Halogenation: No Carbocation intermediate If alkene attacking Br2 , forming a carbocation in a similar way as protonation, carbocation intermediate would allow nucleophilic attack from both sides Such mechanism DOES NOT match the stereospecificity of the reaction.

Bromination via Bromonium ion The intermediate brominium ion was detected by NMR spectroscopy in 1967 (http://pubs.acs.org/doi/abs/10.1021/ja00994a031 )

Anti addition for Halogenation Only anti addition is observed Can you design a synthesis for ?

Predict the major halogenation product

V. Halohydrin from HOX addition Alkene reacts with Cl2 or Br2 in water, forming halohydrin Regioselectivity: The –OH group adds to the more substituted carbon Stereochemistry: Anti addition

Halohydration Mechanism 1st step: Reaction with halogen to form bromonium ion 2nd step: water as nucleophile attack on backside. Due to the excess water (solvent) Finally, deprotonation

Halohydrin Regioselectivity Water attacks the bromonium from one side that goes through the lower energy transition state: remember the stability of carbocation affects transition state. Steric effect is negligible due to small size of water Transition state

-halogenated Ether from X2 in Alcohol Alkene reacts with Cl2 or Br2 in alcohol (ROH), forming -halogenated ether Regioselectivity and Stereochemistry: The –OR group adds to the more substituted carbon, with anti addition

Practice: Halohydrin formation Predict the major product(s) or Find the reagents

VI. Anti Dihydroxylation Dihydroxylation (addition of TWO hydroxyl groups) occurs when two –OH groups are added across a C=C double bond Anti dihydroxylation involves peroxy acid (RCO3H) /acid hydrolysis:

Formation of Epoxide First, an epoxide is formed Alkene as nucleophile attacking electron deficient O-O bond, thermodynamic driven Epoxide is unstable Meta-chloroperbenzoic acid (MCPBA)

Activation and Attacking of Epoxide epoxide is activated/protonated with an acid Water as nucleophile attack backside Deprotonation

Protonated Epoxide Allows for Anti addition Note the similarities between three key intermediates Ring strain and a +1 formal charge makes these structures GREAT electrophiles Each yield anti products, because the nucleophile must attack from the side opposite the leaving group

VII. Syn Dihydroxylation Like other syn additions, syn dihydroxylation adds across the C=C double bond in ONE step

OsO4 for Syn Dihydroxylation Because OsO4 is expensive and toxic, conditions have been developed where the OsO4 is regenerated after reacting, so only catalytic amounts are needed

MnO4- in Syn Dihydroxylation MnO4- is similar to OsO4 but more reactive Syn dihydroxylation can be achieved with KMnO4 but only under mild conditions (cold temperatures) Diols are often further oxidized by MnO4-, and MnO4- is reactive toward many other functional groups as well The synthetic utility of MnO4- is limited

Synthetic idea for Dihydroxylation Choose the proper reagent for the transformation below

Oxidative Cleavage with O3 C=C double bonds are also reactive toward oxidative cleavage: >C=C< + O3  >C=O + O=C< Ozonolysis is one such process

Ozonolysis Mechanism Common reducing agents: dimethyl sulfide (DMS) and Zn/H2O.

Practice: Oxidative Cleavage with O3 Predict the major product(s) for the reaction below

***Predicting Addition Products Analyze the reagents used to determine what groups will be added across the C=C double bond Determine the regioselectivity (Markovnikov or anti-Markovnikov) Determine the stereospecificity (syn or anti addition) Memorization required: Reagent/Solvent; Mechanistic rationale (the intermediate) The more familiar you are with the mechanisms (through practice), the easier predicting products will be

***Organize your notes Substrate Reagent/solvent, steps involved Key Rxn Intermediate Main product(s) Regioselectivity, Stereoselectivity RCO3H H3O+ Anti

***One Step Syntheses To set up a synthesis, assess the reactants and products to see what changes need to be made Label each of the processes below

One Step Syntheses To set up a synthesis, assess the reactants and products to see what changes need to be made Give reagents and conditions for the following Practice with SkillBuilder 9.10

Additional Practice Problems If you want to favor addition rather than elimination, do you generally want a high or low temperature, and why?

Additional Practice Problems Predict the major product for the addition reaction below. Be aware of possible rearrangements and stereochemical concerns.

Additional Practice Problems How and why will the concentration of acid affect whether an acid catalyzed hydration will favor products or reactants at equilibrium?

Additional Practice Problems Give an example reaction for Markovnikov hydration without the possibility of rearrangement. Give an example reaction for syn antiMarkovnikov hydration.

Additional Practice Problems Should a halogenation reaction be overall first or second order kinetics? Also, Explain why it gives anti addition rather than syn.

Additional Practice Problems What reagents are necessary to achieve the following synthesis?

Predict the major product of Hydroboration-Oxidation major product(s) for the reactions below

Homogeneous catalyst for Catalytic Hydrogenation If catalysis takes place on the surface of a solid surrounded by solution, the catalyst is heterogeneous. Homogeneous catalysts (Wilkinson et al, 1966; 1973 Nobel) have been developed:

Asymmetric Hydrogenation In 1968, Knowles (2001 Nobel) modified Wilkinson’s catalyst by using a chiral phosphine ligand A chiral catalyst can produce one desired enantiomer over another. Particularly important for bio/medicinal related purpose, such as drug or insecticide.

Energy diagram for asymmetric hydrogenation A chiral catalyst allows one enantiomer to be formed more frequently in the reaction mixture Kinetically favored or thermodynamically favored? Some chiral catalysts give better enantioselectivity than others. WHY?

Asymmetric Catalysis: A “Hot” Field BINAP is a chiral ligand that gives pronounced enantioselectivity For any reaction, stereoselectivity can only be achieved if at least one reagent (reactant or catalyst) is chiral

Mechanism for Addition Reaction The rate law of Markovnikov rxn : rate = k[alkene][HX] Thus a two step mechanism: Protonation of C=C bond by HX (slow) gives carbocation Addition of X- to carbocation (fast) gives alkyl halide

Rearrangements on Carbocation Rearrangements (hydride or methyl shifts) occur for the carbocation if the shift makes it more stable

Hydration Mechanism: Carbocation Similar to Markovnikov Hydrohalogenation

Mechanism for Addition Reaction The rate law of Markovnikov rxn : rate = k[alkene][HX] Thus a two step mechanism: Protonation of C=C bond by HX, followed by nucleophilic attack by halide

Mechanism: Bromonium ion bromine atom shares lone pair electrons with carbocation  bromonium ion The intermediate brominium ion was detected by NMR spectroscopy in 1967 (http://pubs.acs.org/doi/abs/10.1021/ja00994a031 )

Backside Bromide attack on Bromonium

Halohydration Mechanism 1st step: Reaction with halogen to form bromonium ion 2nd step: water as nucleophile attack on backside. Due to the excess water (solvent) Finally, deprotonation

Practice: Asymmetric Hydrogenation Predict the major product(s) for the reactions below

Practice: stereochemistry in halogenation Predict the major product(s) for the reactions below

Practice: Halohydrin Regioselectivity Predict the major product(s) for the reactions below

Practice: Predict Addition Products Predict the major product(s) for the reaction below

Practice: Oxidative Cleavage with O3 Predict the major product(s) for the reaction below Treasure Hunt (2 extra credits due next class meeting): Find all the bicyclic reactants might give the product below