Reactions in Organic Compounds As we first learned with acid/base reactions with Lewis definition, any reaction can be considered as a nucleophile reacting with an electrophile electrophile The closer in energy LUMO the HOMO is to the reaction LUMO means there will be a greater Energy gain energy gain HOMO nucleophile product All reactions thus involve a filled molecular orbital (called HOMO, representing the nucleophile) reacting with an empty molecular orbital (called LUMO, representing the electrophile) electrophile nucleophile product Studying an Organic Reaction How do we know if a reaction can occur? And – if a reaction can occur what do we know about the reaction? CH3ONa CH3Cl CH3OCH3 NaCl Information we want to know: How much heat is generated? (What is the THERMODYNAMICS of the reaction?) How fast is the reaction? (What is the KINETICS of the reaction?) Are any intermediates generated? (What is the reaction mechanism?) All of this information is included in an Energy Diagram Possible Mechanism 1 Possible Mechanism 2 Transition Transition states states Potential Potential Intermediate energy energy Starting material Starting Products material Products Reaction Coordinate Reaction Coordinate If we know the “shape” of the reaction coordinate, then all questions about the mechanism can be answered (thermodynamics and kinetics) Equilibrium Constants Equilibrium constants (Keq) indicate thermodynamically whether the reaction is favored in the forward or reverse direction and the magnitude of this preference A B C D ΔG Keq = ([C][D]) / ([A][B]) = ([products]) /([starting material]) Reaction Coordinate Gibb’s Free Energy The Keq is used to determine the Gibb’s free energy ΔG = (free energy of products) – (free energy of starting materials) If we use standard free energy then ΔG˚ (25˚C and 1 atm) Keq = e(-ΔG˚/RT) or ΔG˚ = -RT(ln Keq) = -2.303 RT(log10 Keq) A favored reaction thus has a negative value of ΔG˚ (energy is released) Contributions to Free Energy ΔG˚ = ΔH˚ -TΔS˚ The free energy term has two contributions: enthalpy and entropy Enthalpy (ΔH˚): heat of a reaction (due to bond strength) Exothermic reaction: heat is given off by the reaction (-ΔG˚) Endothermic reaction: heat is consumed by the reaction (+ΔG˚) Entropy (ΔS˚): a measure of the freedom of motion - Reactions (and nature) always prefer more freedom of motion Organic reactions are usually controlled by the enthalpy Bond Dissociation Energies The free energy of organic reactions is often controlled by the enthalpic term -The enthalpic term in organic reactions is often controlled by the energy of the bonds being formed minus the energy of the bonds being broken The energies of bonds is called the Bond Dissociation Energy Many types of bonds have been recorded (both experimentally and computationally) we can therefore predict the equilibrium of a reaction by knowing these BDE’s Kinetics A second important feature is the RATE of a reaction The rate is not determined by Keq, Ea But instead by the energy of activation (Ea) ΔG Knowing the Ea of a reaction tells us how fast a reaction will occur Rate therefore depends on the structure of the transition state along the rate determining step Reaction Coordinate While both the thermodynamics and kinetics depend on the structure of the starting material, the thermodynamics depends on product structure while rate depends on transition state structure Rate Equation The rate of a reaction can be written in an equation that relates the rate to the concentration of various reactants A B C D a b Rate = kr [A] [B] The exponents are determined by the number of species involved for the reaction step - The exponents also indicate the “order” of the reaction with respect to A and B Overall order of the reaction is a summation of the order for each individual reactant Relationship between Rate and Energy of Activation Referring back to our energy diagram the rate can be related to the energy of activation (Ea) (-Ea/RT) kr = Ae A is the Arrhenius “preexponential” factor Ea is the minimum kinetic energy required to cause the reaction to proceed As a general guide, the rate of a reaction generally will double every ~10˚C increase in temperature (as the temperature of a reaction increases, there are more molecules with the minimum energy required to cause a reaction to occur) Reactivity with Substituted Alkyl Halides Substituted alkyl halides will undergo reactions not seen with alkanes Consider electron density distribution Chlorine causes a bond dipole Chloromethane Ethane This dipole results in electron density being distributed toward chlorine and away from carbon Thus the halogen substitution has made the carbon more “electrophilic” Reactivity with Substituted Alkyl Halides The alkyl halide is “electrophilic” due to the relative placement of the LUMO orbital Remember that we compare reactivity due to the relative placement of orbitals RELATIVE to the unreactive C-C bonds * σ C-C Also why nucleophile reacts at carbon in LUMO * σ C-Cl And why C-Cl bond 3 3 3 C (sp ) C (sp ) C (sp ) is broken (node in C-Cl bond) Cl (p) σ C-C σ C-Cl C-C single bonds are relatively unreactive In a C-Cl bond, an sp3 orbital from carbon due to large overlap of sp3 hybridized is still being mixed so same energy level orbital and energy match, therefore very It is mixed, however, with a p orbital on low HOMO and high LUMO energy chlorine which is much lower in energy (more electronegative) Poor energy match means orbitals do not mix as much, therefore LUMO is very low Reactivity with Substituted Alkyl Halides Low energy LUMO makes alkyl halides reactive toward nucleophiles (compounds with a high energy HOMO orbital) Na CH3O H3C Cl CH3OCH3 NaCl When Cl leaves and nucleophile attacks (concerted or sequentially) determines the type of reaction This process does not occur with alkanes (carbon-carbon bonds are difficult to break) CH3O Na H3C CH3 There are many problems with this type of reaction (bond is not polarized therefore carbon is not electrophilic, poor leaving group, breaking a strong bond, etc.), but mainly due to high energy of the LUMO for an alkane bond Type of Reactions that can Occur with Alkyl Halides Substitutions: a halide ion is replaced by another atom or ion during the reaction Therefore the halide ion has been substituted with another species Eliminations: a halide ion leaves with another atom or ion -no other species is added to the structure Therefore something has been eliminated One Type of Substitution, SN2 Substitution – Nucleophilic – Bimolecular (2) One substituent is substituted by another Both the original starting material and the nucleophile (which becomes part of the product) are involved in the transition state for the rate determining step Therefore this is a bimolecular reaction Potential Energy Diagram for SN2 Bond is forming Bond is breaking H H3CO Cl Transition state in a SN2 reaction H H resembles a sp2 hybridized carbon H NUC H H LG CH3O H3C Cl CH3OCH3 Cl Reaction Coordinate Species in a Given SN2 Reaction H H HO Cl HO Cl CH OH Cl H 3 H H H nucleophile electrophile transition state products Electron rich nucleophile reacts with electron poor electrophile A SN2 reaction is dependent upon the characteristics of the nucleophile and substrate (electrophile) Kinetics A SN2 reaction is a second order reaction First order in respect to both the nucleophile and the electrophile Rate = k [CH3Cl][HO-] Both methyl chloride and hydroxide are involved in the transition state so they both are involved in the rate equation *characteristic for all SN2 reactions, second order overall and first order in both substrate and nucleophile Stereochemistry of SN2 Reaction H3C CH3 CH3 HO Cl HO Cl HO Cl D D H D H H Chiral sp3 hybridized Achiral sp2 Chiral sp3 hybridized carbon hybridized carbon carbon As the electrophilic carbon undergoes a hybridization change during the course of the reaction the substituents change in this view from pointing to the left in the starting material to pointing to the right in the product This is referred to as an “inversion of configuration” at the electrophilic carbon Therefore the stereochemistry changes (three-dimensional arrangement in space) *another characteristic of SN2 reactions, all SN2 undergo an inversion of configuration Consequence of Inversion in a SN2 Reaction H H NUC LG NUC H H LG H H A chiral carbon is still chiral but the chirality is inverted (the R and S designation usually change but this depends on the priority of the new substituents) H3C CH3 HO Cl HO Cl D D H H CH3 CH3 Cl D D OH R S Rate of SN2 Reaction As seen with rate equation, the characteristics of both the substrate and the nucleophile will affect the rate of a SN2 reaction In any rate question, need to ask how the energy of the starting materials and transition state along the rate determining step are related Never answer a rate question using the energy of the product, product energy affects thermodynamics not kinetics Only this part of reaction coordinate affects the rate Reaction Coordinate Effect of Substrate As the number of substituents on the electrophilic carbon increases the rate decreases H CH3 CH3 CH3 HO C Br HO C Br HO C Br HO C Br H H H H C H H CH3 3 CH3 Methyl Primary Secondary Tertiary Fast SN2 rate Slower SN2 rate SN2 rate slows No SN2 occurs Sterics of substrate has dramatic effect on rate of SN2 reaction, methyl halides react fast but 3˚ halides do not react at all Consider Approach of Nucleophile Nucleophile must be able to react with electrophilic carbon in a SN2 reaction Br Electrophilic carbon H is artificially