Organization of Organic Reactions • In order to understand and recall the many organic reactions we will cover, several forms of classification and organization are needed. • Organic reactions can be classified into these broad categories: • Brønsted-Lowry acid base reactions • Substitution reactions • Elimination reactions • Addition reactions • Oxidation reactions • Reduction reactions • Rearrangements.
Oxidation and reduction reactions can be also classified further into • Substitution • Elimination • Addition • More about these later. (Confused yet?) Reaction type? What’s the nucleophile? What’s the electrophile? • While other concepts also important in understanding organic reactions, classification of the reaction type is usually the first part of the thought process.
Types of Organic Reactions • Acid-Base Reactions – The transfer of a proton from an acid to a base 2. Substitution Reaction – an atom or group of atoms is replaced by another atom and/or group of atoms.
3. Elimination Reactions – the removal of a pair of atoms (or groups of atoms) from adjacent carbons resulting in a net increase in p bonds. 4. Addition Reactions – the addition of a pair of atoms (or group of atoms) to adjacent carbons, involved in a p bond. This reaction results in a net decrease in p-bonds.
5. Rearrangement. The number and type of atoms in the product are the same as in the reactant but the product is a structural isomer (or stereoisomer) of the reactant.
A-B-C Triangle Approach to Organic Reactions • Most organic reactions can be organized around three components: the substrate, the product and the reagent, A, B and C. Reagent, can be inorganic or organic Useful to classify as acidic, basic or neutral. C Substrate, starting organic compound Useful to classify by functional group Organic product of the reaction Useful to classify by functional group A B • Given two of the three components, one should be able to provide the third component. • Later (synthesis problems), starting just with B, one must provide both A and C.
A-B-C Triangle Flash Cards • The use of flash cards to learn the A, B and C of each reaction isstronglyrecommended. Front of the card w/ substrate (A) and product (B) Back of the card w/ reagents (C) and other pertinent information
Flow Chart for Analysis of a Reaction Reaction type Addition Acid/base ? Elimination Substitution What is being eliminated? Conducted under acidic or basic conditions? Is regioselectivity an issue? Is the newly created p bond a stereocenter? What is being added to the p bond? Is regioselectivity an issue? Are asymmetric carbons being generated? Identify the electrophile and the nucleophile. Which atom is receiving electrons? Which atom is donating electrons? Identify the acid, the base. Be able to draw the conjugate acid and conjugate base
Factors Affecting the Rate of Chemical Reactions • The Number of molecular collisions: chemical reactions occur because of violent collisions between reactant molecules. • An increase in concentration for species involved will increase the number of collisions and, therefore, the reaction rate. • A reaction’s rate is proportional to the concentration of reactant. • Suppose the reaction involved two compounds, A and B. • A + B C + D • The reaction rate law is: Rate = k [A]m [B]n
Suppose the reaction involved two compounds, A and B. • A + B C + D • The reaction rate law is written as: • Rate = k [A]m [B]n • m and n the rate orders of the reaction. • m and n are usually integers (0, 1, 2) • Both must be determined experimentally. • The stoichiometric coefficients of a balanced reaction tell us nothing about rate orders. • The sum of m + n is the molecularity of the reaction • If m and n are both one, the reaction would be bimolecular. • If m + n = 1, then the reaction is unimolecular.
Temperature: the higher the temperature, the faster the rate. With higher temperature, there are more collisions per unit time and each collision has more energy. • Shape of the molecule: some reactions require a specific geometry for an effective collision to allow the transfer of electrons. (bond breaking and bond making). • Catalyst: lowers the energy needed for an effective collision, but has no effect on the reaction energy change.
Reaction energetics • An energy diagram for a one-step exothermic reaction of C and A-B to give C-A and B. Energy diagram: A graph of the energy changes that occur during a chemical reaction; energy is plotted on the y-axis. Reaction progress on the x-axis.
Transition state: An unstable species of maximum energy formed during the course of a reaction. • Activation energy Ea: The difference in energy between the reactants and the transition state. • Ea is a major factor when determining the rate of a reaction. • If the Ea is large, very few molecular collisions occur with sufficient energy to reach the transition state, and the reaction is slow. • If the Ea is small, many collisions generate sufficient energy to reach the transition state, and the reaction is fast.
Also shown on an energy diagram are: • Heat (Enthalpy) of reaction H: The difference in energy between reactants and products. • Exothermic reaction: A reaction in which the energy of the products is lower than the energy of the reactants; a reaction in which heat is liberated. • Surroundings get warmer. • Endothermic: A reaction in which the energy of the products is higher than the energy of the reactants: a reaction in which heat is absorbed. • Surroundings get cooler.
Often multiple collisions are needed to create the product. Energy diagram for a two-step exothermic reaction involving formation of a reaction intermediate.
Reaction intermediate: An collection of atoms (an unstable molecule) that is created in-between two transition states. • Intermediates usually exist for only a small time period. (1 ms – 1 ns) • Intermediates are highly reactive and rarely, if ever, can one be isolated. • Rate-determining step: The step in a reaction sequence that crosses the highest energy barrier; the slowest step in a multistep reaction. • Even in a complicated progression of collisions, often the speed of one step controls the speed of the entire reaction.
Reaction Mechanisms • A reaction mechanism is a step-by-step description of how a reaction occurs. It can be considered to be an ordered list of collisions. • Reaction mechanisms describe: • Which bonds break and which new ones form. • The order and relative rates of the various bond-breaking and bond-forming steps. • The role of the solvent for a reaction in solution. • The role of the catalyst (if one is present). • A reaction mechanism is NOT a list of reagents or experimental conditions that bring about the chemical transformation.
Mechanisms are useful because they provide: • A way to visualize the unseeable. Reaction mechanisms allows us visualize how a substance changes into a new substance at the microscopic level. • Patterns that can adapted to understanding other reactions. That is, a mechanism for one reaction may be slightly modified (rather than constructed from scratch) to understand another reaction.
Patterns in Reaction Mechanisms • Many mechanisms have similar features that can be categorized as patterns. • Pattern 1: Add a proton (to protonate) • A proton (a positive charge) is transferred from an acid to the lone pair (a negative charge) of an electronegative atom. • Understanding the acid/base properties of the reactants and products can give a lot of understanding about the rate of a reaction.
A proton (a positive charge) is added across the pi bond of a C—C double bond to form a new C—H bond. • Adding a proton is typical of all reactions that are catalyzed by an acid.
Pattern 2: Take a proton away (to deprotonate) • Reversing Pattern 1 corresponds removing a proton. • As in protonation, knowing the relative acidity (and basicity) of the substances in the reaction is crucial.
Pattern 3: Reaction of an electrophile and a nucleophile to form a new covalent bond. • Positive charge (an electrophile) is attracted to negative charge (a nucleophile) • Electrophile: an electron-poor species that can accept a pair of electrons to form a new covalent bond; a Lewis acid. • Nucleophile: an electron-rich species that can donate a pair of electrons to form a new covalent bond; a Lewis base.
Pattern 4: Rearrangement of atoms. • A rearrangement occurs when the electrons of a sigma bond break from the bond of one atom and form a new covalent bond to an adjacent atom.
Pattern 5: Break a bond to form an intermediate or stable molecule. • A carbocation can be formed when a chemical species breaks off from a molecule, taking the electrons from the former single bond with it. The chemical species formed is called the leaving group. The bond breaks because doing so forms one or more stable ions or molecules.
Overview of Alkene Reactions • Electrophilic Additions • Addition of hydrogen halides (HCl, HBr, HI) Hydrohalogenation • Addition of water (H2O/H2SO4) Hydration • Acid catalyzed addition of water • Hydroboration/Oxidation • Addition of halogens (Cl2, Br2) Halogenation • Oxidation • Reaction w/OsO4 or KMnO4 • Ozonolysis • Reduction
Electrophilic Additions to Alkenes (Overview) • Addition of hydrogen halides (HCl, HBr, HI) Hydrohalogenation • Addition of halogens (Cl2, Br2) Halogenation
Electrophilic Additions to Alkenes (Overview) • Addition of water (H2O/H2SO4) Hydration • Acid-catalyzed hydration • Hydroboration/Oxidation
Oxidation (Overview) Reduction (Overview) Reaction with OsO4 or KMnO4 Ozonolysis (Reaction with O3)
Addition of Hydrogen Halides (Hydrohalogenation) Reaction carried out with the pure reagents or in a polar solvent such as acetic acid.
Markovnikov’s rule: In additions of HX to a double bond, H adds to the carbon with the greater number of hydrogens already bonded to it. (Them that has, gits!) • Addition is regioselective. • Regioselective reaction: A reaction in which one possibility of bond forming or bond breaking occurs in preference to all other possibilities.
Markovnikov’s rule is but one example of regioselectivity. We will see more examples in this and later chapters.
Reaction Mechanism for Hydrohalogenation • Example: Addition of HCl to 2-Butene • A two-step mechanism • Step 1: Add a proton. Formation of a 2° or 3° carbocation intermediate (ex. sec-butyl cation).
Step 2: Reaction of an electrophile and a nucleophile to form a new covalent bond. Reaction of the sec-butyl cation (an electrophile) with chloride ion (a nucleophile) completes the reaction.
Energy diagram for the two-step exothermic addition of HCl to 2-butene. Note the intermediate that is formed (a carbocation).
Carbocations • Carbocation: A species containing a carbon atom that has only three bonds, six electrons in its valence shell and bears a positive charge. • Bond angles about the positively charged carbon are approximately 120°. • Carbon uses sp2 hybrid orbitals to form sigma bonds to the three attached carbon atoms. • The unhybridized 2p orbital lies perpendicular to the sigma bond framework and contains no electrons • Carbocations are: • Electrophiles: that is, they are electron-loving. • Lewis acids: that is, they’re an electron-pair acceptor
A 3° carbocation is more stable than a 2° carbocation and requires a lower activation energy for its formation. • A 2° carbocation is, in turn, more stable than a 1° carbocation and requires a lower activation energy for its formation. • Methyl and 1° carbocations are so unstable that they are never observed in solution.
Inductive effect: The polarization of the electron density in a covalent bond as a result of the electronegativity of a nearby atom. • The electronegativity of a carbon atom bearing a positive charge exerts an electron-withdrawing inductive effect that polarizes electrons of adjacent sigma bonds toward it. • Thus, the positive charge of a carbocation is not localized on the trivalent carbon, but rather is delocalized over nearby atoms as well. • The larger the area over which the positive charge is delocalized, the greater the stability of the cation.
methyl carbocation tert-butyl carbocation Carbon branches are electron-donating; thus for a 3˚ carbocation, the negative charge from the carbon branches helps to neutralize the positive charge of the carbocation, making the carbocation more stable.
Carbocations and Markovnikov’s Rule The chemical basis for the regioselectivity embodied in Markovnikov’s rule lies in the relative stabilities of carbocation intermediates. The reason why the proton of H—X adds to the less substituted carbon of the double bond is that this mode of addition leads to the more stable carbocation intermediate.
Carbocations—Summary The carbon bearing a positive charge is sp2 hybridized with bond angles of 120° about it. The order of carbocation stability is 3°>2°>1°. Carbocations are stabilized by the electron-withdrawing inductive effect of the positively charged carbon. Methyl and 1° carbocations are so unstable that they are never formed in solution.
Addition of H2O to an Alkene • Addition of H2O to an alkene is called hydration. • Acid-catalyzed hydration of an alkene is regioselective: hydrogen adds preferentially in accordance with Markovnikov's rule.
Reaction Mechanism for Hydration of an Alkene Step 1: Add a proton. Proton transfer from the acid catalyst (H3O+) to propene gives a 2° carbocation intermediate.
Step 2: Collision of a nucleophile with an electrophile to form a new covalent bond. Reaction of the carbocation intermediate with water completes the valence shell of carbon and gives an oxonium ion.
Note that this reaction cannot be used to prepare 1° alcohols, only 2° and 3° alcohols Step 3: Take a proton away. Proton transfer from the oxonium ion to water yields the alcohol and regenerates the acid catalyst.
Addition of Cl2 and Br2 Carried out with either the pure reagents or in an inert solvent such as CH2Cl2 (common name, methylene chloride).
Addition is stereoselective. Stereoselective reaction: A reaction in which one stereoisomer (or geometric isomer) is formed or destroyed in preference to all others. Addition to a cycloalkene, for example, gives only a trans product. The reaction occurs with anti stereoselectivity. “anti” implies that each side of the double bond is attacked, in turn.
Hydroboration-Oxidation The result of hydroboration followed by oxidation of an alkene is hydration of the carbon-carbon double bond.
Because –H adds to the more substituted carbon of the double bond and –OH adds to the less substituted carbon, we refer to the regiochemistry of hydroboration/oxidation as anti-Markovnikov hydration. Hydroboration-Oxidation is the most common way to make a 1 alcohol from an alkene.