Overview of Organic Reactions

Kinds of Organic Reactions In general, we look at what occurs and try to learn how it happens Common patterns describe the changes Addition reactions – two molecules combine Elimination reactions – one molecule splits into two

Kinds of Organic Reactions Substitution – parts from two molecules exchange

Kinds of Organic Reactions Rearrangement reactions – a molecule undergoes changes in the way its atoms are connected

How Organic Reactions Occur: Mechanisms In a clock the hands move but the mechanism behind the face is what causes the movement In an organic reaction, we see the transformation that has occurred. The mechanism describes the steps behind the changes that we can observe Reactions occur in defined steps that lead from reactant to product

Steps in Mechanisms We classify the types of steps in a sequence A step involves either the formation or breaking of a covalent bond Steps can occur individually or in combination with other steps When several steps occur at the same time, they are said to be concerted

Types of Steps in Reaction Mechanisms Bond formation or breakage can be symmetrical or unsymmetrical Symmetrical- homolytic Unsymmetrical- heterolytic

Reaction Thermodynamics: Enthalpy Enthalpy (ΔH or q) is the heat energy exchange between the reaction and its surroundings at constant pressure You must put energy into system to break bonds, but forming a bond releases equivalent amount of energy.

Bond Dissociation Energies Bond dissociation energy (D): amount of energy required to break a given bond to produce two radical fragments when the molecule is in the gas phase at 25˚ C The energy is mostly determined by the type of bond, independent of the molecule The C-H bond in methane requires a net energy input of 106 kcal/mol to be broken at 25 ºC. Table 6.3 lists energies for many bond types Changes in bonds can be used to calculate net changes in heat BDE is ΔH for homolytic cleavage

Bond Dissociation Energies

Enthalpy ΔH In an Exothermic reaction, heat is released into the solvent. In an Endothermic reaction, the reactants absorb heat from the solvent.

Entropy ΔS Although most reactions are EXOthermic, there are many ENDOthermic reactions that occur Enthalphy and entropy must BOTH be considered when predicting whether a reaction will occur ENTROPY (ΔS) can be though of as molecular disorder, randomness, or freedom Entropy may most accurately be thought of as the number of states that a molecule’s energy can be distributed over

Entropy ΔS If the energy of molecules can be distributed in a higher number of vibrational, rotational, and translational states, the sample will have a greater entropy. Molecules exhibit vibrational, rotational, and translational motion.

Entropy ΔS The total entropy change will determine whether a process is spontaneous (favors the forward direction) If ΔStot is positive, the process is spontaneous. For chemical reactions, we must consider the entropy change for both the system (the reaction) and the surroundings (the solvent usually)

Entropy ΔS For each of the reactions below, predict the sign for Δssys Consider how a change in a molecule’s structure affects the number of possible translational, rotational, and/or vibrational distributions for the molecules?

Klein, Organic Chemistry 2e Gibbs Free Energy ΔG If a process at a given temperature is calculated to have a (-) ΔG, the process is exergonic It will be spontaneous and favor the products Note that G is plotted rather than H Does the value for ΔG tell us about the rate of the reaction? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Gibbs Free Energy ΔG If a process at a given temperature is calculated to have a (+) ΔG, the process is endergonic It will be NONspontaneous and favors the reactants

Thermodynamic Quantities

Klein, Organic Chemistry 2e Equilibria Consider an exergonic process with a (-) ΔG. Will every molecule of A and B be converted into products? No, an equilibrium will eventually be reached A spontaneous process will simply favor the products meaning there will be more products than reactants The greater the magnitude of a (-)ΔG, the greater the equilibrium concentration of products Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Equilibria Why doesn’t an exergonic process react 100% to give products? Why will some reactants remain? The diagram shows one unit of A react with one unit of B In reality, moles of reactants are present How will concentrations of A, B, C, and D change as the reaction progresses? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

In any reaction, collisions are necessary Equilibria In any reaction, collisions are necessary As [A] and [B] decrease collisions between A and B will occur less often As [C] and [D] increase, collisions between C and D will occur more often The more often C and D collide, the more often collisions will occur with enough free energy for the reverse reaction to take place Recall that equilibrium is dynamic and occurs when the forward and reverse reaction rates are equal

Equilibria Equilibrium is also the state with the lowest free energy overall

𝑎𝐴+𝑏𝐵 ↔𝑐𝐶+𝑑𝐷 Equilibria An equilibrium constant (Keq) is used to show the degree to which a reaction is product or reactant favored Keq, ΔG, ΔH, and ΔS are thermodynamic terms. They do not describe reaction kinetics. 𝑎𝐴+𝑏𝐵 ↔𝑐𝐶+𝑑𝐷

Magnitudes of Equilibrium Constants If the value of Keq is greater than 1, this indicates that at equilibrium most of the material is present as products If Keq is 10, then the concentration of the product is ten times that of the reactant A value of Keq less than one indicates that at equilibrium most of the material is present as the reactant If Keq is 0.10, then the concentration of the reactant is ten times that of the product

Free Energy and Equilibrium The ratio of products to reactants is controlled by their relative Gibbs free energy This energy is released on the favored side of an equilibrium reaction The change in Gibbs free energy between products and reacts is written as “DG” If Keq > 1, energy is released to the surroundings (exergonic reaction) If Keq < 1, energy is absorbed from the surroundings (endergonic reaction)

Klein, Organic Chemistry 2e Equilibria What trends do you notice in table 6.2? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Kinetics Recall that a (-) sign for ΔG tells us a process is product favored (spontaneous) That does NOT tell us anything about the RATE or kinetics for the process Some spontaneous processes are fast such as explosions. Can you think of other examples? Some spontaneous processes are slow such as C (diamond)  C (graphite). Can you think of other examples?

Kinetics The reaction rate (the number of collisions that will result in product production in a given period of time) is affected by multiple factors The concentrations of the reactants The Activation Energy The Temperature Geometry and Sterics The presence of a catalyst How will an increase in [reactant] generally affect the reaction rate? WHY?

Factors that Affect Rates Locate the Activation Energy in figure 6.13. Why must the free energy (G) increase before the products can be formed? Free energy (G)

Factors that Affect Rates Temperature is a measure of a system’s average kinetic energy Increasing the temperature increases the rate of reaction because more molecules achieve the necessary activation energy Free energy (G)

Factors that Affect Rates Why does a lower Eact result in a greater reaction rate? Free energy (G) Free energy (G)

Factors that Affect Rates How might geometry and sterics affect the reaction rate? How might the presence of a catalyst affect the reaction rate? Free energy (G)

Distinguish between kinetics and thermodynamics Energy Diagrams Distinguish between kinetics and thermodynamics Free energy (G) Free energy (G)

Kinetics vs Thermodynamics For the energy diagram below, which pathway do you think is favored? WHY? Will a decrease in temperature affect which pathway is favored? Will an increase in temperature affect which pathway is favored? Free energy (G)

Kinetics vs Thermodynamics For the energy diagram below, which pathway is kinetically favored? Which pathway is thermodynamically favored? How can temperature be used to control which set of products predominate? Free energy (G)

Transition States vs Intermediates Free energy (G)

A transition state occurs at an energy maxima Transition States A transition state occurs at an energy maxima Transition states exist for a fleeting moment; they cannot be isolated or directly observed Why are transition states so unstable? Free energy (G)

An intermediate occurs at an energy minima Intermediates An intermediate occurs at an energy minima Intermediates often exist long enough to observe because bonds are NOT in the process of breaking or forming Free energy (G)

The Hammond Postulate Two points on an energy diagram that are close in energy should be similar in structure Free energy (G)

The Hammond Postulate For each of the diagrams below, will the transition state structure look more like the reactants or the products? Free energy (G) Free energy (G)

Nucleophiles and Electrophiles A major focus in this course is on predicting reaction products for ionic reactions and explaining HOW such reactions work Ionic or polar reactions result from the force of attraction between opposite charges Ionic reactions are also guided by the octet rule

Nucleophiles When an atom carries a formal or partial negative charge and an available pair of electrons, it is considered a nucleophile. It will love to attack a nucleus. A nucleophile is a Lewis Base.

Electrophiles When an atom carries a formal or partial positive charge and can accept a pair of electrons, it is considered a electrophile It will love available electrons. An electrophile is a Lewis Acid.

Some Nucleophiles and Electrophiles

Electrophile and Nucleophiles Participate in Polar Reactions Molecules can contain local unsymmetrical electron distributions due to differences in electronegativities This causes a partial negative charge on an atom and a compensating partial positive charge on an adjacent atom The more electronegative atom has the greater electron density Elements such as O, F, N, Cl are more electronegative than carbon

Polarity Patterns in Some Common Functional Groups

Polarizability is the tendency to undergo polarization Polarization is a change in electron distribution as a response to change in electronic nature of the surroundings Polarizability is the tendency to undergo polarization Polar reactions occur between regions of high electron density and regions of low electron density

An Example of a Polar Reaction: Addition of HBr to Ethylene HBr adds to the  part of a C-C double bond The  bond is electron-rich, allowing it to function as a nucleophile H-Br is electron deficient at the H since Br is much more electronegative, making HBr an electrophile This shows reaction but NOT mechanism!

Using Curved Arrows in Polar Reaction Mechanisms Curved arrows are a way to keep track of changes in bonding in a polar reaction The arrows track “electron movement” Electrons always move in pairs Charges change during the reaction One curved arrow corresponds to one step in a reaction mechanism

Indicating Steps in Mechanisms Curved arrows indicate breaking and forming of bonds Arrowheads with a “half” head (“fish-hook”) indicate homolytic and homogenic steps (called ‘radical processes’) Arrowheads with a complete head indicate heterolytic and heterogenic steps (called ‘polar processes’)

Rules for Using Curved Arrows The arrow goes from the nucleophilic reaction site to the electrophilic reaction site The nucleophilic site can be neutral or negatively charged

Rules for Using Curved Arrows The electrophilic site can be neutral or positively charged The octet rule should be followed

Mechanisms and Arrow Pushing We use arrows to show how electrons move when bonds break and form There are four main ways that electrons move in ionic reactions Nucleophilic Attack Loss of a Leaving Group Proton Transfers (Acid/Base) Rearrangements

Nucleophilic Attack When you identify a nucleophilic site and an electrophilic site, the arrow shows the nucleophile attacking The tail of the arrow starts on the electrons (- charge) The head of the arrow ends on a nucleus (+ charge) The electrons end up being sharing rather than transferred

Nucleophilic Attack Nucleophilic attack may appear to occur in two steps The alcohol is the nucleophile in this example. It attacks a carbon with a δ+ charge The second arrow shows the flow of negative charge. WHY is it necessary? The second arrow could be thought of as a resonance arrow. HOW?

Loss of a Leaving Group Loss of a leaving group occurs when a bond breaks and one atom from the bond takes BOTH electrons For the molecule below, draw the structure that will result after the leaving group is gone

Proton Transfers Recall from Chapter 3 that a base is protonated when it uses a pair of electrons to take an H+ from the acid. The acid retains its electron pair A group can also be deprotonated (sometimes shown by writing –H+ over the reaction arrow) or

Proton Transfers Multiple arrows may be necessary to show the complete electron flow when a proton is exchanged Such electron flow can also be thought of as a proton transfer combined with resonance

Arrow Pushing Rules To draw reasonable mechanisms, a few key rules should be followed The arrow starts ON A PAIR OF ELECTRONS (a bonded pair or a lone pair)

Arrow Pushing Rules A few key rules should be followed The arrow ends ON A NUCLEUS (electrons become a lone pair) or between two NUCLEI (electrons move into position to become a bond)

Arrow Pushing Rules A few key rules should be followed Avoid breaking the octet rule. NEVER give C, N, O, or F more than 8 valence electrons

Arrow Pushing Rules A few key rules should be followed Draw arrows that follow the 4 key patterns we outlined

Arrow Pushing Rules Fill in necessary arrows for the reaction below

Describing a Reaction: Energy Diagrams and Transition States The highest energy point in a reaction step is called the transition state The energy needed to go from reactant to transition state is the activation energy (DG‡)

First Step in Addition The C–H bond begins to form In the addition of HBr the (conceptual) transition-state structure for the first step The  bond between carbons begins to break The C–H bond begins to form The H–Br bond begins to break

Describing a Reaction: Intermediates If a reaction occurs in more than one step, it must involve species that are neither the reactant nor the final product These are called reaction intermediates or simply “intermediates” Each step has its own free energy of activation The complete diagram for the reaction shows the free energy changes associated with an intermediate

Carbocation Structure and Stability Carbocations are planar and the tricoordinate carbon is surrounded by only 6 electrons in sp2 orbitals the fourth orbital on carbon is a vacant p-orbital the stability of the carbocation (measured by energy needed to form it from R-X) is increased by the presence of alkyl substituents (via both induction and hyperconjugation)

Carbocation Structure and Stability A plot of DH dissociation shows that more highly substitued alkyl halides dissociate more easily than less highly substituted ones

Carbocations are stabilized by Induction An inductively stabilized cation species

Carbocation Stability Carbocations can be stabilized by neighboring groups through slight orbital overlapping called hyperconjugation

Carbocation Rearrangements Two types of carbocation rearrangement are common Hydride shift Methyl shift Shifts can only occur from an adjacent carbon. Methyl shifts will occur first (lower energy). These shifts can and will occur when they result in a more stable carbocation.

Carbocation Rearrangements When you encounter a carbocation, you must consider all possible rearrangements (Hydride and methyl shifts) Identify all adjacent carbons Identify all –H and –CH3 groups on the adjacent carbons that are capable of shifting

Carbocation Rearrangements When you encounter a carbocation, you must consider all possible rearrangements (Hydride and methyl shifts) Imagine each of the groups shifting to see which yields the most stable resulting carbocation In this case, a hydride shift will result in a more stable tertiary carbocation

Carbocation Rearrangements Complete the same analysis for the molecule below Identify all adjacent carbons Identify all –H and –CH3 groups capable of shifting Determine which shift yields the most stable carbocation Recall that allylic carbocations are especially stable

Reversible and Irreversible Reaction Arrows If the attacking nucleophile is also a good leaving group, it will be a reversible attack The reverse reaction will have a relatively low transition state energy (kinetically favored) The reactants and products of the reaction will be similar in energy allowing significant quantities of both to exist at equilibrium (thermodynamic equilibrium)

Reversible and Irreversible Reaction Arrows If the attacking nucleophile is a poor leaving group, it will essentially be an irreversible attack The reverse reaction will have a relatively HIGH transition state energy (kinetically disfavored) The products will be much lower in energy so an insignificant quantity of reactant will remain at equilibrium

Reversible and Irreversible Reaction Arrows Consider proton transfer If the pKa difference is 10 units or more, it is generally considered irreversible

Mechanism of Addition of HBr to Ethylene HBr electrophile is attacked by  electrons of ethylene (nucleophile) to form a carbocation intermediate and bromide ion Bromide adds to the positive center of the carbocation, which is an electrophile, forming a C-Br  bond The result is that ethylene and HBr combine to form bromoethane All polar reactions occur by combination of an electron-rich site of a nucleophile and an electron-deficient site of an electrophile