1. An Overview of Organic Reactions
Chapter 6
An Overview of Organic Reactions
Suggested Problems -
1-13,17,19-23,26,28-32,
37,41

2. Kinds of Organic Reactions
Four kinds
Addition reactions – two molecules combine
2) Elimination reactions – one molecule splits into two
The IUPAC name for ethylene is ethene. The ene suffix indicates an alkene and the eth prefix indicates two carbons.
Similarly ethanol has the suffix ol indicative of an alcohol (an OH group), and ethan refers to the molecule being of the alkane type and containing two carbons.

3. Kinds of Organic Reactions (Continued)
3) Substitution – parts from two molecules exchange
Another example of a substitution reaction involves the reaction of hydroxide ion with an alkyl iodide. What are the two products of this reaction?

4. Kinds of Organic Reactions (Continued)
4) Rearrangement reactions – a molecule undergoes changes in the way its atoms are connected
Here the double bond between the 1 and 2 carbon changes position (rearranges) to a position between the 2 and 3 carbons. Note that the molecular formula of the reactant does not change in going to the product.

5. How Organic Reactions Occur: Mechanisms
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.

6. 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
An example of a concerted reaction is a Diels-Alder reaction which we will study later in this course.
A non-concerted rxn

7. Types of Steps in Reaction Mechanisms
Bond formation or breakage can be symmetrical or unsymmetrical
Symmetrical- homolytic
Unsymmetrical- heterolytic
Bond breakage and formation involves movement of electrons. Two electrons are involved in each bond. One atom in the breaking (forming) bond can receive (contribute) both electrons from (to) the other atom.
Alternatively, each atom in the breaking bond (forming) bond receives(contributes) one electron.
Processes that involve symmetrical (homolytic) bond-breaking and bon-making are called radical reactions. A neutral atom that contains an odd number of electrons (and hence contains one unpaired electron) is referred to as a radical (often called a “free radical”).
Processes that involve unsymmetrical (heterolytic) bond-breaking and bond-making are called polar reactions. Polar reactions involve species that have an even number of electrons and thus have only electron pairs in their orbitals.
Polar processes are far more common than processes involving radicals.

8. 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’)

9. Radical Reactions Not as common as polar reactions
Radicals react to complete electron octet of valence shell
A radical can break a bond in another molecule and abstract a partner with an electron, giving substitution in the original molecule
The driving force behind a radical reaction is the tendency of the radical to complete its octet.
The radical can complete its octet by abstracting an atom and one bonding electron from another reactant, leaving behind a new radical. The net result is a radical substitution reaction.
Alternatively, as shown on the next slide, the radical can add to a double bond, taking one electron from the double bond and yielding a new radical. The net result is a radical addition reaction.

10. Radical Reactions
A radical can add to an alkene to give a new radical, causing an addition reaction

11. A Radical Substitution Reaction
Light is a common initiator in radical reactions.

12. Steps in Radical Substitution
Three types of steps
Initiation – homolytic formation of two reactive species with unpaired electrons
Propagation – reaction with molecule to generate radical
Example - reaction of chlorine atom with methane to give HCl and CH3.
Light is a common initiator in radical reactions.
Once generated the radical can react with any molecule in its presence. This implies careful control of concentrations is necessary to form only the desired product.
Note that once a radical reaction is initiated, the reaction becomes a self-sustaining cycle of repeating steps (a) and (b) making the overall process a chain reaction.

13. Steps in Radical Substitution
Termination – combination of two radicals to form a stable product: CH3. + CH3.  CH3CH3
A radical reaction ends when radicals react with themselves ending the chain reaction. Since the concentration of radicals in the reaction at any given moment is small, the likelihood that two radicals will collide is also small.
For this reason, and because radicals can react with the initial product generated to form other products, radical reactions are very difficult to control.

14. Radical Reactions in Biological Systems
Prostaglandins are a large class of molecules found in virtually all body tissues and fluids. Many pharmaceuticals are based on or derived from prostaglandins including medicines that induce labor, reduce intraocular pressure in glaucoma, control bronchial asthma, and help treat congenital heart defects.
The biosynthesis of prostaglandins results from a radical adding to a double bond in arachidonic acid.
The initially formed radical reacts with oxygen to generate another radical as outlined on the next slide.

15. Radical Reactions in Biological Systems
Radicals can rearrange to form other radicals as shown in the top reaction. Does this resemble resonance to any degree?
p. 189b

16. Radical Reactions in Biological Systems
How might the radical at right react to produce Prostaglandin H2?
Here a radical adds to a double bond to form a cyclopentane ring. Note that a new radical on the other carbon of the double bond is generated.
How is Prostaglandin H2 generated? The radical at top left is donated into the carbon bearing the double bond to its right. This places the radical in the 3-position relative to the initial radical. This latter radical reacts with oxygen to form a peroxide – R-O-O-H. The peroxide is cleaved by a peroxidase to form the alcohol in PGH2.
p. 189b

17. Polar Reactions
Polar reactions occur because of the electrical attraction between positively and negatively polarized centers on functional groups in molecules.
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

18. Polar Reactions
The more electronegative atom has the greater electron density
Elements such as O, F, N, Cl are more electronegative than carbon
Metals such as Li, Mg are more electropositive than carbon

19. Polarity Patterns in Some Common Functional Groups

20. Polar Bonds
Polar bonds can also result from the interaction of functional groups with acids or bases.
In neutral methanol, the carbon atom is somewhat electron-poor because of the electronegative oxygen.
On protonation of the methanol oxygen with an acid, a full positive charge on oxygen makes carbon even more electron-poor.

21. Polarizability
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.
Larger atoms with more loosely held electrons are more polarizable, and smaller atoms with fewer, tightly held electrons are less polarizable.

22. Polarizability
Sulfur is more polarizable than oxygen, and iodine is more polarizable than chlorine.
The effect of the higher polarizability for sulfur and iodine is that carbon-sulfur and carbon-iodine bonds, although nonpolar according to electronegativity values, nevertheless react as if they were polar.
Polar reactions occur between regions of high electron density and regions of low electron density

23. Generalized Polar Reactions
The fundamental characteristic of all polar organic reactions is that electron-rich sites react with electron-poor sites.
Bonds are made when an electron-rich atom donates a pair of electrons to an electron-poor atom.
Bonds are broken when one atom leaves with both electrons from the former bond.

24. Generalized Polar Reactions
An electrophile, an electron-poor species, combines with a nucleophile, an electron-rich species.
An electrophile is a Lewis acid (accepts electrons)
A nucleophile is a Lewis base (donates electrons)
The combination is indicated with a curved arrow from nucleophile to electrophile
“Phile” from the Greek – denoting fondness for a specified thing.
An electrophile seeks out electrons because it itself is electron poor.
A nucleophile seeks out a positively charged nucleus because it itself is electron rich.

25. Some Nucleophiles and Electrophiles
Nucleophiles can be either neutral or negatively charged. Ammonia, water, hydroxide ion, and chloride ion are examples.
Electrophiles can be either neutral or positively charged. Acids (H+ donors), alkyl halides, and carbonyl compounds are examples.
Note that neutral compounds can often react either as nucleophiles or as electrophiles, depending on the circumstances. If a compound is neutral yet has an electron-rich nucleophilic site, it must also have a corresponding electron-poor electrophilic site. Water, for instance, acts as an electrophile when it donates H+ but acts as a nucleophile when it donates a nonbonding pair of electrons.
Similarly a carbonyl compound acts as an electrophile when it reacts at its positively charged carbon, yet acts as a nucleophile when it reacts at its negatively polarized oxygen atom.

26. An Example of a Polar Reaction: Addition of HBr to Ethylene (Ethene)
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 is an example of a polar reaction type known as an electrophilic addition reaction.
The double bond in ethene consists of a sigma bond, in which the electrons exist between the two carbon atoms and are therefore relatively inaccessible, and a  bond in which the electrons are located above and below the plane of the two carbon atoms and are therefore relatively accessible to approaching reactants.
As a result the double bond is nucleophilic and the chemistry of alkenes is dominated by reactions with electrophiles.
As a strong acid, HBr is a powerful proton (H+) donor and electrophile.
Thus, the reaction between HBr and ethene is a typical electrophile-nucleophile combination, characteristic of all polar reactions.
Note - Ethylene is the common name but ethene is the more correct IUPAC name.

27. Mechanism of Addition of HBr to Ethylene (Ethene)
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
Note that one curved arrow begins at the middle of the double bond (the source of the electron pair) and points to the hydrogen atom in HBr (the atom to which a bond will form). This arrow indicates that a new C-H bond forms using electrons from the former C=C bond. Simultaneously, a second curved arrow begins in the middle of the H-Br bond and points to the Br, indicating that the H-Br bond breaks and the electrons remain with Br atom, giving Br-.
When one of the alkene carbon atoms bonds to the incoming hydrogen, the other carbon atom, having lost its share of the double-bond electrons, now has only six valence electrons and is left with a positive charge. This “carbocation” is itself an electrophile that can accept an electron pair from nucleophilic Br- anion in a second step, forming a C-Br bond and yielding the observed addition product. A curved arrow shows the electron-pair movement from Br- to the positively charged carbon.
All polar reactions take place between an electron-poor site and an electron-rich site and involve the donation of an electron pair from a nucleophile to an electrophile.

28. 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 (in a polar reaction)
Charges change during the reaction
One curved arrow corresponds to one step in a reaction mechanism

29. Rules for Using Curved Arrows
Electrons move from a nucleophilic source (Nu: or Nu:-) to an electrophilic sink (E or E+)
The electrophilic sink must be able to accept an electron pair
Must have a positively charged atom, or
A positively charged atom in a functional group
The nucleophilic source must have an electron pair available, usually as a lone pair or in a multiple bond.
The electrophilic sink must be able to accept an electron pair, usually because it has either a positively charged atom or a postively polarized atom in a functional group.

30. Rules for Using Curved Arrows
The nucleophile can be negatively charged or neutral
If the nucleophile is neutral, the atom that donates the electron pair acquires a positive charge.

31. Rules for Using Curved Arrows (Continued)
The electrophile can be either positively charged or neutral
If positively charged, the atom bearing the charge becomes neutral
If neutral, the atom accepting the electrons acquires a negative charge
If the electrophile is positively charged, the atom bearing that charge becomes neutral after accepting an electron pair.
If the electrophile is neutral, the atom that ultimately accepts the electron pair acquires a negative charge. For this to happen, however, the negative charge must be stabilized by being on an electronegative atoms such as oxygen, nitrogen, or a halogen. Carbon and hydrogen do not typically stabilize a negative charge.
Charge is conserved during the reaction.

32. Rules for Using Curved Arrows (Continued)
The octet rule should be followed
If an electron pair moves to an atom that already has an octet, another electron pair must simultaneously move from that atom to maintain the octet.

33. An Example
Add curved arrows to the following polar reaction to show the flow of electrons:
If an electron pair moves to an atom that already has an octet, another electron pair must simultaneously move from that atom to maintain the octet.

34. Describing a Reaction: Equilibria, Rates, and Energy Changes
Reactions may go either forward or backward to reach equilibrium
The multiplied concentrations of the products divided by the multiplied concentrations of the reactants is the equilibrium constant, Keq
Each concentration is raised to the power of its coefficient in the balanced equation.

35. 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
What does a value of Keq= 1 symbolize?

36. Free Energy and Equilibrium
For a reaction to proceed as written, the energy of the products must be lower than the energy of the reactants.
ie. Energy must be released.
The energy change that occurs during a chemical reaction is called the Gibbs free energy (DG).
(DG = Gproducts – Greactants)
This energy is released on the favored side of an equilibrium reaction
For a favorable reaction, DG has a negative value, meaning energy is lost by the chemical system and released to the surroundings, usually as heat – exergonic.
For an unfavorable reaction, DG has a positive value, meaning that energy is absorbed by the chemical system from the surroundings – endergonic.

37. Numeric Relationship of Keq and Free Energy Change
The standard free energy change at 1 atm pressure and 298 K is DGº
The relationship between free energy change and an equilibrium constant is:
- DGº = - RT ln Keq where
R = J/(K . mol) or cal/(K . mol)
T = temperature in Kelvin
ln Keq = natural logarithm of Keq

38. Relationship between Keq and DG
If Keq > 1, energy is released to the surroundings (exergonic reaction)
If Keq < 1, energy is absorbed from the surroundings (endergonic reaction)

39. A Problem
The reaction of ethylene (ethene) with HBr has Keq = 7.1 x What is DGº in kJ/mol at 298K?
- DGº = - RT ln Keq where
R = J/(K . mol)
T = 298 K
ln Keq = natural log of Keq = ln (7.1 x 107) = 18.08
DGº = - RT ln Keq = - [8.314 J/(K . Mol)] (298 K) (18.08)
= - 44,800 J/mol = kJ/mol

40. Free Energy Change - Enthalpy Component
DG made up of an enthalpy term and an entropy term
- DGo = DHo –TDSo
Enthalpy change, (DH), also called heat of reaction
Measures the change in total bonding energy during a reaction.
DH = negative
Products have less energy than reactants
Products more stable, have stronger bonds
Heat is released (exothermic)
DH = positive
Products have more energy than reactants
Products less stable, have weaker bonds
Heat is absorbed (endothermic)

41. Free Energy Change - Entropy Component
DG made up of an enthalpy term and an entropy term
- DGo = DHo –TDSo
Entropy change, (DS)
- Measures the change in molecular randomness during a reaction.
DS = positive
Increase in entropy
More freedom of movement; more randomness
eg. A B + C
DS = negative
Decrease in entropy
Freedom of movement restricted; less randomness
eg. A + B C

42. Free Energy Change, DG
For the reaction of ethene with HBr at RT, the approximate values are:
What does this data say about the bond energies?
The entropy?
Does the reaction proceed as written?
Do both of these favor the reaction proceeding as written?

43. Thermodynamic Quantities

44. Describing a Reaction: 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 439 kJ/mol to be broken at 25 ºC.
Conversely 439 kJ/mol of energy is released when a methyl radical and a hydrogen atom combine.
Changes in bonds can be used to calculate net changes in heat: bond breaking requires heat; forming releases heat

45. Bond Dissociation Energies
The value for ethylene in this table is the total value for the double bond – the sigma plus the pi bond. The pi bond of ethylene is estimated to be 62 kcal/mol or kJ/mol.
p bond =
62 kcal/mol

46. Calculating ∆H°
Values for ΔHo can be calculated from bond dissociation energies (bond dissociation energy is symbolized by the term DH).
Since entropy values can only be measured experimentally, enthalpy is often used (ignoring any entropy changes) in evaluating reactions. If a significant change in entropy accompanies a reaction, or if the reaction is done at high temperature, this can lead to erroneous results.
Note – the bond dissociation energy for the pi bond of ethene is not given in the table.
This slide shows how ΔHo can be calculated from tables of bond dissociation energies as shown on the next slide .

47. 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‡)
As the reaction in this slide proceeds, ethylene and HBr must approach each other, the ethylene pi bond and the H-Br bond must break, a new C-H bond must form in step 1, and a new C-Br bond must form in step 2.
An energy diagram can be used to graphically depict what happens during this reaction. Shown in this diagram is the progress of the reaction during Step 1.
At the beginning of the reaction, ethylene and HBr have the total amount of energy indicated by the reactant level on the left side of the diagram. As the two reactants collide and reaction commences, their electron clouds repel each other, causing the energy level to rise. If the collision has occurred with enough force and proper orientation, the reactants continue to approach each other despite the rising repulsion until the new C-H bond starts to form. At some point, a structure of maximum energy is reached, a structure called the transition state.
The transition state represents the highest energy structure involved in this step of the reaction. It is unstable and can’t be isolated. We can nevertheless imagine it to be an activated complex of the two reactants in which both the C-C pi bond and H-Br bond are partially broken and the new C-H bond is partially formed.
The energy difference between reactants and transition state is called the activation energy, delta G dagger, and determines how rapidly the reaction occurs at a given temperature. A large activation energy results in a slow reaction because few collisions occur with enough energy for the reactants to reach the transition state. A small activation energy results in a rapid reaction because almost all collisions occur with enough energy for the reactants to reach the transition state.
Once the transition state is reached, the reaction can either continue on to give the carbocation product or revert back to reactants. When reversion to reactants occurs, the transition-state structure comes apart and an amount of free energy corresponding to negative delta G dagger is released. When the reaction continues on to give the carbocation, the new C-H bond forms fully and an amount of energy corresponding to the difference between transition state and carbocation product is released.
The net energy change for the step, delta Go, is represented in the diagram as the difference in level between reactant and product. Since the carbocation is higher in energy than the starting alkene, the step is endergonic, has a positive value of delta Go, and absorbs energy.

48. 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
This represents the hypothetical transition state structure for the first step of the reaction. The C=C pi bond and H-Br bond are just beginning to break and the C-H bond is just beginning to form.

49. Possible Energy Profiles
a) Fast and exergonic
Small DG‡, negative DGo
b) Slow and exergonic
Large DG‡, negative DGo
Each reaction has its own energy profile. Some reactions are fast (small delta G dagger) and some are slow (large delta G dagger); some have a negative delta Go, and some have a positive delta Go.
c) Fast and endergonic
Small DG‡, positive DGo
d) Slow and endergonic
Large DG‡, positive DGo

50. 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
A reaction intermediate exists only transiently during a reaction. As soon as the carbocation intermediate is formed in the first step of the reaction, it reacts further with Br- in a second step to give the final product, bromoethane.
This second step has its own activation energy, delta G‡, its own transition state, and its own energy change, delta Go. We can picture the second transition state as an activated complex between the electrophilic carbocation intermediate and the bromide anion, in which Br- donates a pair of electrons to the positively charged carbon atom as the new C-Br bond just starts to form.
Coupling the diagrams for the two steps is illustrated here. Note the curves for the two steps are joined whereby the carbocation product of step 1 is the reactant for step 1. The reaction intermediate lies at a minimum between the two steps. The intermediate lies higher in energy than either the reactants or the product and cannot normally be isolated. It is however more stable than the two transition states that flank it.
The overall activation energy that controls the rate of the reaction is the energy difference between the initial reactants and the highest transition state, regardless of which step that occurs in.
The overall delta Go of the reaction is the energy difference between reactants and final products.

51. A Comparison between Biological Reactions and Laboratory Reactions
Laboratory reactions are usually carried out in organic solvent
Biological reactions in aqueous medium inside cells
They are promoted by catalysts that lower the activation barrier (so lower temperatures are required)
The catalysts are usually proteins, called enzymes
Enzymes provide an alternative mechanism that is compatible with the conditions of life

52. Molecular Models of Hexokinase
The active site has precisely the right shape and groups to bind and hold a substrate molecule in the orientation necessary for reaction to occur.

53. Biological Reactions Typically Involve Many Steps
Many steps with small activation energies prevent large energy changes that could overheat the organism.

54. Differences Between Laboratory and Biological Reactions

55. Let’s Work a Problem
Examine the following compounds and identify which will undergo radical chlorination to give a SINGLE monochloro- product?

56. Answer
To properly identify the compounds that will give monochloro- products, we must examine the compounds to identify those with only 1 kind of hydrogen atom. Of the compounds shown, compound b has 2 types of H’s (1˚ and 2˚), and compound d has 3 different types of H’s.
Therefore, the compounds identified by a,c,e, and f will give monohalogenated products because they all have only 1 type of hydrogen.