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CHEM 532, Fall 2010

Advanced Physical Organic Chemistry
Lectures: MWF 11:00 a.m. in 163 Noyes Lab (NL). Class begins promptly at 11:00 a.m.
Instructor: Scott K. Silverman, 140 Roger Adams Laboratory (RAL)
Office hours are by appointment. For an appointment, see me after class,
stop by my office, or send an e-mail message to [email protected].
This is an advanced course on Physical Organic Chemistry. We assume that you have a solid understanding
of fundamental organic chemistry as typically taught at the undergraduate level.
Purposes of this course:
(1) To help you achieve a comprehensive understanding of structure and bonding in organic compounds.
(2) To help you grasp the scope of organic reaction mechanisms, including reactive intermediates, and to
help you be aware of how these mechanisms and intermediates are studied.
(3) To help you understand how to write reasonable mechanisms for organic reactions.
(4) To help you appreciate the content of seminars and published papers related to organic chemistry.

(1922)

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Textbooks, exams, and problem sets
Textbooks: (required, recommended)

• “Modern Physical Organic Chemistry”, E. V. Anslyn & D. A. Dougherty; University Science Books, 2005.
• “Advanced Organic Chemistry, Part A”, 5th ed., F. A. Carey and R. J. Sundberg; Plenum Press, 2007.
(The 4th ed. should be okay if that’s what you have, although I will be citing 5th ed. page numbers.)
• “The Art of Writing Reasonable Organic Reaction Mechanisms”, 2nd ed., R. B. Grossman; Springer, 2003.
• “Mechanism and Theory in Organic Chemistry”, 3rd ed., T. H. Lowry & K. S. Richardson; Harper & Row, 1987.
• “Advanced Organic Chemistry”, 6th ed., M. B. Smith & J. March; Wiley, 2007.
• “Stereochemistry of Organic Compounds”, E. L. Eliel et al.; Wiley, 1994.
• “Frontier Orbitals: A Practical Manual”, N. T. Anh; Wiley, 2007.
• “Molecular Orbitals and Organic Chemical Reactions”, I. Fleming; Wiley, 1976 (Student Edition 2009).
• “Pushing Electrons”, D. P. Weeks; Thomson Brooks/Cole, 1998.
• “Arrow Pushing in Organic Chemistry”, D. E. Levy; Wiley, 2008.

Exams: First Exam (200 pts) Fri., Oct. 8 (7:00 p.m., 161 NL)
Second Exam (200 pts) Thur., Nov. 18 (7:00 p.m., 161 NL)
Final Exam (300 pts) Thur., Dec. 9 (time and room to be announced)
Exams during the semester will be 2 hours long. The comprehensive final exam will be 3 hours long.

Problem Sets: Five problem sets will be distributed during the semester. The problem sets will
be graded on a +, , – scale. They will be consulted in the case of borderline grades.
The problem sets will be due on Sept. 17, Oct. 4, Oct. 27, Nov. 15, and Dec. 6.

Course credit: 4 hours of credit

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Tentative course schedule
Bonding and Structure of Organic Molecules
1. Aug. 23 Introduction and bonding
2. Aug. 25 Bonding and resonance (part 1)
3. Aug. 27 Resonance (part 2)
4. Aug. 30 Aromaticity
5. Sept. 1 Conformational analysis (part 1)
6. Sept. 3 Conformational analysis (part 2)
Sept. 6 Labor Day
7. Sept. 8 Baldwin’s rules; stereochemistry (part 1)
8. Sept. 10 Stereochemistry (part 2)
9. Sept. 13 Stereochemistry (part 3); Hammond postulate

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Tentative course schedule (cont.)
Tools for Determining Reaction Mechanisms
10. Sept. 15 Substituent effects and linear free energy relationships (LFER) (part 1)
11. Sept. 17 Substituent effects and linear free energy relationships (LFER) (part 2)
12. Sept. 20 Kinetics (part 1)
13. Sept. 22 Kinetics (part 2)
Sept. 24 NO CLASS
14. Sept. 27 Reaction mechanisms (part 1)
15. Sept. 29 Reaction mechanisms (part 2)
16. Oct. 1 Reaction mechanisms (part 3) and Curtin-Hammett effect
17. Oct. 4 Kinetic isotope effects (KIE)
Oct. 8 Midterm Exam I – will cover topics from Aug. 23 through Oct. 1

Organic Reactions and Reactive Intermediates

18. Oct. 6 Acid-base chemistry (part 1) – note that Midterm Exam I is two days after this lecture
19. Oct. 11 Acid-base chemistry (part 2)
20. Oct. 13 Catalysis (part 1)
Oct. 15 NO CLASS
21. Oct. 18 Catalysis (part 2)
22. Oct. 20 Nucleophilic substitution (part 1)
23. Oct. 22 Nucleophilic substitution (part 2)
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Tentative course schedule (cont.)
Organic Reactions and Reactive Intermediates (cont.)
24. Oct. 25 Carbonyl chemistry (part 1)
25. Oct. 27 Carbonyl chemistry (part 2)
Oct. 29 NO CLASS
26. Nov. 1 Carbocations (part 1)
27. Nov. 3 Carbocations (part 2)
28. Nov. 5 Pericyclic reactions (part 1)
29. Nov. 8 Pericyclic reactions (part 2)
30. Nov. 10 Pericyclic reactions (part 3)
Nov. 12 NO CLASS
31. Nov. 15 Pericyclic reactions (part 4)
32. Nov. 17 Pericyclic reactions (part 5)
Nov. 18 Midterm Exam II – will cover topics from Aug. 23 through Nov. 3 (Nov. 19, NO CLASS)
Nov. 23–27 Fall Break (Thanksgiving)
33. Nov. 29 Carbanions
34. Dec. 1 Carbenes
35. Dec. 3 Free radicals
36. Dec. 6 Photochemistry (part 1)
37. Dec. 8 Photochemistry (part 2)
Dec. 19 Comprehensive Final Exam – will cover topics from Aug. 23 through Dec. 3

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Course introduction (cont.)
B. K. Carpenter (Determination of Organic Reaction Mechanisms; NY: Wiley, 1984), p. 1:

“One can never determine the mechanism of a reaction with 100% certainty.”

Stevens rearrangement

We must grow accustomed to ambiguity in physical organic chemistry — uncertainty is common. Much of
physical organic chemistry involves formulating mechanistic models and testing them. We must recognize
that simply because something is published, it is not necessarily correct!

www.cartoonstock.com
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Things are not always as they seem...

vases & faces

Necker cube
& impossible cube

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Structure and bonding in organic molecules
Many theories have been used to explain structure and bonding in organic molecules.
Which theory is “correct”?

Please review Section 1.1 of A&D (“A Review of Basic Bonding Concepts”).
We assume that you are familiar with essentially all aspects of this section.

Lewis structures
Section 1.1.3

VSEPR (valence-shell
electron-pair repulsion) Orbital hybridization
Section 1.1.5 Section 1.1.6

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Molecular Orbital (MO) theory
MO theory is central to physical organic chemistry. We will invoke MO theory throughout the semester.

LCAO-MO
approach

Other concepts to understand from Section 1.1:

electronegativity; inductive effects; dipoles; resonance; polarizability; steric effects

QMOT and “group orbitals” (Section 1.2): These topics will not be discussed explicitly in this course.

Are orbitals real?

Schwarz, W. H. E. “Measuring Orbitals: Provocation or Reality?” Angew. Chem. Int. Ed. 2006, 45, 1508-1517
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Appendices in the Anslyn & Dougherty textbook
Appendix 5: Pushing electrons

• Electron-pushing fundamentals
• Common errors with electron-pushing
• How to draw reasonable reaction mechanisms
• Practice problems

Appendix 6: Reaction mechanism nomenclature (SN1, SN2, SE1, SE2, E1, E2, E1cb, etc.)

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Resonance
Similar to MO theory, the concept of resonance is central to physical organic chemistry. The basic idea is that
more than one structural representation may be needed due to electron delocalization. Stated differently, the
bonding of a molecule frequently requires drawing two or more Lewis structures. The actual molecule is a
hybrid of these limiting resonance structures. For a review of resonance, see the handout “Brief Review of
Electronic Structure and Bonding” or any good basic organic chemistry textbook.

The resonance arrow is used to connect two Lewis The equilibrium arrow is used to connect two sets of
structures that are resonance contributors to the actual molecules that are related by an equilibrium process
resonance hybrid of a particular organic molecule (“both at (“back & forth”). A simple example of such a process is
once”). Neither resonance structure alone is a complete loss of a proton by an acid. Two separate arrows are on
description of the molecule’s structure. Both arrowheads top of each other; the overall arrow is used to describe at
are on a single, common shaft; the arrow is used to least two things (two different molecules).
describe one thing (the single molecule).

? both
real = theoretical

analogy by
rhinoceros unicorn dragon
P. Bruice
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Resonance (cont.)
Although simple Lewis structures along with the concept of resonance can frequently be used with substantial
success, a deep understanding of organic structure often requires more sophisticated methods that involve
quantum chemical calculations (i.e., computational methods).

Chapter 14 of A&D: Advanced Concepts in Electronic Structure Theory

14.1 Introductory quantum mechanics

14.2 Calculational methods—Solving the Schrödinger
equation for complex systems

Ab initio approaches

Ab initio means “derived from first principles”,

not “without approximation”. (A&D, p. 826)

Semi-empirical methods
Components of the equations are parameterized
to reproduce experimental data (H°f values).

Some caution is required in applying the method to unusual

structures not represented in the parameterization.
Nevertheless, there will always be systems that are simply
too large for ab initio theory. In such cases, only the semi-
Figure 14.3. The general form of the Hamiltonian for empirical methods will be computationally feasible.
any molecule, along with the meaning of each term. (A&D, p. 834)

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Experimental manifestations of resonance
We generally think of resonance (conjugation) as leading to greater stability within a molecule.
• Is this actually correct? How do we know?
• How do we measure resonance energies (i.e., determine extent of stabilization)?

Resonance, stabilities of anions, and pKa values of organic compounds

pKa ~16 pKa ~5

pKa ~50 pKa ~20

The more stable the anion, the lower the pKa value of the conjugate acid (i.e., more acidic).
Resonance increases the stability of the anion.

O OH
What is the pKa value for
the enol form of acetone?

How does this relate to the

equilibrium constant for the
O–
keto/enol equilibrium? + H+
thermodynamic cycle
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Experimental manifestations of resonance (cont.)
What about resonance in a carbon-centered radical adjacent to a double bond (e.g., allyl radical)?

For rotation around the C–C bond,

G‡ = 15 kcal/mol

This value is considered as the

“delocalization energy”.

Significantly, this value is in good agreement with

the difference in C–H bond dissociation energies
(BDEs) for propane and propene of 14 kcal/mol.

There are many other examples in which stabilization is considered to arise from resonance (conjugation):

pKa (guanidinium pKa (methylammonium

cation) ~15 cation) ~10

But how strong is the connection between resonance and stabilization?

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Alternative view of the importance of resonance to stabilization
The notion that “more resonance structures” leads to “increased stability” is a well-accepted principle of organic
chemistry. For example, on page 6 of Lowry & Richardson:

“The carboxylic acids, for example, are much stronger acids than the alcohols;
this difference must be due largely to greater stability of the carboxylate ion
over the alkoxide ion. It is the possibility of writing two equivalent Lewis
structures for the carboxylate ion that accounts for this difference.

Another example is the allylic system…”

However... Wiberg has pointed out that resonance and stabilization were never shown conclusively to be linked.
For example, in Wheland’s classic 1955 text entitled Resonance in Organic Chemistry, he notes that the greater
acidity of formic acid as compared with methanol can be explained by two factors:

(1) Resonance stabilization of the anion

(2) Electrostatic stabilization of – charge
by the + charge on the carbonyl carbon

What is the relative importance of these two factors?

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Alternative view of resonance and stabilization (cont.)

A B C

Ab initio calculations by Wiberg & coworkers indicated that the carbonyl O atom and the H atom attached to the
carbonyl group both gain approximately 0.15 e– upon deprotonation of formic acid. What does this imply?

The implication is that for (neutral) formic acid itself, the polarized
resonance structure contributes substantially to the resonance hybrid.
These and other results suggest that resonance structure C must be
drawn to account properly for the properties of formate anion. neutral polarized

Wiberg, K. B. Acc. Chem. Res. 1999, 32, 922-929; J. Chem. Educ. 1996, 73, 1089-1095

Resonance and the amide (peptide) bond

What is the importance of resonance for the amide bond (peptide bond)?

If this is a correct and complete

description of formamide, what
experimental predictions would
we make?

bond lengths reactivity e– density rotational barrier

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Resonance and the amide (peptide) bond, cont.

Typical resonance structures for the amide bond:

Traditionally, resonance structures A and B are

considered to be important. In contrast, C would
normally be deemed “minor” due to charge separation.
A&D,
Is “A  B” an accurate representation? p. 23

Similar to the situation with carboxylic acids, computational methods suggest that
resonance structures B and C are both of considerable importance for the amide bond.

Calculations: Upon rotation from planar amide to perpendicular form (rotational transition state), the C=O bond
shortens only slightly (–0.01 Å), but the C–N bond lengthens substantially (+0.08 Å). However, if only resonance
structures A and B were important, then disallowing resonance (by rotation) should shorten the C=O bond length
and increase the C–N bond length by approximately the same amount. Importance of C helps to explain the data.

Consideration of the partial charges (+, –) on the various atoms also suggest that resonance structure C is more
important than often appreciated. For example, there is much less + on N than would be expected if resonance
structure B were much more important than C.