Organicchem Probsets

CHEMISTRY 235 ORGANIC CHEMISTRY I
Review of Structural Topics 2010
For use by sections: 01A 05A

For use by instructors: Graham, Gunsaru, Peterson & Schaller
Edited By: Kate J. Graham

Contributions from Kate Graham, T. Nicholas Jones, Edward McIntee, Alicia Peterson, Chris
Schaller
Copyright: Kate Graham, T. Nicholas Jones, Edward McIntee, Alicia Peterson and Chris Schaller,
Department of Chemistry, CSB/SJU
TABLE OF CONTENTS
Review
Structural Representations
Nomenclature
Acyclic Conformational Analysis
91
Cyclic Conformational Analysis
96
Stereochemistry
128
Molecular Orbital Theory
152
Aromaticity
168
Acid-Base Chemistry
175
Carbonyl Reactions
199
Review
Importantquestionsyoushouldbeabletoanswerbasedonyour
firstyearofchemistry:
i. Whatisabond,andwhydobondsform?
ii. Whatphysicalforcesareresponsiblefortheformationof
bonds?
iii. Aretheredifferenttypesofbonding?Explainthedifferences.
iv. Moleculeshaveshapeandtakeupspace.Why?
v. Givenamolecularformula,canyoupredictamolecule'sshape?
[e.g.ifyoucombineoneN,oneC,oroneOwithenough
hydrogenstomakeneutral,closedshellmolecules,whatwould
betheshapeofeachmolecule?]
vi. Whatisanatomicorbital?Whatisamolecularorbital?
vii. Whatistheaufbauprocess?
viii. Whatismeantbytheterm"valenceshell"?
ix. Whyareorbitalsimportantintermsofbonding?
x. Whatareintermolecularforcesandwhyaretheyimportant?
We have provided some practice problems for you to start getting back on track with.
Enjoy!
1. Arrangethefollowingatomsbyincreasingelectronegativity:Li,Br,Pb,K,Mg,C.
2. DrawLewis(orKekule)structuresforthefollowingcompounds.Includeatleasttwo
resonancestructuresforeachcompoundandALWAYSincludeformalchargesifpresent.
a. carbonmonoxide(CO)
b. potassiumcyanate(KNCO)
3. Indicatepartialpositiveornegativechargesontheatomsinthefollowingmoleculesof
fragments.
a. HF
b. NaH
c. H2
d. C-H
e. C-Cl
f. Si-Li
g.Si-Cl
h. N-Mg
4. IntermolecularForces.Explainwhatismeantbythefollowingtypesofintermolecular
forces.Useillustrations.
a. Hbonding(e.g.water,H2O)
b. dipoledipole(e.g.formaldehyde,CH2O)
c. vanderWaals[alsocalledLondonordispersion](e.g.bromine,Br2)
5. Usepicturestoillustratechangesinintermolecularforces/bondinginthefollowing
cases:
a. methanolisheatedupuntilitboils.
b. sodiumchlorideisdissolvedinwater.
c. ethylacetateismixedwithacetonitrile.
6. Methanol(CH3OH;bp=65C)boilsnearly230higherthanmethane(CH4;bp=164C),
but1decanol(C10H21OH;bp=229C)boilsonly55higherthandecane(C10H22;bp=
174C).Explain.
7. Whichshouldhavethehigherboilingpoint,methanol(CH3OH)orbromomethane
(CH3Br)?Why?
8. Predictthebondanglesinacrylonitrile.
9. Listthefollowingcompoundsinorderfromleastacidictomostacidic.
a. CH4,H2O,NH3
b. HF,HBr,HCl
10. Makearough,qualitativeplotofthechangeinenergythatoccursasthebondinanH2
moleculeisbroken.
DrawLewis/Kekulestructures,includinganyresonancestructuresyoucanthinkof,for
thefollowingmoleculesandions:
a. ethylacetateCH3CO2CH2CH3(noteabbreviatedformulaee.g.CH3means3H
attachedtothatC)
b. acetonitrileCH3CN
c. nitromethane,CH3NO2(Nisconnectedto2oxygensandacarbon)
d. diazomethaneCH2N2(connectedCNN)
e. sodiumazideNaN3
f.
potassiumthiocyanateKSCN
g. sodiumborateNa3BO3
h. calciumcarbonateCaCO3
i.
potassiumphosphateKPO4H2
j.
potassiumphosphiteKPO3H2
k. potassiumhypophosphiteKHPO2H
A. Assign formal charges as appropriate:

CH2
CH3
CH3OH2
CH4
CH3OCH3
HC
CH2
H 2C
H3C
CH3
H 2C O
HN
CH2
H 2C
H3C
(CH3)3N NH4
NH2
H2C OH
Br
CH2
H 2C
CH3NH2
NH
PH3
H 2C C O
BF4
H2C
CH2
H2C
HS
N
CH2
H2C
O
CH2
H 2C
H3C NH2
H 3C N O
H2N
CH2
H 2C
CH3OH
BF3
HC
CH2
H 2C
CH3O
HC
CH2
H2C
HO
CH2
H 2C
O
OH
B. Add electron dots where appropriate:
CH3
CH3
H3C O CH3
O O
CH2
(CH3)3P
O O O
P
CH2
H2C
CH2 H3C N
PCl3
S
CH2
H 2C
H2B
H3C NH
H2B
H2N NH2
H3C S CH3
H2C N N
H O O H
CH3
H3C
H Cl
N
O
H 3C
H Br
H3C C N H
O
H B
H3C C N
Structural Representations
We will start this semester looking spectroscopy of simple organic compounds.
However, we need a common language and common symbols to discuss the
molecules and some common 2D representations of molecules.
Fill in the missing information on the table above.
Condensed Formula
Line-Bond
H
CH3CH3
Skeletal
H
C
H
H
CH3CH2CH3
H
H
H
(CH3)2CHCH3
CH3COCH3
CH3CO2H
H
C
C
H
CH3CH2OCH3
H
C
H
Draw a line bond representation of the molecule shown below.
Could you draw a reasonable condensed formula for this compound?

or why not?
In skeletal representations the hydrogens are not shown. Is it still possible to

tell how many hydrogens there are on a particular carbon? How?
Why
Take Home Message: If you draw an atom, then Hydrogen atoms must be
drawn! Hydrogens are implied ONLY in skeletal representations of carbon
atoms.
In most of the representations, the electrons are not shown. How can you
tell if there are any lone pairs on atoms?
Define Isomer
Draw all the isomers of heptane, C7H16 using line bond representation.
Nomenclature
Chapters 5 & 12
Alkanes -- Fill in the Blanks
All alkane names have a prefix telling how many carbons are in the longest chain, and
the suffix "ane", meaning alkane.
Prefixes: meth = 1 carbon; eth = 2; prop = 3; but = 4; pent = 5; hex = 6; hept = 7; oct = 8; non = 9; dec = 10.
Rings have the additional prefix, "cyclo".
branched alkanes
normal alkanes (carbons in one long chain)
formula
skeletal structure
H
CH4
C2H6
C3H8
H
H
H
H
H
H
H
name
draw 1 isomer
name
(none)
methane
ethane
(none)
1-carbon branch
on 2nd carbon
3-carbon chain
C4H10
(none)
2-methylpropane
2,2-dimethylpropane
C5H12
di means there are 2 methyl groups;

tri = 3 of them, tetra = 4, penta = 5...
C6H14
C7H16
C8H18
C9H20
3-ethyl,2-methylheptane
C10H22
cyclopentane
Alkenes, Alkynes & Aromatics -- Fill in the Blanks

All alkene names have a prefix telling how many carbons are in the chain (see "Alkanes"), and the suffix
"ene", meaning alkene. Alkynes end in "yne". A number indicates where in the chain the double (or
triple) bond can be found.
formula
C2H4
C3H6
C4H8
skeletal structure name

H
H
ethene
H
H
propene
add 1 isomer (w/ names)

none
no alkene isomer
1-butene
number identifies where
double bond begins (always
the lowest possible number)
C5H10
C5H8
1,4-pentadiene
C6H10
C7H12
Aromatics -- Some Examples
benzene
methylbenzene or toluene
1,2-dimethylbenzene or o-dimethylbenzene
1,2-substitution on benzene is sometimes called ortho- or o1,3-substitution on benzene is sometimes called meta- or m1,4-substitution on benzene is sometimes called para- or p-
Br
Cl
name:
Priority Table
Additional Nomenclature Problems:

Part I. Using IUPAC Nomenclature, provide names for the following compounds:
O
O
OH
O
CN
Part II. Using IUPAC name, provide structures for the following compounds:
N,N-dimethylpropanamide
3-methoxyhexanoic acid
isopropyl alcohol
4-bromoheptanal
N,N-dimethylheptylamine
Acyclic Conformational Analysis

Chapter 6
Build a 3-D model of ethane (C2H6) using the model kits. Look at the
following 2-D representations of ethane.
Build propane (C3H8) using the model kits.

o Wedge and Dash Representation
o Sawhorse Representation
o Newman Projection
Draw propane in:
At room temperature, the carbon-carbon bond of ethane is spinning

rapidly. The following graph shows the Potential Energy of ethane in
different conformations different shapes as it rotates.
HH
HH
HH
HH
HH HH
HH HH
HH
HH HH
HH
Potential Energy
2.8 kcal/mol
H
H
60
120
180
240
300
360
Degrees of Rotation
Clearly define the difference between conformational isomers (often called

conformers) and constitutional isomers.
Some conformations are lower energy and some are higher energy.
Propose some ideas for why these conformations differ in energy.
Consider rotations around the C2C3 bond of 2methylbutane. Build

molecular models of all the different conformations.
Draw the conformations using Newman projections.
Circle the low energy conformation(s). Explain your choices. Construct

a qualitative plot of energy versus angle of rotation around the C2C3
bond.
Conformational Analysis
ImportantTakeHomePoints:
a. Conformationalisomersareinterconvertedbyrotationaroundcarbon
carbonsingle(sigma)bonds.
b. Intramoleculardistancesvarywithconformation.
c. ExaminationofchangesinvanderWaalsrepulsionscanbeusedto
qualitativelypredictrelativeconformationalenergiesand,therefore,
relativeconformationalpopulationsatequilibrium.
d. Constitutionalisomersdonotinterconvertbyrotationsaroundsingle
bonds.
ADDITIONAL PROBLEMS
For this activity consider 1,2-diiodoethane:
0. Here is the data from calculations on 1,2-diiodoethane:
I-C-C-I
Energy
Conformation
dihedral (Kcal/mol) description
angle
0
12
60
0
120
4.5
180
0
Unfavorable
interactions, if
any.
Draw 1,2-diiodoethane.
Draw Newman projections for each of the 4 conformations.
Fill in the remaining column in the table above.
Fill in the graph below showing the energy of the conformations.
Why is there such a BIG energy difference between the conformation with
a dihedral angle of 0 and 120?

Chapter 6
In acyclic compounds, we have looked at some of the factors that affect the
stability of different conformers.
List all of these factors:
Using molecular models, build cyclopropane, cyclobutane and cyclopentane.
What types of strain do you notice?
What are the bond angles of these molecules? What are the usual bond
angles of a tetrahedral carbon?
Are these planar molecules?
Using molecular models, build cyclohexane.
Find the conformation of this molecule that has the least torsional, steric
and ring strain.
Draw a 2D chair representation of this molecule including all of the
hydrogens.
Label each hydrogen as axial or equatorial.
Using molecular models:

a. Build methylcyclohexane. Carefully draw the two chair
conformations of this compound.
b. Assess the possibility of steric hindrance between the hydrogens of
the methyl carbon and the hydrogens on carbons at the 3- and 5positions of the ring.
c. Based on the distances between the hydrogens, predict which
conformation is more stable. Predict which of the two cyclohexane
conformations will predominate at equilibrium. Is the methyl group
axial or equatorial in the more stable conformation? Explain your
reasoning.
Cyclic Alkanes
Conformational Analysis
H
H
H
H
H
H
H
HH
H
H
7-atom interactions usually increase the energy of conformer

by approx. 3 kcal/mol
Thus, the chair conformation of t-butylcyclohexane with the tert-butyl axial

has 8 kcal/mol increased energy due to steric strain
Additional Problem:
Draw the other ring conformation of t-butylcyclohexane with the tert-butyl equatorial.
Calculate the amount of increased energy due to steric strain in this chair
conformation.
Decalin and Adamantane Structures

One of the decalin isomers has conformational flexibilty and
the other is considered a rigid system. Which one is which?
Draw as many conformers as possible for each isomer.
DECALIN SYSTEMS
H
TRANS
H
H
CIS
Rimantadine and Adamantadine are antiviral compounds. Rimantadine has

been used to treat Influenzavirus A infection. Adamantadine has been shown
effective as an Anti-Parkinsonian agent.
ADAMANTANE
DRAW Adamantadine
[AKA 1-aminoadamantane]
DRAW Rimantadine
[AKA 1-(1-adamantyl)ethylamine]
DIAMOND LATTICE
Diamond Lattice

Important Take-Home Points (to date):
a.
b.
c.
d.
e.
f.
g.
h.
i.
Alkane Nomenclature
Constitutional isomers do not interconvert by rotations around
single bonds.
Conformational isomers are interconverted by rotation around
carbon-carbon single (sigma) bonds.
Examination of torsional, steric and angle strain can be used to
qualitatively predict relative conformational energies (acyclic or
cyclic) and, therefore, relative conformational populations at
equilibrium.
5-atom interactions cause no increase in steric strain
There are two chair conformations for each cyclohexane
compound. These are rapidly interconverting.
In general, substituents larger than hydrogen prefer to be
equatorial on a cyclohexane ring.
The presence of two or more substituents on a cyclohexane ring
introduces the possibility of cis/trans isomers.
Wedge-and-Dash indicates tetrahedral geometry but a chair
conformation must be drawn to determine whether a
substituent is axial or equatorial.
Different cis/trans isomers will have different conformations.
The larger substituent will prefer to be equatorial if possible.
All chairs can be drawn on diamond lattice. Substituents should
fall on the extended lattice.
Trans-decalin systems cannot ring flip. Cis-Decalins systems
can.
Additional Problems
1. Now consider cis-1,2-dimethylcyclohexane.
a. Draw the two possible chair conformers.
b. Calculate the relative energy of each and determine which is the most
stable.
2. Now consider trans-1,2-dimethylcyclohexane.
stable.
stable.
stable.
stable.
stable.
7. For the following questions consider the molecule drawn below:
Draw the molecule in its two chair conformations.
Calculate the energy difference between the two chair conformations

above and label them as best and worst chairs.
8. For the questions on this page please consider the set of molecules found
below.
Calculate the energy difference between all pairs of chair conformations

Using the calculations you made above, Circle the molecule below that
has the lowest energy best chair conformation?
9. For the questions on this page please consider the set of molecules found
below.
Calculate the energy difference between all pairs of chair conformations

Using the calculations you made above, Circle the molecule below that
has the lowest energy best chair conformation?
10. Consider the reaction of 4-tert-butyl-1,3-cyclohexanediol with acetone and

acid to form an acetal. Experimental results indicate that only the isomer with
all three substituents cis will form the product.
a. Draw the most stable chair conformations of each of the four isomers
shown below.
b. Explain the observation that only the all cis isomer reacts.
O
HO
H+
OH
HO
OH
HO
OH
HO
OH
O
O
11. Predicting Hydrogen bond formation:

a. Draw the most stable conformation of each of the two following
isomers.
b. Indicate which of these compounds can form an intramolecular
hydrogen bond.
c. Show the hydrogen bond in your drawing.
OH
OCH3
OH
OCH3
12. Draw all isomeric dimethylcyclobutanes, clearly showing stereochemistry.

a. Designate as cis or trans where appropriate.
b. Indicate whether structures are related as constitutional isomers or
stereoisomers.
13. Acetylcholine is a neurotransmitter of the autonomic nervous system that

sends information through the neurons to target organs. Most drugs which
affect the nervous system tend to act at the synapse to alter chemical
neurotransmission. The structure of ACh is drawn below. The structure is
also drawn as N(Me)3+-CH2-CH2-OAc.
a. What are the two main functional groups involved in this structure?
b. Draw the Newman projections for the different conformations
obtained through 60 bond rotations around the CH2-CH2 bond of
this molecule. Label each conformation with the appropriate term
such as gauche, etc.
c. Draw an energy diagram for the complete rotation around this
bond. Indicate which conformer is the most stable. Which
conformer is the least stable?
d. The two compounds below were synthesized and tested for
cholinomimetic properties - that is tested for the production of a
response resembling that of ACh. Isomer 1 had about the same
activity as ACh; isomer 2 had about 1/500th of the potency of ACh.
Which conformer of ACh must be the active form that binds to the
receptor? Show Newman Projections to support your answer.
e. Four different trans-decalin isomers were synthesized

corresponding to four conformers of ACh. Sketch each isomer in
its most stable chair conformation.
f. The above isomers were synthesized as potential drugs to act as

neurotransmitters. They were designed to resemble conformers of
ACh and, thus, to mimic the acetylcholine. Predict which isomer
would be most biologically active (bind to acetylcholine receptor).
Why?
g. These decalin isomers are not as biologically active as the ACh or
the cyclopropane isomers. Why?
NMR Conformational Effects

Nuclei that are interchangeable by rotational symmetry are said to be
homotropic. Rotation about carbon-carbon single bonds is so rapid that the
chemist rarely considers the fact the three protons of a methyl group are not
always equivalent.
At room temperature, rapid CC rotation, however, results in an average
environment in which they are equivalent. Sometimes, these different effects
can be seen in rigid systems and/or when the molecule doesnt have enough
energy (ie too cold!) to rapidly rotate around single bonds.
Fill in the table below:
Molecule
Most Stable Conformer
Number of 13C-NMR Signals

Low
High
Temperature Temperature
Explain why the observed number of 13C-NMR peaks can change with a change in
temperature.
Stereochemistry
Chapter 7
Isomers
Constitutional
Isomers
Conformational
Isomers
Enantiomers
Stereoisomers
Diastereomers
Geometric
Isomers
Diastereomers
with multiple
chiral centers
Simple Stereochemistry Ideas

Before Class, read Chapters SC3 (Enantiomers), SC4 (Organic
Enantiomers) and SC5 (Biological Small Molecules) from Dr. Schallers
website:
http://employees.csbsju.edu/cschaller/Principles%20Chem/stereochem/st
ereo_index.htm
Passport to Class:
Define these terms
Chiral Center
Chiral Compound
Achiral Compound
Enantiomers
Optically Active
Plane of Symmetry
Optical Rotation
R/S (Cahn-Prelog-Ingold Rules)
Circle the compounds that have enantiomers:

O
Cl
Cl
CH3
Br
C
Cl
OH
C
CH3
Label these compounds with R/S nomenclature:

Br
OCH3
O
H
Cl
HOH2C
CH2Ph
CH3

b. Build 1,1,1-chlorobromofluoroethane.
c. How many stereoisomers are there?
d. Draw all of the stereoisomers.

e. Define the relationship between these isomers.
f. Use R/S Designation to clearly label your drawings.
Label the following compounds as chiral or achiral:

O
Ph
Cl
Cl
OH
HO
Br
Ph
OH
Cl
OH
O
Ph H
OH
OH

a. Build all isomers of 2,3-dihydroxybutanoic acid.
b. How many stereoisomers are there?
c. Draw all of the stereoisomers with wedges and dashes.

d. Define the relationship between these isomers.
e. Use R/S Designation to clearly label your drawings.

a. Build all isomers of 2,3-butanediol.
b. How many stereoisomers are there?
c. Draw all of the stereoisomers.
d. Define the relationship between these isomers.
e. Use R/S Designation to clearly label your drawings.
Diastereomers
Before Class, read Chapters SC8 (Biological Building Blocks), SC9
(Carbohydrates and Diastereomers) and SC10 (Diastereomers and
Physical Properties) from Dr. Schallers website:
http://employees.csbsju.edu/cschaller/Principles%20Chem/stereochem/st
ereo_index.htm
Passport to Class:
Define these terms:

Racemic Mixture
Diastereomer
Meso Compound
Problems SC10.1, SC10.2 and SC10.3
Additional Problems
Tell whether the compounds in each of the following pairs are

nonisomeric, identical, constitutional isomers, enantiomers, or
diastereomers.
Assign a configuration (R or S) to all stereocenters.
Identify the optically active (chiral) compounds.
Identify any meso compounds.
Chiral Resolution
Amphetamines are potent central nervous system stimulants capable
of causing addiction. Amphetamines are prescribed as diet pills and
for hyperactivity in children. The basic structure of amphetamine is
shown below.
a. Amphetamine is synthesized as a racemic mixture, which must

be resolved to isolate the biologically active S isomer. Draw
both enantiomers of amphetamine. Label each one with R or S.
b. Racemic amphetamine can be resolved using the chiral

reagent, (+)-tartaric acid. Tartaric acid, (2R, 3R)-2,3dihydroxybutanedioic acid, is shown below.
Each enantiomer of the racemic mixture of amphetamine reacts

with (+)-tartaric acid in a 1:1 stoichiometry. Draw the two salts
formed from this reaction. Clearly draw and label all chiral
centers.
c. How are these two stereoisomers related to each other? Can

they be separated?
Concept Mapping
Definition: Concept maps offer a method to represent information visually. There are a
variety of such maps.
Purpose: Concept maps harness the power of our vision to understand complex
information "at-a-glance." The primary function of the brain is to interpret incoming
information to make meaning. It is easier for the brain to make meaning when
information is presented in visual formats..
Making Your Own Concept Maps: Here are some resources for getting started on
making you own concept maps:
Theory of Concept Maps: http://www.msu.edu/~luckie/ctools/
Kinds of Concept Maps: http://classes.aces.uiuc.edu/ACES100/Mind/c-m2.html
Tips on Making Concept Maps: http://classes.aces.uiuc.edu/ACES100/Mind/c-m3.html
Develop a Concept Map of Isomers that covers these topics:

Constitutional, Conformers, Enantiomers, Diastereomers, Meso, E/Z,
properties, Geometric Isomers, Optical Activity, purification, spectroscopy,
Chairs, Chiral Centers, etc.
IR Unknown
An unknown compound was determined to be one of the three shown below. Use the
data provided to determine which one of the compounds is the actual unknown.
IR (cm-1): 3030, 2915, 2713, 1727, 1456, 1397, 1117, 1016, 985, 828.
Optical rotation = +13.1o
O
O
Another compound was isolated with an identical IR spectra to the

unknown above. What is the optical rotation of this molecule?
Murder Mystery Problem:

One of my favorite mystery authors, Dorothy Sayers, wrote a book entitled
Documents in the Case in1930. George Harrison, an expert in edible fungi, is
found dead in his country cottage apparently by accidental ingestion of
muscarine, the toxin of the deadly mushroom Aminita muscaria. Aminita
muscaria is closely related to the edible fungus, Aminita rubescens. However,
Harrisons son does not believe that his father could have made such an
amateurish mistake when it came to mushrooms. His suspicions are furthered
when it becomes clear that there was enough muscarine in Harrisons soup to kill
30 people. Harrisons son turns to Sir James Lubbock, the English Home Office
Analytical Chemist, who looks at the muscarine from Harrisons stomach in a
polarimeter and discovers that it is optically inactive. Explain briefly how this
clearly proves that Harrison has been murdered.
O
N
HO
Muscarine
Cholic Acid
Cholic acid (structure shown below) is a major steroidal constituent of human
bile.
COOH
H
OH
CH3
CH3
H
H
HO
H
OH
H
Draw a three dimensional representation of the lowest energy conformation of

this molecule (HINT: chairs).
Label the hydroxyl groups as axial or equatorial.

Can this molecule undergo a ring flip?
Circle all of the stereocenters in cholic acid in the drawing provided.

Label each stereoisomer as R or S.
How many stereoisomers are possible?
Calcium Blockers
Calcium channel blockers inhibit the flow of calcium ions into the smooth
muscle cells of blood vessels. This inhibition results in a relaxation of the
muscles in the blood vessels, with the result that there is less resistance to
the flow of blood and a lowering of blood pressure. A critical step in the
synthesis of a pharmaceutically important calcium channel blocker,
diltiazem, is shown below. The single enantiomer of (-)-trans-2phenylcyclohexyl chloroacetate (A) is converted into two compounds (B
and C).
a. Draw the two chair conformations of A. Use models if necessary.

Be sure to draw the correct enantiomer of A.
b. Indicate which conformer will predominate at room temperature.
c. Circle all of the stereocenters in A.
d. Label all of the stereocenters in A as either R or S.
e. Draw the mirror image of A.
f. What is the stereochemical relationship between B and C?
Glucose
CH2OH
CH2OH
HO
HO
O
Ha
HO
OH
OH
!-D-glucose
O
OH
HO
OH
Ha
"-D-glucose
a. Draw the 2 chair conformers for D-glucose. Circle the most stable chair.
b. Draw the 2 chair conformers for D-glucose. Circle the most stable
chair.
c. How many chiral centers in glucose?

d. How many possible stereoisomers?
e. What is the relationship between D-glucose and D-glucose?
enantiomers
diastereomers
conformers
constitutional isomers
f. Draw the mirror image of D-glucose.

g. NMR of glucose. If you were given an unknown sample of glucose and
asked to determine if it was D-glucose or D-glucose:
i. Predict the shift for Ha.
ii. How does this protons chemical shift differ from all the other
protons in this molecule?
iii. How will the coupling change in D-glucose vs Dglucose? (Review rigid systems!)
Hydrogen Bonding:
CO2H
OCH3
CO2H
OCH3
a. Draw the 2 chair conformers for compound A. Circle the most stable chair.
b. Draw the 2 chair conformers for compound B. Circle the most stable
chair.
c. What is the relationship between compound A and compound B?

enantiomers
diastereomers
conformers
d. Which one of these compounds can form an internal hydrogen bond?
Testosterone Doping in Athletes

In order to aid you in the following problems, please read the article found at
http://pubs.acs.org/isubscribe/journals/cen/84/i35/html/8435sci4.html
1. What is the difference between Testosterone and Epitestosterone (structurally)?
2. Why are these molecules considered stereoisomers?
3. What kind of stereoisomer are they? How do you know?
4. Draw Testosterones isomer Epitestosterone.
5.a. Place asterisks at all chiral carbon centers, and then circle the center that relates to
the difference between Testosterone and Epitestosterone.
b. Calculate the max number of stereoisomers.
6. Assign priorities to each group on the circled carbon from question 5a and label the
center as either R or S. What does this tell you about the molecule?
7. Draw Testosterone and Epitestosterone in their most stable chair conformations.
8. Label the axial and equatorial groups on the five-membered rings of each molecule.
9. Which is the more stable stereoisomer? Why or how do you know?
10. Below is the mass spectrum for Testosterone. Based on the information in the paper,
predict how the mass spectrum for the synthetic testosterone would differ.
11. Considering what you have read and discussed did Floyd Landis cheat?
Practice Exam
Problem-Solving using spectroscopy, stereochemistry, and conformational analysis
1. An organic chemistry student wanted to form an acetal functional group in an

independent synthesis reaction. A sample reaction is shown below.
This student wanted to start with 1,3 cyclohexanediol and 2-propanone rather than
the reagents shown above.
Draw the starting material: 1,3 cyclohexanediol.
Draw the reagent: 2-propanone.
Draw the product of this reaction with the acetal functional group.
2. The student looked up the structures in CSB stockroom inventory and found more
than one entry for 1,3 cyclohexanediol.
How many possible stereoisomers for 1,3 cyclohexanediol are there?
Draw 2 stereoisomers of 1,3 cyclohexanediol with wedges and dashes?
Label the two isomers above with R and S.
What is the relationship of the two isomers above:

enantiomers
diastereomers
conformers
3. Knowing that water would be produced as a side-product and the reaction was run in
acidic conditions, the student decided to work up the reaction using a liquid-liquid
extraction. Describe the extraction.
What solvents should the student use?
Which solvent would be the top layer?
Which compounds (products, remaining starting material, 2-propanone, acid)

would go into which solvents?
4. Further purification concerns:

If 2-propanone still remained after the purification, what key peak would the
student expect to see in the IR spectrum?
If the student still had some methyl tert-butyl ether left in solution, what peaks
(include shift, integration and multiplicity) would be present in the 1H NMR?
If the reaction did not go to completion and the student had a solution of 25%
starting material (1,3-cyclohexanediol) and 75% of the acetal product, draw
the expected GC trace. Label each peak to indicate which compound would
have a longer retention time.
5. The spectra below were obtained after cis-1,3 cyclohexanediol was reacted with 2propanone in acid. Fully analyze the spectra (on the following page) in the tables
below.
IR
Frequency
Bond Type
13C
Chemical Shift
Type of Carbon
1H
Chemical Shift
Integration
Multiplicity
Interpretation
cis-1,3 cyclohexanediol rxn
6. The spectra below were obtained after trans-1,3 cyclohexanediol was reacted with 2propanone in acid. Fully analyze the spectra (on the following page) in the tables
below.
IR
Frequency
Bond Type
13C
Chemical Shift
Type of Carbon
1H
Chemical Shift
Integration
Multiplicity
Interpretation
trans-1,3 cyclohexanediol rxn
7. One of these reactions worked and one did not.

Which reaction worked?
In order to understand why one of these reactions worked, draw the two
conformers of cis-1,3 cyclohexanediol in chair form.
In order to understand why one of these reactions worked, draw the two
conformers of trans-1,3 cyclohexanediol in chair form.
In order to understand why one of these reactions worked, draw the acetal
product of each diol in chair form.
Explain why only one of these reactions worked.
8. Isotopic experiment
This student noticed that there are 3 oxygens in the starting materials, but there are
two oxygens in the acetal product. The student decided to run the reaction below
with 18O isotope in the aldehyde to determine whether this oxygen is included in the
acetal product. The student used Mass Spectrometry to look at the product.
Explain what the mass spectrum would look like if the 18O isotope was NOT
incorporated into the acetal.
Explain what the mass spectrum would look like if the 18O isotope was incorporated
into the acetal.
Molecular Orbital Theory

Chapter 3
Atomic Orbitals (AOs)
What is an orbital?
What do s and p orbitals look like?
List the rules for putting electrons into atomic orbitals.
Molecular Orbitals (MOs)

How can two orbitals interact?
What is a molecular orbital?
Simple Rules for making Molecular Orbital Diagrams:

1) There must be the same number of molecular orbitals as atomic
orbitals.
2) There must be the same number of electrons in the molecule as in the
atomic orbitals.
3) The overall combined energy of the molecular orbitals must equal the
overall combined energy of the atomic orbitals.
Simple Diatomic Molecules
MOs for simple diatomic molecules can be constructed by combining the

AOs from the two atoms. This is shown in the example below:
Construct an MO diagram for He2.
Additional Problems (MO diagrams of diatomics)

Problem 1:
a. Draw Lewis Dot Structure for carbon monoxide (CO).
b. Draw any resonance structures for this molecule.
c. Draw a Molecular Orbital Diagram for CO.
d. Draw a dipole moment for each Lewis dot structure.

e. Experimental data indicates that CO has a very small dipole moment.
Explain this observation using your resonance structures and your MO
diagram.
f. Carbon Monoxide is highly toxic because it binds tightly to iron in

hemoglobin and thus prevents that molecule from binding to and carrying
oxygen in the blood. The carbon atom in carbon monoxide binds to iron
(II), Fe2+. Explain this observation using your resonance structures and
your MO diagram.
Problem 2:
The electron configuration of O2 in MO terms is: ((1s)2, (1s)2, (2s)2, (2s)2,
(2p)2, (2p)2, (2p)2, ( 2p*)1, (2p*)1.
e. Draw the Lewis dot structure of molecular O2. How many unpaired
electrons are in this structure?
f. Liquid molecular oxygen is visibly held in place between the poles
of a strong magnet. Explain this in terms of the electron
configuration.
g. Molecular O2 has a bond length of 0.121 nm while the molecule O2+
has a bond length of 0.112 nm and the oxygen anion, O2-, has a
bond length of 0.126 nm. Explain the trend in bond lengths.
Problem 3:
The electron configuration of NO in MO terms is: (1s)2, (1s)2, (2s)2, (2s)2,
(2p)2, (2p)2, (2p)2, ( 2p*)1.
a. Draw the Lewis dot structure of molecular NO. How many unpaired
electrons are in this structure?
b. Calculate the bond order for NO based on the electron
configuration.
c. The bond length in NO is 0.115 nm while the bond length in NO+ is
0.1062 nm. Calculate the bond order for NO+ and explain the
change in bond length based on this difference.
Problem 4:
a. Propose a reasonable electron configuration in MO terms for BN.
b. Determine the bond order for BN.
c. Is BN diamagnetic or paramagnetic according to the electron
configuration?
Hybrid Orbitals
What is the geometry of the carbon in methane?
Looking at the atomic electron configuration, would you expect methane to

have four equivalent bonds?
Below is shown a method to create equivalent hybrid orbitals by mixing

appropriate s and p AOs.
Draw MO diagrams for ethane, ethene, ethyne, HCN, H2CO.
Conjugation and Resonance
1,3-butadiene is a common example of a conjugated system (see Table 1:

Acyclic Molecular Orbital Patterns) for a table of MO diagrams of conjugated
systems).
o Fill in the electrons in the MO shown below.
In the figure above, an energy plot is shown for the rotation about the C2-C3
bond in 1,3-butadiene.
o Use the MO diagram to explain the rotational barrier observed.
o Looking at the two different MO diagrams below:

o Indicate the highest occupied molecular orbital (HOMO)
o Indicate the lowest unoccupied molecular orbital (LUMO)
o Indicate the number of nodes for each orbital (frequency).
o Define conjugation and delocalization.
o Indicate which are conjugated.
!4
!3
!2
!1
!2C1C2
!2C5C6
!1C1C2
!1C5C6
1,3-butadiene has some properties not found in 1,4-pentadiene or butane.
Thinking about the MO diagrams on the previous page, explain these

observations:
The C2-C3 bond in 1,3 butadiene has a length of 148 pm which is 5 pm

shorter than the length of the analogous single bond in butane.
1,3 butadiene is 17 KJ/mol more stable than 1,4-pentadiene.
o Is cumulene (shown below) conjugated?
Allyl systems are the shortest systems to be conjugated the orbitals for a
three atom conjugated system look like this:
o Draw the lewis dot structures of the allyl radical, cation, anion and 1propene.
o Draw the MO diagram for the allyl radical, cation, anion and 1-propene.
o The reaction below yields two products (shown).

However, the
constitutional isomer, 2-chloro-2-butene, is not observed. Based on the
MO diagram for the allyl system, account for the two products that are
formed and explain why 2-chloro-2-butene is not formed.
Table 1: Acyclic Molecular Orbital Patterns
Additional Problems
Torsional Strain:
(you may want to read the following reference: Nature, 2001, Vol 411, p 539)
a. Make careful stick or line drawings of staggered and eclipsed ethane.
b. Make careful Newman projections of staggered and eclipsed ethane.
c. Which is better (lower energy)? Why?

d. You probably suggested the reason for lower energy conformer was
torsional strain. This is true. However, most organic textbooks claim that
torsional strain is an electron repulsion problem. This is not true.
Instead, the current understanding of torsional strain is rationalized using
MO arguments. Make four careful drawings of ethanes orbitals: 1) the
two eclipsed orbitals involving the C-H bonds, sp3 + 1s and sp3 -1s
( and *); 2) the two eclipsed orbitals involving the C-H bonds, sp3 + 1s
and sp3 +1s ( and ); 3) the two staggered orbitals involving the C-H
bonds, sp3 + 1s and sp3 -1s ( and *); and 4) the two staggered orbitals
involving the C-H bonds, sp3 + 1s and sp3 +1s ( and ).
e. Make corresponding MO diagrams of the interactions between the

and orbitals or the and * orbitals.
f. What factor destabilizes the eclipsed form of ethane as compared to the
staggered form? Consider the orbital interaction of the two filled co-planar
C-H bonds.
g. What factor stabilizes the staggered form of ethane over the eclipsed
form?
Problem 2:
a. Draw resonance forms for the following two molecules:
b. Draw Hckel Molecular Orbital Diagrams for these two molecules.
c. How do these MO diagrams differ?
d. What do the MO diagrams tell you about the geometry/free rotation of

these two molecules?
Problem 3:
Unsaturated compounds, such as naphthalene and tetrahydronaphthalene, can
act as Lewis bases to react with Lewis acidic organic molecules. For instance,
addition of an acid chloride such as ethanoyl chloride would result in the following
reactions:
These product distributions cannot be explained with Lewis dot structures;

instead, we must rely on molecular orbital theory to tell us why certain positions
on molecules are more nucleophilic than others. Using the pictures of the HOMO
of naphthalene and tetrahydronaphthalene (shown below), explain the observed
product ratios in these reactions.
Problem 4:
Use Spartan to generate the molecular orbitals and electron density for
the following molecules:
a.
b.
c.
d.
e.
f.
pyridine
toluene
aniline
1,3-cyclohexadiene
maleic anhydride
phthalic anhydride
Use the electron density maps to predict where these molecules would be
willing to accept electrons (susceptible to nuclephilic attack) or which sites
might be willing to donate electrons (act as nucleophiles).
Aromaticity
Chapter 16
On a separate sheet(s) of paper, draw Hckel MO Diagrams of:
a) cyclobutadiene
b) cyclohexatriene (benzene)
c) cyclooctatetraene
d) cyclodecapentaene
e) cyclododecahexaene
Example:
Cyclobutadiene (orbital pictures are viewed from the top):
cyclohexatriene has this special quality, aromaticity that makes it

exceptionally stable (as compared to its acyclic counterpart, hexatriene)
cyclobutadiene is particularly unstable, anti-aromatic (as compared to its
acyclic counterpart, butadiene)
What is the trend? What would you predict for:

cyclooctatetraene
cyclodecapentaene
cyclododecahexaene
cyclic 14 member ring compound (C14H14)
1.
2.
Use the previous MO diagrams to derive a set of rules of defining aromatic,

anti-aromatic and non-aromatic compounds. This works well with the
group working to develop a concept map. A concept map is a diagram that
shows connections between concepts.
Provide reasonable explanations for the following observations. Be sure to
discuss Hckel molecular orbitals where appropriate. As you work these
problems, you may need to modify your concept maps.
a. Explain the stabilities of the following molecules (least to most stable):
b. Neither of the following compounds shows more stability than their

acyclic counterparts. You may need to build these compounds.
c. The following compound reacts with HCl to give a weak acid. What is
the structure of that weak acid?
b. Conductivity measurements show that this dibromide ionizes to give a

dication.
c. Cyclopropenyl cation is quite stable, but cyclopropene is not.

Diphenylcyclopropenone has a dipole moment equal to 5.08 D,
whereas diphenylketone has a dipole moment equal to 2.97 D.
d. 1,3-Cyclopentadiene is extremely acidic for a hydrocarbon (pKa 15)

while 1,3,5-cycloheptatriene is extremely nonacidic (pKa too high to
measure).
e. This compound is very stable!
Heteroaromatic Compounds
Additional Problems:
Problem 1:
Using your concept map,
f. Predict whether each of the following systems is aromatic, antiaromatic or non-aromatic.
g. Justify your choices.
Problem 2:
Generate the molecular orbital diagrams for the following molecules:
o Cyclopentadienyl anion (C5H5-)
o Furan
o Cycloheptatrienyl cation (C7H7+)
Are either of these compounds aromatic? Justify your choice.
Problem 3:
Cyclooctatetraene readily reacts with potassium metal to form a dianion.
Draw a Hckel MO diagram for this molecule. Include energy levels, electron
filling, and labels. Label the HOMO and the LUMO.
Discuss the stability of this molecule based on its MO diagram.
Based on the MO diagram, would you predict this compound to be:

aromatic, anti-aromatic
or
nonaromatic
What is the hybridization of the carbons in this molecule?
What would you predict the bond angles to be?
Planar cyclooctatetraene would have bond angles of 135. This is not stable so
the molecule assumes a nonplanar, tub-shaped geometry. Each double bond is
twisted relative to the adjacent double bonds. Based on this data, what would
you predict for the bond lengths for this compound? Keep in mind:
C-C
1.5
C=C
1.3
Benzene
1.4
Based on the geometry and bond lengths of cyclooctatetrene, would you predict
this compound to be:
aromatic, anti-aromatic
or
nonaromatic
Draw the atomic orbital energy level diagram with electron filling for potassium metal.
Cyclooctatetraene reacts with potassium metal to form the dianion. Draw the Hckel
MO diagram of the dianion.
Based on the MO diagram of the dianion of cyclooctatetrene, explain why it is formed

so readily.
Acid-Base Chemistry
Chapter 4
We will use pKa tables frequently. Print a copy from one of these sources:
http://www.chem.wisc.edu/areas/reich/pkatable/
http://www2.lsdiv.harvard.edu/labs/evans/pdf/evans_pKa_table.pdf
http://www.cem.msu.edu/~reusch/VirtualText/acidity2.htm
http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf
Part I.
Definitions and Review
Define the following:

Bronsted-Lowry Acids
Bronsted-Lowry Bases
Lewis Acids
Lewis Bases
Write equations illustrating the following acid/base reactions. Show structures

in the equations. Stoichiometry is 1:1 in each reaction.
1 H3PO4
1 NaOH
1 H2SO4
1 K2CO3
1 AlCl3
1 PH3
1 NH3
1 HBr
The pKa of water is 16. What does this number say about the equilibrium
constant in the ionization reaction? (K = 10-pka) Is it greater or less than
1? What does this mean?
Part II. Factors Controlling Acidity

To determine the acidity of a compound, look at the stability of the conjugate
base. The more stable the conjugate base, the more likely the compound will be
willing to give away the H+.
Which of these compounds is more acidic? Draw the conjugate base for
each. What factor controls the trend in acidity among these three
molecules?
Same question, new molecules.
Same questions, new molecules.
Same questions, new molecules.
Same question, new molecules (except that we are now looking at Lewis
Acids!)
Same question, new molecules (except that we are now looking at Lewis
Acids!)
Additional Problems
1. In each pair of compounds, choose the stronger acid:
O
a.
OCH3
OH
b.
NH3
H2O
c.
SH
OH
d.
e.
O
OH
Br
OH
Br
2. In each pair of compounds, choose the stronger base:

NH2
a.
Cl
b.
Ph3C
d.
e.
c.
HO
f.
P(CH3)3
H
N
N(CH3)3
3. Lets make some predictions about organic acids!

Acid
Predicted Experimental
pKa
pKa
MeOH
MeOH2+
MeNH2
MeNH3+
As a group predict the pKa of the 4

organic acids.
What did you base your predictions
on?
How close were your predictions?
Part III. Factors Controlling Basicity
What is the relationship between acidity and basicity?
Knowing the relationship between basicity and acidity, order the following
ion by increasing basicity (weakest to strongest).
What is the strongest base possible in water?
Looking at the pKa table in Hornback (p 129-131), what are the strongest
bases?
ACID-BASE SUMMARY
Explain each of the structural features that effect pKa using an example:
1. Electronegativity
2. Atomic size
3. Delocalization (resonance)
4. Hybridization
5. Inductive
Part IV. Curved Arrow Notation

The organic chemists most valued tool is neither beaker nor Bunsen burner, but
a curved arrow. We will use curved arrows extensively in this course to keep
track of actual and imaginary electron movement. It is critical that arrow notation
be used correctly if you expect other chemists (or the person grading your exam)
to understand what you mean.
Rules for Arrows:
1. Arrows always begin at the source of electrons!!!
2. Arrows always end at the electrophilic (electron deficient or partially
positive site).
A. Using Arrows to Draw Resonance Structures: Imaginary Reactions
You may move a lone pair of electrons on an atom so as to form

new double bond to that atom (see Arrow 1).
You may move electrons from a double bond to make those two
electrons a lone pair on one of the atoms originally involved in the
double bond (see Arrow 2).
You may move two electrons in a double bond so as to form a new

double bond next door (see Arrow 3).
For resonance structures, you may not move any nuclei or break
any single bonds.
You may not change the total number of electrons.
Additional Problems
Use curved arrows to find the resonance structures of the following

compounds.
Explain why the minus charge is never on C3 of this structure! Show

arrows.
Explain why the 1,4 disubstituted isomer is more acidic than the 1,3
disubstituted isomer. Draw the conjugate bases and several resonance
structures of each.
OH
OH
CN
CN
Chirality Problem:
Consider the set of ketones shown below:
1. Circle the ketones that would be optically active.
2. Which of the ketones would lose their optical activity under KOH/H2O treatment.
O
H Ph
Ph
Ph
H Ph
tBu
Ph H
tBu
O
tBu
B. Using Arrows to Draw Mechanisms: Real Reactions
Curved arrows can also be used to depict electron movement in

reactions. This accounting of bonds formed and broken is called a
reaction mechanism.
Arrows always move from the source of electrons (nucleophile or
Lewis Base) to the electron deficient site (electrophile or Lewis
Acid).
Application Problem
Use curved arrows to show the mechanism of the following

reactions (below).
Also, label the Nucleophile (Lewis Base) and the Electrophile
(Lewis Acid) in the starting materials.
Additional Problems
1.
Butyl Lithium (BuLi) is often used to prepare other important bases used in
organic chemistry. Examine the reaction below and answer the
questions that follow.
a. Add arrows to the above reaction to indicate the movement of electrons.

b. Describe why BuLi is an effective base for this reaction in terms of pKa.
c. Can you think of any other factors which make BuLi an attractive base?
e. Tetrahydrofuran (THF) is the typical solvent for such reactions. Why?
2.
Complete the following substitution reactions including the arrows

indicating the movement of electrons, and label the nucleophile,
electrophile and leaving group.
a.
b.
3.
There is a very high market value on converting the following natural

compound to its conjugate base (the free base).
a. How would you carry out this reaction using acid-base extraction?
b. Be specific about solvents and strength of base and solubilities.
c. Draw the product.
4.
Tautomers are a form of isomers that are created by the deprotonation

and then reprotonation.
Draw the proton tautomers of each of the following structures.
1. Remove an acidic proton
2. Draw a resonance structure.
3. Reprotonate
Acid-Base Extraction
An organic chemistry student was given a mixture of four compounds for his lab practical. He decided
to use an acid base extraction. Label each compound as neutral, acidic or basic.
OCH3
CO2H
OH
NH2
CH3
CH3
CH3
CH3
This student proposed the following separation outlined in the flow chart below.
1, 2, 3, 4 dissolved in CH2Cl2
Extract with 3M aq HCl
CH2Cl2 layer
aqueous layer
Basify with 10% NaOH and
extract with CH2Cl2
Extract with 10% NaOH
aqueous layer
Acidify with 3M
HCl and extract
with CH2Cl2
Solution C
CH2Cl2 layer
Extract with
5% NaHCO3
CH2Cl2 layer
CH2Cl2 layer
Solution A
aqueous layer
Solution B
aqueous layer
Acidify with 3M
HCl and extract
with CH2Cl2
Solution D
Solution E
Indicate what is in each solution:

Solution A
Solution B
Solution C
Solution D
Solution E
There is a problem with the students proposed separation scheme. What is the problem and
how could it be fixed?
Further Examples of Acidic Systems

Examine the following pKa table for allylic and propargylic ( to an alkyne)
systems:
1. Draw the conjugate bases for each acid below.
2. Using their conjugate bases, compare the pKa values of each acid relative
to the others in the table.
Acid
pKa
44
Conjugate base
Rationale for acidity
35
22
11
22
3. Draw Huckel MO energy diagrams for the first two acids in the table
above.
4. Draw Huckel MO energy diagrams for the conjugate bases of the first
two acids.
5. What do these Huckel MO energy diagrams illustrate and how does that
help us understand their relative acidities?
To continue exploring the effect of delocalization on pKa consider the following

acids:
Acid
Ph-H
pKa
43
PhCH3
41
Ph2CH2
34
Ph3CH
32
Conjugate base
20
18
8. Why are the last two acids on the table so much more acidic than the
others?
9. Draw Huckel MO energy diagrams for the last acid in the table above.
10. Draw Huckel MO energy diagrams for the conjugate base of the last acid.
What happens when we throw heteroatoms into the mix?

Acid
pKa
44
Conjugate base
27
31
31
17
13. What structural feature do all of the conjugate bases have in common?
14. Explain the relatively large pKa difference between 2-methylpropene and
acetone.
15. Draw the Huckel MO diagram for both acetone and its conjugate base.
More is better!?!?
Acid
pKa
20
Conjugate base
11
11
10
18. Draw the Huckel MO energy diagrams for both 2,5-pentadione and its
conjugate base.
Carboxylic acids
Acid
pKa
27
Conjugate base
Now lets see what happens to the carboxylic acid pKa as we make systematic
changes to the methyl group.
Acid
pKa
5
Conjugate base
3
2.8
2.8
2.6
1
0.5
21. Draw the Huckel MO energy diagrams for both acetic acid and its
conjugate base.
Additional Problems
Problem 1:
Cis and trans isomers of 3-methoxycyclohexanol are found as components of a
group of antibiotics called macrolides.
Draw both of the chair conformations of cis-3-methoxycyclohexanol.
On your drawings in part a) indicate all 6 and 7 atom interactions.
Indicate the most stable conformation of cis-3-methoxycyclohexanol.
Draw the most stable chair conformation of trans-3-methoxycyclohexanol.
Both isomers are capable of reacting with a strong base. Draw the
reaction of cis-3-methoxycyclohexanol reacting with a strong base.
Is the conjugate base of cis-3-methoxycyclohexanol an electrophile or a
nucleophile?
The conjugate base of cis-3-methoxycyclohexanol can then react with
methyl iodide (CH3I). Is methyl iodide an electrophile or a nucleophile?
Explain (show the dipole moment).
Draw arrows to show the reaction of the conjugate base of cis-3methoxycyclohexanol with methyl iodide.
Both 3-methoxycyclohexanols are chiral. However, one diasteromer
reacts with base and then methyl iodide to give an optically inactive
product. Which one?
Problem 2:
a) Draw a Lewis Dot Structure for formaldehyde (CH2O) including formal charge
and non-bonding pairs.
b) What is the geometry of the molecule?
c) What is the hybridization of the carbon?
d) The question of the hybridization of the oxygen is more interesting. There

are two reasonable possibilities for the hybridization of oxygen. Draw
pictures of the orbitals on oxygen if is 1) sp2 or 2) sp.
e) A technique called photoelectron spectroscopy reveals that there are

non-equivalent lone pairs on oxygen. Based on your pictures in part d,
what is the hypridization of oxygen in formaldehyde?
Formaldehyde Reaction with Lewis Acids

When formaldehyde reacts with a Lewis acid (E+), there are two possible
geometries for the product, bent and linear (see below).
f) What is the hybridization of the oxygen in bent and linear?
Formaldehyde Reaction with Sodium

g) Provide the atomic orbital energy level diagram with electron filling for
sodium metal.
h) Sodium metal is quite reactive.

(electron acceptor)?
Is it a Base (electron donor) or an Acid
i) Why does Na metal want to react?
j) When sodium reacts with formaldehyde, it transfers an electron to the

formaldehyde to form the radical anion of formaldehyde (a species with an
odd number of electrons and a negative charge). Draw two Lewis Dot
Structures of the radical anion of formaldehyde (resonance structures).
k) By using MO theory, it is easier to understand what happened in this

molecule. Draw the MO diagram of the radical anion of formaldehyde.
l) Do the Lewis Dot Structures agree with MO picture of the radical anion of
formaldehyde? How do they differ?
m) Why does formaldehyde accept the electron from Na?
Amide Cumulative Problem

Cox and Lectka, Accounts of Chemical Research, 2000, 33, 849-858.
The observation of slow cis-to-trans isomerization (rotation) around the C-N bond in
amides has fascinated chemists for years.
O
R'
N
R1
R2
catalyst
R'
N
R2
R1
Draw the structure of N,N-dimethylethanamide.
Draw a resonance structure for this compound.
Using the resonance structure, explain why there is slow rotation around the C-N
bond.
Label the hybridization of each of the atoms of the amide functional group.
Draw the Huckel MO diagram for N,N-dimethylethanamide.

Include energy levels, electron filling, s and P labels.
Label the HOMO and the LUMO.
Draw pictures of molecular orbital at each energy level.
In the figure above, an energy plot is shown for the rotation about the C-N
bond of an amide. Depending upon the substituents, the barrier to rotation
can range from 18 to 22 kcal/mol.
Use the MO diagram to explain the rotational barrier observed.
Draw the Huckel MO diagram for pyrrole (shown below).

Include energy levels, electron filling, s and P labels.
Label the HOMO and the LUMO.
Draw pictures of molecular orbital at each energy level.
H
N
Circle which attributes apply to this compound:

Aromatic
Anti-Aromatic
Non-aromatic
The barrier to rotation for N,N-dimethylethanamide is 18 kcal/mole. This barrier is

reduced by 6 kcal/mol in N-acetyl pyrrole (shown below).
Fraser, Roustan and Mahajan, Canadian Journal of Chemistry, 1979, 57, 2239.
Explain why the barrier to rotation around the amide bond is much
lower in N-acetylpyrrole.
Some of the first evidence of cis-trans isomerisation came from nmr spectra of
amides.
Assign all of the peaks in the 1H and 13C spectra of N,Ndimethylethanamide.
When amides are dissolved in water (or other hydrogen-bonding solvents), the
barrier to rotation increases by up to 3 kcal/mol!
Drakenberg, et.al., Journal of Physical Chemistry, 1969, 73, 3177-3180.
Draw N,N-dimethylethanamide when hydrogen-bonding with water.
Propose a reason why hydrogen bonding INCREASES the barrier to

rotation (ie decreases the isomerization) in amides.
Bronsted Acids can effect the rate of isomerization in amides. For example, the
rate of isomerization of N,N-dimethylacetamide increases 130 fold when the pH
is changed from 7.0 to 1.8.
Gerig, Biopolymers, 1971, 10, 2435-2443.
List 2 Bronsted acids that could protonate this amide.
Draw the two possible protonated forms of N,N-dimethylethanamide.
Circle the protonated compound that responsible for the DECREASED

barrier to rotation (i.e. increased isomerization of this amide bond).
Importance in biological systems

Cis-trans isomerization in prolyl peptides is known to be a critical step in
the folding of proteins.
A favorable C=O - -C=O electrostatic interaction (shown below) can stabilize a
conformation by 0.7 kcal/mol.
Raines, et. al., Journal of the American Chemical Society, 2002, 124, 2497-2505.
Several proline derivatives were investigated to probe the relative

importance of various factors in determining the position of the
cistrans prolyl amide equilibrium to model protein folding.
Taylor, Hadre, Edwards and Park, Organic Letters, 2003, 5(23), 4413-4416.
Draw a Newman Projection looking down the N-CH bond of the ring
for the cis-prolyl analogue.
Draw a Newman Projection looking down the N-CH bond of the ring
for the trans-prolyl analogue.
Which of these two conformations can be stabilized by the nP*

stabilization shown above?
Binding of biological metal ions such as copper may also play a role in
these systems.
Circle all that pertain to Cu+2:
Bronsted Acid
Base
Bronsted Base
Lewis Acid
Lewis
Show why the copper ion is held in the position shown below.
Explain why the presence of copper may catalyze cis-trans

isomerism.
Another possible factor in determining the position of the cistrans

prolyl amide equilibrium was investigated to model protein folding.
Taylor, Hadre, Edwards and Park, Organic Letters, 2003, 5(23), 4413-4416.
Circle the conformer that is more favored in this experiment?

cis
or
trans
There is a significant increase in Ktrans/cis when the R group changes

from CH3 to CH3(C=O)NHCH2. What factor causes this significant
shift?
Show where this factor occurs on the drawing above.
Intramolecular catalysis of Amide Isomerization

Cox and Lectka, Journal of the American Chemical Society, 1998, 120, 10660-106668.
As discussed earlier, amide isomerization can be catalyzed by the

presence of Bronsted acids. However, in a biological system, harsh acids
(low ph) are not usually found. Rotamase enzymes, peptidylprolyl
isomerases (PPIases) are known to catalyze protein folding through cistrans proline isomerization.
It has been proposed that these PPIases can catalyze cis-trans

isomerisation through an intramolecular H-bond or through a H-bond
donor (shown above).
Propose a reason why hydrogen bonding to the amide N could catalyse

amide isomerization.
Cox and Lectka proposed that small peptides should show

intramolecular catalysis in an organic medium that mimics the
desolvated environment of the binding pocket of FKBP. First, they
developed a locked peptidomimetic.
Propose a reason why this analogue is referred to as locked.
Cox and Lectka compared a typical proline analogue (top spectrum) to

their locked peptidomimetic (bottom spectrum) by 1H NNMR.
Identify all NH resonances in the spectra above.
Why is there a difference in the number of NH resonances in the

two spectra?
What do the relative sizes of the NH resonances tell you about

the cis-trans equilibrium?
Cox and Lectka compared a typical proline analogue (top spectrum) to

their locked peptidomimetic (bottom spectrum) by IR.
It is important to consider why OH and NH peaks can show up at

different positions in the IR spectrum under different conditions. For
example, in an IR spectrum of a dilute solution of 2-octanol in CH2Cl2
(left), the OH peak shows up in a different position than in a pure
sample of 2-octanol (right).
Explain what factor causes a pure sample of octanol to appear

different from a dilute sample in the IR spectra. HINT: CH2Cl2 is
simply a solvent!
Explain why that difference would affect the OH-stretching

frequency.
By comparison, explain the reason for the difference between the

appearance of the NH peak in the IR spectra of a typical proline and
the locked peptidomimetic.
Pin1 Inhibition: Anti-cancer drug?

Pin1 is a PPIase that catalyzes the cis-trans isomerization of phosphorylated SerineProline amide bonds triggering a conformational change in a key cell cycle protein
(shown below). Pin1 inhibits the G2 to M transition. Pin1 is found in high
concentraion during mitosis and is overexpressed in a large number of cancer cells.
Wang, Xu, Mullins, Neiler and Etzkorn, Journal of American Chemical Society, 2004, 126, 15533-15542.
Two isosteres (compounds with similar shape) of serine-proline peptides were

synthesized by Etzkorn, et. al (shown below).
Why did Etzkorn choose to replace the amide bond with an alkene?
Isosteres are supposed to look similar to the original substrate.

o Match isostere 1 with its corresponding Serine-Proline
peptide.
o Match isostere 2 with its corresponding Serine-Proline
peptide.
The competitive inhibition constant (Kis) is 23-fold larger for Isostere

2 than isostere 1. What does this tell you about the direction of
isomerization catalyzed by Pin1?
cis trans
OR
trans cis

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CHEMISTRY 235 ORGANIC CHEMISTRY I

Review of Structural Topics 2010

For use by sections: 01A 05A

Edited By: Kate J. Graham

Acyclic Conformational Analysis

Cyclic Conformational Analysis

Molecular Orbital Theory

A. Assign formal charges as appropriate:

B. Add electron dots where appropriate:

Fill in the missing information on the table above.

Draw a line bond representation of the molecule shown below.

Could you draw a reasonable condensed formula for this compound?

In skeletal representations the hydrogens are not shown. Is it still possible to

normal alkanes (carbons in one long chain)

di means there are 2 methyl groups;

Alkenes, Alkynes & Aromatics -- Fill in the Blanks

skeletal structure name

add 1 isomer (w/ names)

Aromatics -- Some Examples

Additional Nomenclature Problems:

Acyclic Conformational Analysis

Build propane (C3H8) using the model kits.

Draw propane in:

At room temperature, the carbon-carbon bond of ethane is spinning

Clearly define the difference between conformational isomers (often called

Consider rotations around the C2C3 bond of 2methylbutane. Build

Draw the conformations using Newman projections.

Circle the low energy conformation(s). Explain your choices. Construct

Cyclic Conformational Analysis

List all of these factors:

Using molecular models, build cyclopropane, cyclobutane and cyclopentane.

What types of strain do you notice?

Are these planar molecules?

Using molecular models, build cyclohexane.

Using molecular models:

7-atom interactions usually increase the energy of conformer

Thus, the chair conformation of t-butylcyclohexane with the tert-butyl axial

Decalin and Adamantane Structures

Rimantadine and Adamantadine are antiviral compounds. Rimantadine has

Cyclic Conformational Analysis

7. For the following questions consider the molecule drawn below:

Draw the molecule in its two chair conformations.

Calculate the energy difference between the two chair conformations

Calculate the energy difference between all pairs of chair conformations

Calculate the energy difference between all pairs of chair conformations

10. Consider the reaction of 4-tert-butyl-1,3-cyclohexanediol with acetone and

11. Predicting Hydrogen bond formation:

12. Draw all isomeric dimethylcyclobutanes, clearly showing stereochemistry.

13. Acetylcholine is a neurotransmitter of the autonomic nervous system that

e. Four different trans-decalin isomers were synthesized

f. The above isomers were synthesized as potential drugs to act as

NMR Conformational Effects

Most Stable Conformer

Number of 13C-NMR Signals

Simple Stereochemistry Ideas

Circle the compounds that have enantiomers:

Label these compounds with R/S nomenclature:

Using molecular models:

d. Draw all of the stereoisomers.

f. Use R/S Designation to clearly label your drawings.

Label the following compounds as chiral or achiral:

Using molecular models:

c. Draw all of the stereoisomers with wedges and dashes.