CH3H

CH3H

H

H3CCl

F

Br

Br

H

H

Br

H

H

Br

CH3

H3C CH3

H3C

H3C H

Chirality

H

CH3ClF

1. For each of the following species, indicate if it is chiral or achiral. For those molecules that are chiral, circle all stereocenters, and draw the structure of the enantiomer.

chiral

chiral

Br

Br

H

H

achiral

chiral

achiral ("meso")

chiral

H3C

CH3H3C

CH3

Week 2 47

H

H

HCl

O

NHO

H3C

OHH

2. Draw an unambiguous structural representation of the following molecules:

R and S Nomenclature

1. Circle all the stereocenters in the following molecules. For each stereocenter, assign an R or S designation according to the standard rules.

(S)-4,5-dimethyl-(Z)-2-hexene

H

R

R

R

SS

S

R

S

S

(R)-3,5,6-trimethyl-(E)-3-heptene

H

3. Provide the best possible systematic name for the following compound:

(S)-(E)-5-isopropyl-2,3,7-trimethyl-4-octene

Week 2 48

CH3 CH3

H3CCH3

Br

Br

H3CBr

Br

CH3

Enantiomers and Diastereomers

1. For each of the following pairs of stereoisomers, indicate if they are enantiomers, diastereomers, or identical compounds.

diastereomers

diastereomers

identical

enantiomers

identical

Week 2 49

Identifying Isomers

H

H

1. For each of the following pairs of isomers, indicate whether they are Identical, Enantiomers, Diastereomers, or None of the above by circling the appropriate term for each.

Identical Enantiomers Diastereomers None

Identical Enantiomers Diastereomers None

Identical Enantiomers Diastereomers None

Identical Enantiomers Diastereomers None

HN

H

Me

HN

Me

H

HN

Me

H

HN

Me

H

Identical Enantiomers Diastereomers None

Identical Enantiomers Diastereomers None

Week 2 50

CH3 CH3

1. Which of the following are true? Give counterexamples for those that are false.

(a) In some cases, constitutional isomers are chiral.

(b) In every case, a pair of enantiomers have a mirror-image relationship.

(c) Mirror-image molecules are in all cases enantiomers.

(d) If a compound has an enantiomer, it must be chiral.

(e) Every chiral compound has a diastereomer.

(f) If a compound has a diastereomer it must be chiral.

(g) Any molecule containing an asymmetric carbon must be chiral.

(h) Any molecule with a stereocenter must have a stereoisomer.

(i) Some diastereomers have a mirror image relationship.

(j) Some chiral compounds are optically inactive.

(k) All chiral molecules have no plane of symmetry.

(l) If a compound has a stereocenter, it has an enantiomer.

(m) A meso compound will necessarily have at least two diastereomers.

H

H3CCl

F

Stereochemical Concepts

Br

H

H

Br

identical

has no diastereomer

and

are diastereomers

achiral ("meso")

Br

H

H

Br

F; no diastereomers have a mirror image relationship.

F; all PURE chiral compounds are optically active

achiral ("meso")

T

T

F

T

F

F

F

T

T

F

T

Week 2 51

2,3-butanediol

H3C

HO OH

CH3

Working with Stereoisomers

1. Consider the species 2,3-butanediol, whose structural formula is:

a) There are three distinct, pure, configurational stereoisomers of 2,3-butanediol, all of which have the same structural formula above. Using any unambiguous notation, draw the three different stereoisomers in the boxes below. (The boxes have been arbitrarily labeled A, B, and C.)

b) By circling the appropriate terms below, indicate whether each of the three species you drew above is chiral or achiral.

A: chiral achiral B: chiral achiral C: chiral achiral

c) Two of the above species have the same melting point (19°C). The other species has a different melting point (34°C). Circle the letter of the species which has a melting point of 34°C:

A B C

What characteristic of the other two stereoisomers causes them to share the same melting point (19°C)?

H3C

HO OH

CH3 H3C

HO OH

CH3 H3C

HO OH

CH3

B and C are enantiomers, and enantiomers always have identical physical properties;for instance, they will have the same melting point.

A B C

Week 2 52

Principles of Reaction Stereochemistry

1. Each of the following statements is false. Discuss why the statement is false. Then make the statement true by changing only the underlined word or phrase.

Two molecules which are diastereomers should be expected to have the same melting point.

Two molecules which are enantiomers would exhibit different rates of reactivity with an achiral reagent.

An achiral starting material can react with an achiral reagent to give a single chiral product.

Two molecules which are enantiomers would exhibit identical reaction rates when reacting with a chiral reagent (such as a biological enzyme).

When an achiral starting material is treated with an achiral reagent to yield a pair of diastereomers, both products must always be produced in equal amounts.

enantiomers

diastereomers

single achiral product

or

racemic mixture of products

different

enantiomers

Week 2 53

Mechanism and Stereochemistry

1. a) In the box below, draw the product of the following reaction. Your product must match the chemical formula provided. Indicate stereochemistry clearly, if appropriate.

OH Br2

O

Br

Chemical Formula: C6H11BrO

b) Provide a complete curved arrow mechanism for the transformation indicated above. Explain the stereochemical outcome, if any.

OH

Br Br

OH

Br

O

Br

Hsolv

O

Br

c) Explain the regioselectivity of this reaction; in other words, why is the particular isomer you drew in (a) the one that's formed.

(+/-)

The intermediate bromonium ion is unsymmetrical: there is much more partial positive charge on the tertiary carbon. This is similar to the relative stabilization conferred by tertiary vs. secondary carbocations. The nucleophile (ROH) then reacts by breaking the weaker of the two C–Br bonds.

Bromonium ion can form above or below the plane.

OH attacks from the opposite plane, either from above or below, leading to a racemic mixture.

Week 2 54

Br

Br Br

Br

OH

Br HO

Br

OH

OH

H H

H

H

Stereochemistry of Alkene Additions

2. H2O2, OH–

1. Fill in each box with the organic product(s) of the indicated transformation. Be sure to indicate the correct stereochemistry. (If the product is formed as a racemic mixture, please indicate this!)

Br

Br

Br2, H2O

Br

1. BH3

Br

H2 / Pt

+

(racemic mixture)

+

OH

(racemic mixture)

Br

+

OH

(racemic mixture)

Br

(achiral)

H

** Note: I have shown theserings as planar hexagons toemphasize the syn- or anti-relationships. I have also drawnthe proper chair forms below.

H

+

OH

+

OH

+

Br2

Week 2 55

Cyclohexanes

2. Draw each of the following dimethyl cyclohexanes (on the planar ring), then identify whether the substituents would be either: "Axial and Equatorial" or "Both Equatorial"

1,2-cis 1,3-cis 1,4-cis

1,2-trans 1,3-trans 1,4-trans

3. Draw each of the following in the most stable chair conformation:

1. Look at a chair. Notice the axial and equatorial substituents. Pay close attention to the parallel lines!

Ax. and Eq. Ax. and Eq.

Ax. and Eq.

Both Eq.

Both Eq. Both Eq.

Notice the confomation of thatethyl group: avoid syn-pentane!

A chair has 3 sets of parallel lines, plus vertical lines for axial groups.Once that is drawn in, every subsequent line must be parallel to a line that has already ben drawn! Try drawing t-butyl groups in the equatorial positions.

Week 2 56

1. Consider the following molecule:

a) This molecule is expected to have two relatively stable "chair" conformations. Draw clear representations of the two different conformations in the boxes below. (The boxes have been arbitrarily labeled A and B.)In addition, please be sure to draw the isopropyl substituent in its best conformation in each case.

b) Which of the two chair conformations is more stable? (circle one of the statements below)

Chair Conformations

CH3

H3C CH3

1) A is more stable than B.

2) Both conformations are equally stable.

3) B is more stable than A.

Cl

Cl

CH3

H

H3C

H3C

H

H

H

H3C

H3C

Cl

CH3

A B

Week 2 57

CH3

CH3

CH3

CH3

H

H

Bicyclic Compounds and Bredt's Rule

H

H

1. Draw each of the following bicyclic compounds in a good "perspective" drawing.

H

H

2. The molecule trans-cyclooctene is known to exist. (It is chiral, by the way). Why is the analagous molecule trans-cyclohexene unstable?

=

trans-cyclooctene(planar representation)

CH3

CH3

trans-cyclooctene(perspective representation)

H3C CH3

trans-cyclohexene????

3. Draw each of the following bicyclic alkenes in a good "perspective" representation. Only one of these three compounds actually exists. Which one, and why?

trans-decalin: two chairs

norbornane skeleton:

Far too strained to have a trans-alkene in a six-membered ring.

BAD! BAD!Ok!

In these two,the alkenescan't be planar.Highly strained.(Try to model!)

Or, notice thetrans-alkenesin small rings.

** Bredt's Rule:

Can't have sp2 carbon at

a bridgehead. (No alkenes,

no carbocations!)

Week 2 58

1. Consider compounds A and B shown on the right:

Chairs and Stereochemistry

A B

a) Is A chiral? (circle) Yes No

b) Would a solution of B in a polarimetry cell at room temperature rotate plane-polarized light? (circle)

Yes No

c) What is the stereochemical relationship of A and B? Diastereomers

Draw the products of the following transformations in their lowest energy conformations. Be sure to include all unique stereoisomers that will be produced in each reaction.

d) A

Br2

CH2Cl2

e) B

H2O

H3O+

f) A

H2

Pd/C

g) B

H2

Pd/C

h) Label each of the products above as chiral or achiral as appropriate. (You do not need to worry about labeling anything meso.)

i) For all products of the same formula in d-g above, identify pairwise stereochemical relationships.

CH3

H3C

CH2Br

Br

CH3

H3C

Br

CH2Br

achiral achiral

diastereomers

CH3

CH3 OH

CH3 only one compound and one lowest energy conformer.

chiral

CH3

H3C CH3

CH3

H3C

CH3achiral achiral

diastereomers

CH3

H3C

CH3achiral

same compound

diastereomers

Week 2 59

Br OH

Br

Br OH

OH

An Introduction to SN2, E2, SN1, and E1 Mechanisms

H

1. Provide complete curved-arrow mechanisms for the following transformations.

conc. H2SO4

OH

H

+ Br–

tBuO:–+ Br–

+ tBuOH

+

OH

H

+

:Solvent

+

H

+

:Solvent

OH–

KOtBu

H2O

HO:–

:OH2

H+

Week 2 60

I

CH3H

Br

O

O

SHHO

O

S

Br Br

OHHO

Mechanisms and Stereochemistry

SCH3

CH3H

H

1. Predict the product.

3. Explain the difference in reactivity.

Br

–:O

O

SH

2. Provide a curved-arrow mechanism, and explain the observed stereochemistry.

no reaction!

SH

O

O

but

S:–

O

O

conc.

4. Explain the difference in reactivity.

conc.no reaction!

–:O

O

S

but

Br

H

HO—H

axial Brperfect forantiperiplanarE2 elimination

With SN2, "retention" is ALWAYS "double inversion"

Br

equatorial Brcan't get antiperiplanarwith any H, so can'tdo E2 elimination.

E1 elim. OK, withsecondary carbocationwhich can be planar(as required)

+

This tertiary carbocationcannot be planar,and the product violatesBredt's Rule +

CH3S–

:OH–

KOtBu KOtBu

H2SO4 H2SO4

:OH–

:OH–

:B

Week 2 61

+ OH–

Choosing a Reaction Pathway 1

Consider the following conditions:

for SN2 reactions:

for E2 reactions:

O–

need good steric interaction (Me, 1° is good, 2° OK, 3° bad)

Br

Br

Br

need strong attacking base (at least as strong as OH–)

for SN1/E1 reactions: need stable carbocation (3° is good, 2° is OK, 1° is bad)

All things being equal, choose the reaction higher up on the above list.For each of the following, predict the major product, and indicate the type of mechanism.

1.

3.

O–

2.

Br

Br

4.

5.

6.

7.

Br8.

Br9.

Br

OH11.

CH3I + OH–

CH3I +

+ OH–

+ CN–

10.

+

+ CN–

+ OH–

+ H2O

+ CH3OH

+ H2SO4

OCH3

rule 1

rule 2

rule 3

sterics poor, but no possibility for E2 or SN1/E1

sterics are only OK, but base is not so strong, so SN2

tertiary carbocation stable, mainly SN1

OH

CN

CN

OH

OCH3

excellent SN2

excellent SN2

sterics make SN2 bad, so goes E2

excellent SN2

sterics terrible; E2 all the way

With secondary carbon, get some SN2, but the main

product is likely to be the alkene from E2 elimination.

tertiary carbocation stable, mainly SN1

tertiary carbocation stable, conc. sulfuric favors E1

CH3OH

Week 2 62

Choosing a Reaction Pathway 2

1. Which product (or) products would you expect to obtain from each of the following reactions? In each case

identify the mechanism by which each product is formed (SN1, SN2, E1, or E2) and predict the relative amount

of each (i.e. would the product be the only product, major product, minor product, etc?).

a)

Br + CH3ODMSO

25° COCH3

+

SN2: major E2

b)

Br + (CH3)3CO25° C

E2

(CH3)3COH

c)+(CH3)3CCl

25° C

E2

(CH3)3COHCH3O

d)+

50° C

EtOHEtOH

Br OEt

SN1

+

E1

+

E1: minor

e)+

25° C

(CH3)3COH(CH3)3CO

Br

E2: major(saytzeff)

+

E2: minor

+

E2: minor

Week 2 63

Substitution and Elimination: Synthesis

CN

H3C H

OH

1. Each of the following products can be synthesized in one step from an alkyl halide. Show the starting material that could serve as an immediate precursor to the indicated target, and fill in the reactions conditions required to obtain the desired product. Be sure to consider stereochemistry where relevant!

1.

I

1.

H3C H

Br

1.Br

KOH or anystrong base (E2)

(could also be E1)

H2O (SN1)

(SN2, so inversion!)

NaCN

Week 2 64

C

Cl

Cl

H

H

Cl

Cl

Carbenes and Cyclopropanes

1. Chloroform can react with strong bases to yield dichlorocarbene, :CCl2. Provide a curved-arrow

mechanism for this transformation:

2. Dichlorocarbene can react with alkenes to yield cyclopropanes. For instance:

+

This reaction involves two significant donor-acceptor orbital interactions between the two reactants. Identify the donor and acceptor orbitals in each interaction.

CH

Cl

Cl

Cl C

Cl

Cl

• Include both a verbal description and a picture of each orbital.

Donor: Acceptor:

Donor: Acceptor:

Interacts With

C

Cl

Cl

Cl—

Carbene lone pair

(sp2-hybridized)ClCl

Interacts With

p* orbital of alkene

ClCl

Carbene vacant p-orbitalp orbital of alkene

This is the (perhaps surprising) geometry requiredfor all the orbital overlap between the carbene and thealkene orbitals!

KOtBu

tBuO–

Week 2 65

CH3

Br

Br

Putting It Together: Products

OHHO

1. Fill in each box with the major organic product of the indicated transformation. Be sure to indicate stereochemistry when relevant.

CH3

1. Mg

2. H2O

O

often prefer more subst. alkene

Mechanism? Intramolecular SN1

Form carbenoid, then use it to make cyclopropane

Form Grignard, then protonate it-get an alkane!

1. Zn

2.

NaOH

H+

CH2I2

Week 2 66

More Putting It Together: Products

I I

CH3

Cl

1. Fill in each box with the single major organic product of the indicated transformation. (Any chiral starting materials are provided as single, pure enantiomers.) Be sure to give the stereochemistry of the product if it is relevant!

a)

b)

c)

d)

CH3

H3C CH3NaN3

N3 I

H3C CH3

(those areiodine substituents)

OHH3C

BrH3C

CH3Br

Racemic mixture (from SN1 reaction)

HBr

KOtBu

1. NaOEt

2. IZnCH2I H3C

H

H

Cl

Week 2 67