Stereochemistry Arrangements of Atoms in 3-d Space.

Stereochemistry

Arrangements of Atoms in 3-d Space

Stereochemistry

• Stereochemistry:The study of the three-dimensional structures of

molecules, particularly stereoisomers

• Structural isomers:Have the same molecular formula, same types of

bonds, but different bonding sequences, “connectivity”

• Stereoisomers:Have the same molecular formula, same bonding

sequences, but different spatial arrangements & relative orientations

Stereochemistry

CHIRALITY: If an object’s mirror image (i.e. a molecule’s 3-d reflected shape) … “cannot be brought to coincide with itself” (i.e. It is non-superimposable), it is chiral.

• To maintain orbital overlap in the pi bond, C=C double bonds cannot freely rotate.

• Although the two molecules below have the same connectivity, they are NOT identical.

Stereochemical cis-transIsomers

Naming Alkene Stereoisomers : the E-Z Notational System

vs. “cis-trans”

Triglycerides & Unsaturated Fatty AcidsSaturated & Unsaturated: cis- vs. trans-

Stereochemical Notation

cis and trans are useful when substituents are identical or analogous

Oleic acid, an unsaturated fatty acid, has a cis double bond; (Hs are identical.)

cis and trans references are ambiguous when analogies are not obvious

C C

CH3(CH2)6CH2 CH2(CH2)6CO2H

H H

Oleic acid

Example

A systematic body of rules for ranking substituents must be used, which is related to, but different from the cis and trans references.

C C

H F

Cl Br

When there are four different substituents, cis and trans does not work.

C C

E : higher ranked substituents on opposite sides

Z :higher ranked substituents on same side higher

lower

The E-Z Notational System

Consider each sp2 carbon of the double bond

separately.

Rank the pair of substituents relative to

each other.

C C


Z : higher ranked substituents on same side

higher

lower

The E-Z Notational System

Consider each sp2 carbon of the double bond

separately.

Rank the pair of substituents relative to

each other.

C C


Z : higher ranked substituents on same side

(E) Entgegen

higher

higherlower

lower

C C

(Z) Zusammen

lower

higher

lower

higher

The E-Z Notational SystemCompare the pairs

C CC C

The substituents are ranked in order of

decreasing atomic number on each carbon.

(E) Entgegen (Z) Zusammen

higher

higherlower

lower

lower

higher

lower

higher

The E-Z Notational SystemRanking

The Cahn-Ingold-Prelog (CIP) System

The system used was devised byR. S. CahnSir Christopher IngoldVladimir Prelog

Their rules for ranking groups were devised for another kind of stereochemistry, chirality, but have been adapted to alkene stereochemistry.

Higher atomic number outranks lower atomic number

Br > F Cl > H

higher

lower

Br

F

Cl

H

higher

lower

C C

Example

Higher atomic number outranks lower atomic number

Br > F Cl > H

higher

lower

Br

F

Cl

H

higher

lower

C C

Example

(Z )-1-Bromo-2-chloro-1-fluoroethene

When two atoms are identical, compare the

atoms attached to them on the basis of their atomic numbers. Precedence is established

at the first point of difference. —CH2CH3 outranks —CH3

—C(C,H,H)

CIP Rules

—C(H,H,H)

higher lower

Work outward from the point of attachment,

comparing all the atoms attached to a particular atom before proceeding furtheralong the chain.

—CH(CH3)2 outranks —CH2CH2CH3

—C(C,C,H) —C(C,H,H)

CIP Rules

higher lower

CIP Rules

higher

lower—CH(CH3)2 outranks —CH2CH2CH3

—C(C,C,H) —C(C,H,H)

higher lower

CIP Rules

higher

lower—CH2CH(CH3)2 outranks —CH2CH2CH(CH3)2

higher

lower

lowerhigher

(Z)- configuration

Evaluate substituents one by one. The ranking is not cumulative:Do not add atomic numbers within groups.

—CH2OH outranks —C(CH3)3

—C(O,H,H) —C(C,C,C)

CIP Rules

higher lower

An atom that has double or triple bonds to another atom is considered to be replicated as a substituent on that atom. See oxygen:

—CH=O outranks —CH2OH

—C(O,O,H) —C(O,H,H)

CIP Rules

lowerhigher

The molecules above are (E) configurations.

True (A) False (B)

Question

The molecules above are (Z) configurations.

True (A) False (B)

Question

Disubstituted Cyclohexanescis-trans Isomerism

In cyclic structures (rings) cis and trans notation is used to distinguish between stereoisomers just as in C=C double bonds, Cis— identical groups are positioned on the SAME side

of a ring -drawn as being planar. Trans— identical groups are positioned on OPPOSITE

sides of a ring -drawn as being planar.

Cyclic Stereoisomers

Cycloalkane Stereochemistrycis -trans Isomers

Cyclohexane StereochemistryDrawings: cis isomers & the need for perspective

Are the methyl groups axial or equatorial?What is the actual conformational shape of the cyclohexane ring?

H

CH3H

CH3 cis-1,4-dimethylcyclohexane

H

H3C

CH3

Hring-flip

Chair Conformers cis-1,4-dimethylcyclohexane

Cyclohexane StereochemistryTrans isomers

H

CH3H3C

Htrans-1,4-dimethylcyclohexane

CH3

H

CH3

Hring-flip

Chair Conformers trans-1,4-dimethylcyclohexane

Stereochemistrycis-1,2-disubstituted-cyclohexane

axial

equatorial

Stereochemistrytrans-1-tert-Butyl-3-Methylcyclohexane

Cyclohexane StereochemistryCis -Trans Isomers

Position cis trans

1,2 e,a or a,e e,e or a,a

1,3

1,4

a = axial; e = equatorial

e,a or a,e e,e or a,a

e,e or a,a a,e or e,a

Indicate the relationship of the pair of molecules shown.

A. same molecules B. mirror images C. different molecules D. constitutional isomers E. cis and trans isomers

Question

Consider the molecule below. What is the maximum number of methyl groups that can be in the equatorial position at the same time?

A. 0B. 1C. 2D. 3E. 4

Question

Conformations of Fused Rings

Stability of Fused Rings

Trans-fused cyclohexane rings are more stable than cis-fused

Conformations of Fused Rings

Worksheet 7 (Part 2): Ambrox

• There are many important structures that result when one ring is fused to another.

.

• Camphor, which you smelled the first day of class, and camphene are fragrant natural products isolated from evergreens.

Many Bicyclic Systems

Representing compounds with two fused rings.

To name a bicyclic compound, include the prefix “bicyclo” in front of the total carbon alkane name. For example, the compounds below could both be

named, bicycloheptane.

Bicyclic CompoundsNomenclature

The two molecules are not identical, therefore they cannot have the same name.

Count the number of carbons connecting the bridgeheads.


1. Start numbering at a bridgehead carbon and number the longest carbon chain connecters first.

2. Then give the substituents the lowest numbers possible.

• Practice with SKILLBUILDER 4.5.



Decalin = Bicyclo[4.4.0]decane

Structure of Steroids

• Fundamental framework of steroids is a tetracyclic carbon framework.

A B

C D

Decalin-like

Steroids

Structure of Cholesterol

HO

CH3

H

H

H

CH3

CH3 CH3

CH3

Cholesterol is an important steroid endogenously produced in all plants and

animals.

Cholesterol

• Cholesterol is essential to life. It is the biosynthetic precursor of a large number of important molecules: Sex hormones, Vitamin D, Bile acids, Corticosteroids

HO

CH3

H

H

H

CH3

CH3 CH3

CH3

• There are many biologically important steroids, two related to primary sex traits are:

Hormonal Steroids

Vitamin D3

HO

H

CH3

CH3 CH3

CH3

• Insufficient sunlight can lead to a deficiency of vitamin D3, interfering with Ca2+ transport and bone development. Rickets may result; as well as very bad moods.

Cholesterol: Biochemical Reactions

HO

CH3

H

H

H

CH3

CH3 CH3

CH3

+ H2

H2

H2

H

H

Cholic Acid

Cholic Acid

HO

CH3

H

H

H

CH3

CH3

HOH

HO

O

OH

• Oxidation in the liver degrades cholesterol to produce Cholic acid which is the most abundant of the bile acids.

• Is the A/B ring system cis or trans?

• What functions are present?

|H

Cortisone

•Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in mediating allergic reactions by suppressing the immune system.

O

CH3

H

H

H

CH3OH

O

O

OH

• What principal functions are present?

Progesterone

• Supresses ovulation during pregnancy.

O

H

H

H

H3C

H3CO• What

principal functions are present?

Conformations of Multi-fused Rings

• Trans-fused cyclohexane ring is more stable than cis-fused cyclohexane ring. DIAMOND:

Molecular Chirality: Enantiomers

Chirality

Chirality

“I call any geometrical figure, or group of points, chiral, andsay that it has chirality, if its image in a plane mirror … cannot be brought to coincide with itself. Two equal and similar righthands are homochirally similar.”

Sir William Thomson (Lord Kelvin)The Baltimore Lectures, 1904

A molecule is chiral if its two mirror image forms are not superimposable upon one another.

A molecule is achiral if its two mirror image forms are superimposable.

Chirality

Tetrahedral Atoms

Achiral:

Chirality in Three Dimensions

BrCl

H

F

Bromochlorofluoromethane is chiral

It cannot be superimposed point for point on its mirror image.

BrCl

H

F

Bromochlorofluoromethane is chiral

H

ClBr

FTo show nonimsuperposability, rotate this model 180° around a vertical axis.

Chirality & nonsuperimposable mirror images

Enantiomers

Isomers

stereoisomersconstitutionalisomers

Isomers

stereoisomersconstitutionalisomers

diastereomersenantiomers

Stereochemistry

• Two types of stereoisomers:enantiomers

• pairs of compounds that are nonsuperimposable mirror images of each other

diastereomers• stereoisomers that are not mirror images of each

other– Eg. geometric isomers (cis-trans, E-Z isomers)

Stereochemistry

• Many molecules and objects are achiral:– identical to its mirror image– not chiral

Stereochemistry

• Cis-1,2-dichlorocyclopentane is achiral even though it contains 2 chiral carbon atoms:– It contains an internal mirror plane of symmetry

• Any molecule that has an internal mirror plane of symmetry is achiral even if it contains chiral carbon atoms.

Both cis- and trans-1,2-dimethylcyclohexane are chiral.

True (A) False (B)

Question

Question How many of the following compounds contain an internal mirror plane of symmetry?

A) 1 B) 2 C) 3 D) 4

QuestionWhich of the following molecules is chiral?

A B

C D

a carbon atom with fourdifferent groups attached to it

also called:chiral center; chiral carbonasymmetric centerasymmetric carbonstereocenterstereogenic center

The chiral carbon atom

w

x y

z

C

• There are 8 chiral carbon atoms in chlolesterol, which can have a total of 28 stereoisomers.

• SEE: SKILLBUILDER 5.7.

Stereoisomers

• Molecules with an even number of chiral centers that have a plane of symmetry are achiral and called MESO compounds.

• Another way to test if a compound is a MESO compound is to see if it is identical to its mirror image. If identical, it is NOT chiral. It is achiral.

• Meso compounds have less than the predicted number of stereoisomers based on the 2n formula.

• SEE: SKILLBUILDER 5.8.

Symmetry and Chirality

Enantiomers

Stereochemistry• Enantiomers are different stereochemical

compounds:They have the same boiling point, melting

point, density. Their physical/chemical properties are identical.

They differ in rotation of plane polarized light, doing so in equal but opposite directions. (polarimetry)

They behave differently with other chiral molecules • Enzymes• Receptors: eg. taste and scent

Importance of Stereochemistry

• Enzymes are capable of distinguishing between stereoisomers:

Red Wine / StereochemistryAbsolute Configuration

In 1847, Louis Pasteur performed the first resolution of enantiomers from a racemic mixture of tartaric acid salts.

The different enantiomers formed different shaped crystals, which he microscopically separated with tweezers.

O O

CH3 CH3

H3C H3CCH2 CH2

Smells

(–)-Carvonespearmint oil

(+)-Carvonecaraway seed oil

Ibuprofen is chiral, but normally sold asa racemic mixture, which is 50% of each

enantiomer

Chiral drugs

CH2CH(CH3)2

HH3C

CO

C

HO

The enantiomer above is responsible for its analgesic and anti-inflammatory properties.

Stereochemistry

• The pharmacological activity of many drugs depends on their stereochemistry:

(S)-(+)-ketamine (R)-(-)-ketamine

anesthetic hallucinogen

A Sedative or a Potent Teratogen?

Stereochemistry

A molecule with a single stereogenic center is chiral. A carbon atom with four different substituents is a stereogenic center and chiral.2-Butanol is an example.

Chirality and Chiral Carbon Atoms

CH3

OH

H

C CH2CH3

Examples of molecules with 1 chiral carbon

CH3

C

CH2CH3

CH2CH2CH2CH3CH3CH2CH2

a chiral alkane


Linalool, a naturally occurring chiral alcohol

OH


1,2-Epoxypropane: a chiral carboncan be part of a ring

O

H2C CHCH3

attached to the chiral carbon are:

—H

—CH3

—OCH2

—CH2O


Limonene: a chiral carbon can be part of a ring

CH3

H C

CH3

CH2

attached to thechiral carbon are:

—H

—CH2CH2

—CH2CH=

—C=


Chiral as a result of isotopic substitution

CH3CD

T

H

Optical Rotation

Relative Configuration and

Absolute Configuration

Optical Activity• Chiral compounds are optically active:

– capable of rotating the plane of polarized light

• Enantiomers rotate the plane of polarized light by exactly the same amount but in opposite directions.

(S)-(+)-d-2-butanol (R)-(-)-l-2butanol

+13.5o rotation -13.5o rotation

Optical Activity

• Compounds that rotate the plane of polarized light to the right (clockwise) are called dextrorotary.

• d• (+) IUPAC convention

• Compounds that rotate the plane of polarized light to the left (counterclockwise) are called levorotary.

• l• (-) IUPAC convention

Optical Activity

Relative configuration compares the arrangement of atoms in space of one compound with those of another.

Absolute configuration is the precise arrangement of atoms in space.

Configuration

Relative configuration compares the arrangement of atoms in space of one compound with those of another.

Until the 1950s, all configurations were relative

Absolute configuration is the precise arrangement of atoms in space.

Now, the absolute configuration of almost any compound can be determined

Configuration

No bonds are made or broken at the chiral carbon

in this experiment. Therefore, when (+) d-3-buten-2-ol

and (+) d -2-butanol have the same sign of rotation, the

arrangement of atoms in space at the chiral carbon

atom

is analogous. The two have the same relative

configuration.

CH3CHCH2CH3

OH

Pd

[a] + 33.2° [a] + 13.5°

Relative configuration: Optical Rotation

CH3CHCH

OH

CH2

HHO

H OH H2, Pd

HHOH2, Pd

H OH

Two possibilities

But in the absence of additional information, we can't tell which structure corresponds to(+) d -3-buten-2-ol, and which one to (–) l-3-buten-2-ol.

HHO

H OH H2, Pd

HHOH2, Pd

H OH

Two possibilities

Nor can we tell which structure corresponds to(+)-2-butanol, and which one to (–)-2-butanol.

HHO

H OH H2, Pd

HHOH2, Pd

H OH

Absolute configurations

[a] +33.2°[a] +13.5°

[a] –13.5° [a] –33.2°

Not all compounds that have the same relative

configuration have the same sign of rotation. No bonds

are made or broken at the chiral carbon in the

reaction shown, so the relative positions of the atoms

are the same. Yet the sign of rotation can change.

CH3CH2CHCH2Br

CH3

HBr

[a] -5.8° [a] + 4.0°

Relative configuration

CH3CH2CHCH2OH

CH3

Absolute Configuration

Rank the 4 groups (atoms) bonded to the chirality center

The R,S system of nomenclature

There is NO DIRECT CORRELATION between (R) and (S) configurations, and the relative configuration / the optical rotation: (+)/(-)

Treat the single carbon atom as a double bond, but

taking into account the tetrahedral geometry

1. Rank the substituents at the stereogenic carbon center according to their atomic

number.

2. Orient the molecule so that lowest-ranked substituent points away from you.

3. If the order of decreasing precedence traces a clockwise path, the absolute configuration

is R. If the path is anticlockwise, the configuration is S.

The Cahn-Ingold-Prelog (CIP) Rules

Orient the lowest priority (4) away from you: [Highest is (1)]

Clockwise = R configuration

Counterclockwise = S configuration

Switch any 2 substituents and the new configuration is opposite R S; S R

• The groups attached to the chiral center are the same (-CH2-) below.

• Analyze the atomic numbers of the next atoms in the bonding sequence.

Designating Configurations

14

2 3

TieAdjacent atoms:

Next atoms::

• Double bonds count as two single bonds.

• Is the following molecule is R or S?

Designating Configurations

Cl

A = R- B = S-

Question

Naming from the Perspective Formula

1

23

4

1. Rank the groups bonded to the asymmetric carbon

2. If the group (or atom) with the lowest priority is bonded by hatched wedge,

3. If necessary, rotate the molecule so that the lowest priority group (or atom) is bonded by a hatched wedge

4.

C OH

H3C

HCH3CH2

Enantiomers of 2-butanol

CHO

CH3

HCH2CH3

(S)-2-Butanol (R)-2-Butanol

What is the stereochemical designation of the following molecule?

Question

A. (R)

B. (S)

C. non-chiral (achiral)


A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers

Question

HH3C

H

H

chiral carbon in a ring

R

—CH2C=C > —CH2CH2 > —CH3 > —H

Question

The S-isomer is an effective sedative. The R- is a

teratogen in humans, but not rats.

In the structures above, which is the R-isomer, A or B?

H

A B

What is the stereochemical designation of the following molecule?

Question

A. (R)

B. (S)


Fischer Structures“The Horizontal Bonds Point Towards You!”

Emil Fischer, 1815-1919(the second) Nobel Prize in Chemistry, 1902

Rules for Fischer projections

Arrange the molecule so that horizontal bonds at chiral carbon point toward you and vertical bonds point away from you.

Br Cl

F

H

Rules for Fischer projections

Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.

Br Cl

F

H

What is the stereochemical designation of the indicated chirality center?

A. (R)

B. (S)


Question

Disubstituted CyclohexanesStereoisomerism



Question

Stereochemistry Arrangements of Atoms in 3-d Space.

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