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-trans Isomers

Naming Alkene Stereoisomers : the E-Z Notational System vs. “cis-trans”

Triglycerides & Unsaturated Fatty Acids Saturated & 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 CH 3 (CH 2 ) 6 CH 2 CH 2 (CH 2 ) 6 CO 2 H 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 FClBr 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 sp 2 carbon of the double bond separately. Rank the pair of substituents relative to each other.

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 E :higher ranked substituents on opposite sides Z :higher ranked substituents on same side (E) Entgegen higher higherlower lower C C (Z) Zusammen lowerhigherlowerhigher The E-Z Notational System Compare the pairs

C C C 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 System Ranking

The Cahn-Ingold-Prelog (CIP) System The system used was devised by R. S. Cahn Sir Christopher Ingold Vladimir 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 > FCl > H higher lower Br F Cl Hhigherlower C C Example

Higher atomic number outranks lower atomic number Br > FCl > H higher lower Br F Cl Hhigherlower 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. —CH 2 CH 3 outranks —CH 3 —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 further along the chain. —CH(CH 3 ) 2 outranks —CH 2 CH 2 CH 3 —C(C,C,H) —C(C,H,H) CIP Rules higherlower

higher lower —CH(CH 3 ) 2 outranks —CH 2 CH 2 CH 3 —C(C,C,H) —C(C,H,H) higherlower

CIP Rules higher lower —CH 2 CH(CH 3 ) 2 outranks —CH 2 CH 2 CH(CH 3 ) 2 higher lower lowerhigher (Z)- configuration

Evaluate substituents one by one. The ranking is not cumulative: Do not add atomic numbers within groups. —CH 2 OH outranks —C(CH 3 ) 3 —C(O,H,H) —C(C,C,C) CIP Rules higherlower

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 —CH 2 OH —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 Cyclohexanes cis-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 Stereochemistry cis -trans Isomers

Cyclohexane Stereochemistry Drawings: cis isomers & the need for perspective Are the methyl groups axial or equatorial? What is the actual conformational shape of the cyclohexane ring?

Chair Conformers cis-1,4-dimethylcyclohexane

Cyclohexane Stereochemistry Trans isomers

Chair Conformers trans-1,4-dimethylcyclohexane

Stereochemistry cis-1,2-disubstituted-cyclohexane axial equatorial

Stereochemistry trans-1-tert-Butyl-3-Methylcyclohexane

Cyclohexane Stereochemistry Cis -Trans Isomers a = axial; e = equatorial 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. 0 B. 1 C. 2 D. 3 E. 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 Compounds Nomenclature

The two molecules are not identical, therefore they cannot have the same name. Count the number of carbons connecting the bridgeheads. Bicyclic Compounds Nomenclature

1.Start numbering at a bridgehead carbon and number the longest carbon chain connecters first. 1.Then give the substituents the lowest numbers possible. Practice with SKILLBUILDER 4.5. Bicyclic Compounds Nomenclature

Decalin = Bicyclo[4.4.0]decane

Structure of Steroids Fundamental framework of steroids is a tetracyclic carbon framework. A B CD Decalin-like

Steroids

Structure of Cholesterol HO CH 3 H H H 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 CH 3 H H H

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

Vitamin D 3 HO H CH 3 Insufficient sunlight can lead to a deficiency of vitamin D 3, interfering with Ca 2+ transport and bone development. Rickets may result; as well as very bad moods.

Cholesterol: Biochemical Reactions HO CH 3 H H H + H 2 

H2H2 H2H2 H H Cholic Acid

HOHOHOHO CH 3 H H H H OHOHOHOH HOHOHOHOOOH 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? |HH|HHH

Cortisone Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in mediating allergic reactions by suppressing the immune system. O CH 3 H H H OHOHOHOH O O OHOHOHOH What principal functions are present?

Progesterone Supresses ovulation during pregnancy. O H H H H3CH3CH3CH3C H3CH3CH3CH3CO 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

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

Br Cl H F Bromochlorofluoromethane is chiral It cannot be superimposed point for point on its mirror image.

Br Cl H F Bromochlorofluoromethane is chiral H Cl Br F To show nonimsuperposability, rotate this model 180° around a vertical axis.

Chirality & nonsuperimposable mirror images Enantiomers

Isomers stereoisomers constitutionalisomers

Isomers stereoisomers constitutionalisomers diastereomers enantiomers

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

How many of the following compounds contain an internal mirror plane of symmetry? A) 1B) 2C) 3 D) 4

Question Which of the following molecules is chiral? A B CD

a carbon atom with four different groups attached to it also called: chiral center; chiral carbon asymmetric center asymmetric carbon stereocenter stereogenic center The chiral carbon atom wx y z C

There are 8 chiral carbon atoms in chlolesterol, which can have a total of 2 8 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 2 n 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 / Stereochemistry Absolute 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 CH 3 H3CH3CH3CH3C H3CH3CH3CH3C CH 2 Smells (–)-Carvone spearmint oil (+)-Carvone caraway seed oil

Ibuprofen is chiral, but normally sold as a racemic mixture, which is 50% of each enantiomer Chiral drugs CH 2 CH(CH 3 ) 2 H H3CH3CH3CH3C C O 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 anesthetichallucinogen

A Sedative or a Potent Teratogen? Stereochemistry

A molecule with a single stereogenic center is chiral. 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 CH 3 OH H C CH 2 CH 3

Examples of molecules with 1 chiral carbon CH 3 C CH 2 CH 3 CH 2 CH 2 CH 2 CH 3 CH 3 CH 2 CH 2 a chiral alkane

Examples of molecules with 1 chiral carbon Linalool, a naturally occurring chiral alcohol OH

Examples of molecules with 1 chiral carbon 1,2-Epoxypropane: a chiral carbon can be part of a ring O H2CH2CH2CH2C CHCH 3 attached to the chiral carbon are: —H —CH 3 —OCH 2 —CH 2 O

Examples of molecules with 1 chiral carbon Limonene: a chiral carbon can be part of a ring CH 3 H C CH 2 attached to the chiral carbon are: —H —CH 2 CH 2 —CH 2 CH= —C=

Examples of molecules with 1 chiral carbon Chiral as a result of isotopic substitution CH 3 C D TH

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 o rotation o 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. CH 3 CHCH 2 CH 3 OH Pd [  ] ° [  ] ° Relative configuration: Optical Rotation CH 3 CHCH OH CH 2

HHO HOH H 2, Pd HHO HOH 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 HOH H 2, Pd HHO HOH Two possibilities Nor can we tell which structure corresponds to (+)-2-butanol, and which one to (–)-2-butanol.

HHO HOH H 2, Pd HHO HOH Absolute configurations [  ] +33.2° [  ] +13.5° [  ] –13.5° [  ] –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. CH 3 CH 2 CHCH 2 Br CH 3 HBr [  ] -5.8° [  ] + 4.0° Relative configuration CH 3 CH 2 CHCH 2 OH CH 3

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 (-CH 2 -) below. Analyze the atomic numbers of the next atoms in the bonding sequence. Designating Configurations Tie Adjacent atoms: Next atoms::

Double bonds count as two single bonds. Is the following molecule is R or S? Designating Configurations A = R- B = S- Question

Naming from the Perspective Formula 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 H3CH3CH3CH3CH CH 3 CH 2 Enantiomers of 2-butanol C HO CH 3 H CH 2 CH 3 (S)-2-Butanol (R)-2-Butanol

What is the stereochemical designation of the following molecule? Question A. (R) B. (S) C. non-chiral (achiral)

Indicate the relationship of the pair of molecules shown. A. same molecules B. enantiomers C. diastereomers D. different molecules E. constitutional isomers Question

Indicate the relationship of the pair of molecules shown. A. same molecules B. enantiomers C. diastereomers D. different molecules E. constitutional isomers Question

Indicate the relationship of the pair of molecules shown. A. same molecules B. enantiomers C. diastereomers D. different molecules E. constitutional isomers Question

Indicate the relationship of the pair of molecules shown. A. same molecules B. enantiomers C. diastereomers D. different molecules E. constitutional isomers Question

Indicate the relationship of the pair of molecules shown. A. same molecules B. enantiomers C. diastereomers D. different molecules E. constitutional isomers Question

H H3CH3CH3CH3CH H chiral carbon in a ring R —CH 2 C=C > —CH 2 CH 2 > —CH 3 > —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) C. non-chiral (achiral)

Fischer Structures “The Horizontal Bonds Point Towards You!” Emil Fischer, (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

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) C. non-chiral (achiral) Question

Disubstituted Cyclohexanes Stereoisomerism

A. same molecules B. enantiomers C. diastereomers D. different molecules E. constitutional isomers Indicate the relationship of the pair of molecules shown. Question

Indicate the relationship of the pair of molecules shown. Question A. same molecules B. enantiomers C. diastereomers D. different molecules E. constitutional isomers