Stereochemistry at Tetrahedral Centers

Different Types of Isomerism

Constitutional Isomers Different order of connections gives different carbon backbone and/or different functional groups

Stereochemistry For pharmaceuticals, slight differences in 3D spatial arrangement can make the difference between targeted treatment and undesired side-effects. Isomers that have the same connectivity between atoms but different 3D, spatial arrangement of their atoms are called STEREOisomers

Stereochemistry of Organic Compounds Stereoisomers: Same molecular formula Same sequence of bonded atoms (constitution), Different 3-D orientations of their atoms in space. Enantiomers: Stereoisomers that are mirror images of each other. Diastereomers: Stereoisomers that differ at chiral centers, but no every chiral center. enantiomers Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011; http://web.fccj.org/~ethall/stereo/stereo.htm

Stereochemistry of Organic Compounds Chiral Carbon: Carbon in organic compound that has four different groups attached to it. Chirality: “Handedness”. Refers to compounds that cannot be superimposed on mirror image. -Defined relative to central, chiral atom (carbon) Chiral carbon H H CHO indicates aldehyde OHC C OH HO C CHO CH2OH CH2OH OHC OH HO CHO C C CH2OH CH2OH enantiomers Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011

Cis-trans Isomers C-C bonds that are constrained in a cyclic structure can not freely rotate To maintain orbital overlap in the pi bond, C=C double bonds can not freely rotate.

Klein, Organic Chemistry 2e Cis-trans Isomers With rings and with C=C double bonds, cis-trans notation is used to distinguish between stereoisomers Cis – identical groups are positioned on the SAME side of a ring Trans – identical groups are positioned on OPPOSITE sides of a ring Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Isomers Identify the following pairs as either constitutional isomers, stereoisomers, or identical.

Stereoisomers Beyond cis-trans isomers, there are many other important stereoisomers To identify such stereoisomers, we must be able to identify chiral molecules A chiral object is NOT identical to its mirror image You are a chiral object. Look in a mirror and raise your right hand. Your mirror image raises his or her left hand. You can test whether two objects are identical by seeing if they are superimposable. Chirality is important in molecules. Because two chiral molecules are mirror images, they will have many identical properties, but because they are not identical, their pharmacology may be very different

Stereochemistry Some objects are not the same as their mirror images (technically, they have no plane of symmetry) A right-hand glove is different froma left-hand glove. The property is commonly called “handedness” Organic molecules (including many drugs) have handedness that results from substitution patterns on sp3 hybridized carbon

Stereoisomers Chirality most often results when a carbon atom is bonded to 4 unique groups of atoms.

Stereoisomers Same connections, different spatial arrangement of atoms Enantiomers (nonsuperimposable mirror images) Diastereomers (all other stereoisomers) Includes cis, trans, configurational

Chirality Centers A point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality center (stereocenter). There are two nonsuperimposable ways that 4 different different groups (or atoms) can be attached to one carbon atom A chiral molecule usually has at least one chirality center

Chirality Centers

Stereoisomers Identify all of the chirality centers (if any) in the following molecules

Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer Build molecular models to see this

The Reason for Handedness: Chirality Molecules that are not superimposable with their mirror images are chiral (have handedness) A plane of symmetry divides an entire molecule into two pieces that are exact mirror images A molecule with a plane of symmetry is the same as its mirror image and is said to be achiral.

Plane of Symmetry The plane has the same thing on both sides for the flask There is no mirror plane for a hand

Chirality Centers in Chiral Molecules Groups are considered “different” if there is any structural variation (if the groups could not be superimposed if detached, they are different) In cyclic molecules, we compare by following in each direction in a ring

Designating Configurations Enantiomers are NOT identical, so they must not have identical names Their names must be different, so we use the Cahn-Ingold-Prelog system to designate each molecule as either R or S.

Designating Configurations The Cahn, Ingold and Prelog system Using atomic numbers, prioritize the 4 groups attached to the chirality center Arrange the molecule in space so the lowest priority group faces away from you Count the group priorities 1…2…3 to determine whether the order progresses in a clockwise or counterclockwise direction Clockwise = R and Counterclockwise = S

Designating Configurations The Cahn, Ingold and Prelog system Using atomic numbers, prioritize the 4 groups attached to the chirality center. The higher the atomic number, the higher the priority Prioritize the groups on this molecule

Designating Configurations The Cahn, Ingold and Prelog system Arrange the molecule in space so the lowest priority group faces away from you This is the step where it is most helpful to have a handheld model

Designating Configurations If a decision cannot be reached by ranking the first atoms in the substituents, look at the second, third, or fourth atoms until difference is found

Designating Configurations The Cahn, Ingold and Prelog system Counting the other group priorities, 1…2…3, determine whether the order progresses in a clockwise or counterclockwise direction Clockwise = R and Counterclockwise = S

Designating Configurations Designate each chirality center below as either R or S.

Designating Configurations When the groups attached to a chirality center are similar, it can be tricky to prioritize them Analyze the atomic numbers one layer of atoms at a time First layer Second layer 1 4 Tie Is this molecule R or S? 2 3

Designating Configurations Analyze the atomic numbers one layer of atoms at a time First layer Second layer 4 1 The priority is based on the first point of difference, NOT the sum of the atomic numbers Is this molecule R or S? Tie 3 2

Designating Configurations When prioritizing for the Cahn, Ingold and Prelog system, double bonds count as two single bonds Determine R or S for the following molecule

Designating Configurations Handheld molecular models can be very helpful when arranging the molecule in space so the lowest priority group faces away from you Here are some other tricks that can use Switching two groups on a chirality center will produce its opposite configuration

Designating Configurations Switching two groups on a chirality center will produce its opposite configuration You can use this trick to adjust a molecule so that the lowest priority group faces away from you With the 4th priority group facing away, you can designate the configuration as R Work backwards to show how the original structure’s configuration is also R

Designating Configurations

Designating Configurations The R or S configuration is used in the IUPAC name for a molecule to distinguish it from its stereoisomer(s) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Optical Activity Light restricted to pass through a plane is plane-polarized Plane-polarized light that passes through solutions of achiral compounds retains its original plane of polarization Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active Phenomenon discovered by Jean-Baptiste Biot in the early 19th century

Optical Activity Light passes through a plane polarizer Plane polarized light is rotated in solutions of optically active compounds Measured with polarimeter Rotation, in degrees, is [] Clockwise rotation is called dextrorotatory Anti-clockwise is levorotatory

Measurement of Optical Rotation A polarimeter measures the rotation of plane-polarized light that has passed through a solution The source passes through a polarizer and then is detected at a second polarizer The angle between the entrance and exit planes is the optical rotation.

Optical Activity Enantiomers will rotate the plane of the light to equal degrees but in opposite directions The degree to which light is rotated depends on the sample concentration and the pathlength of the light Standard optical rotation measurements are taken with 1 gram of compound dissolved in 1 mL of solution, and with a pathlength of 1 dm for the light Temperature and the wavelength of light can also affect rotation and must be reported with measurements that are taken

Optical Activity Consider the enantiomers of 2-bromobutane R and S refer to the configuration of the chirality center (+) and (-) signs refer to the direction that the plane of light is rotated The specific rotation of the enantiomer is equal in magnitude but opposite in sign

Optical Activity There is no relationship between the R/S configuration and the direction of light rotation (+/-) The magnitude and direction of optical rotation can not be predicted from a chiral molecule’s structure or configuration. It can ONLY be determined experimentally As long as its bonds are not rearranged, its configuration CANNOT change Racemic Mixtures (samples with equal amounts of two enantiomers) exhibit no optical activity

Klein, Organic Chemistry 2e Optical Activity For unequal amounts of enantiomers, the enantiomeric excess (% ee) can be determined from the optical rotation For a mixture of 70% (R) and 30% (S), what is the % ee? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Optical Activity If the mixture has an optical rotation of +4.6, use the formula to calculate the % ee and the ratio of R/S

Diastereomers Molecules with more than one chirality center usually have mirror image stereoisomers that are enantiomers In addition they can have stereoisomeric forms that are not mirror images, called diastereomers

Stereoisomeric Relationships The number of possible stereoisomers for a compound depends on the number of chirality centers (n) in the compound What is the maximum number of possible cholesterol isomers?

Symmetry and Chirality Any compound with only ONE chirality center will be chiral and have an optical rotation However, compounds with an even number (2,4,6, etc.) of chirality centers may or may not be chiral If a molecule has a plane of symmetry, it will be achiral Half of the molecule reflects the other half Its optical activity will be canceled out within the molecule, similar to how a pair or mirror image enantiomers cancel out each others optical rotation

Symmetry and Chirality Molecules with an even number of chirality centers that have a plane of symmetry are 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 Draw the mirror image of the cis isomer and show that it can be superimposed on its mirror image By definition, when a compound is identical to its mirror image, it is NOT chiral. It is achiral Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Symmetry and Chirality In another example, the plane of symmetry identifies it as a meso compound meso compounds also have less than the predicted number of stereoisomers based on the 2(n) formula Draw all four expected isomers and show how two of them are identical. A handheld model might be helpful

Chirality at Nitrogen, Phosphorus, and Sulfur N, P, S commonly found in organic compounds, and can have chirality centers Trivalent nitrogen is tetrahedral Does not form a chirality center since it rapidly flips Individual enantiomers cannot be isolated

Chirality at Nitrogen, Phosphorus, and Sulfur May also apply to phosphorus but it flips more slowly

Fischer Projections Fischer projections can also be used to represent molecules with chirality centers Horizontal lines represent attachments coming out of the page Vertical lines represent attachments going back into the page

Fischer Projections Fischer projections can be used to quickly draw molecules with multiple chirality centers

Fischer Projections Fischer projections can also be used to quickly assess stereoisomeric relationships

Interconverting Enantiomers Molecules can rotate around single bonds. Recall the gauche rotational conformation of butane Is the gauche conformation of butane chiral? Draw its mirror image. Is it superimposable on its mirror image? Why is butane’s optical rotation equal to zero? To be chiral, a compound cannot be a rotational conformer of its mirror image

Interconverting Enantiomers Compare the (cis)-1,2-dimethylcyclohexane chair with the Haworth projection The Haworth image can be used to quickly identify the compound as an achiral meso compound. However, a plane of symmetry can NOT be found in the chair conformation

Interconverting Enantiomers The freely interconverting mirror images cancel out their optical rotation, so it is achiral This analysis is much easier to do with a handheld models than in your mind If the Haworth image has a mirror plane, then the chair will be able to interconvert with its enantiomer, and it will be achiral.

Prochirality A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule

Prochiral Distinctions: Faces Planar faces that can become tetrahedral are different from the top or bottom A center at the planar face at a carbon atom is designated re if the three groups in priority sequence are clockwise, and si if they are counterclockwise

Prochiral Distinctions: Faces An sp3 carbon with two groups that are the same is a prochirality center The two identical groups are distinguished by considering either and seeing if it wereincreased in priority in comparison with the other If the center becomes R the group is pro-R and pro-S if the center becomes S

Prochiral Distinctions in Nature Biological reactions often involve making distinctions between prochiral faces or groups Chiral entities (such as enzymes) can always make such a distinction Example: addition of water to fumarate

Chirality in Nature and Chiral Environments Stereoisomers are readily distinguished by chiral receptors in nature Properties of drugs depend on stereochemistry Think of biological recognition as equivalent to 3-point interaction