Class Note for CH 231 at UA-Elem Organic Chem I (4)
Class Note for CH 231 at UA-Elem Organic Chem I (4)
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Date Created: 02/06/15
Chapter 9 Outline I 91 Enantiomers and the Tetrahedral Carbon 0 Consider your hands The left hand and right hand are mirror images of each other but they cannot be superimposed A left hand glove does not fit well on your right hand Molecules can also have a handedness due to the tetrahedral nature of carbon and other elements I Consider CHzXY It39s mirror image is identical to the moleculeithey can be superimposed I Now consider CHXYZ The mirror images cannot be superimposed under any circumstances There are two different forms of CHXYZ I These two molecules are known as enantiomers Enantiomers are non superimposable mirror images I Enantiomeric molecules are very common and play important roles in biology I Lactic acid 2hydroxypropanoic acid is an example It exists in two enantiomeric forms we ll call and The two forms are mirror images but cannot be superimposed I 92 The Reason for handedness in Molecules Chirality O Enantiomeric molecules are examples of chiral molecules Chiral molecules have non superimposable mirror images Objects can also be chiral I As discussed before your hand is chiral The left and right hand are mirror images but cannot be superimposed I In contrast a person is not chiral If we have two identical twins they are mirror images when facing each other but they can be superimposed Chiral molecules lack a mirror plane of symmetry I A mirror plane exists when you can cut an object or molecule in half and have the two halves be identical mirror images of each other I If you cut your hand in half not advised the two halves will always be different If you cut a person in half from head to toe also not a great idea the two halves left and right will be mirror images of each other As we said before the hand is chiral but a person is not I The same concept applies to amolecule I In the HzCXY molecule cutting the molecule in half along the YCZ axis will give two mirror image halves I In the chiral HCXYZ molecule there is no way to split the molecule to give two identical halves A common element that makes a molecule chiral is a tetrahedral carbon with 4 different groups attached These are called chirality centers I The difference between the groups can be anywhere in the group not just next to the chiral center I It is possible to have several chirality centers in a given molecule I 93 Optical Activity 0 O The first clue that molecules could have two different forms of what we now know are enantiomers was discovered by Biot in the l9Lh century I He observed that certain organic compounds rotated plane polarized light He called these compounds optically active I The rotation is measured using a polarimeter I Compounds that rotated light to the left were called levorotary or L or Those rotating light to the right were called dextrorotary of D or Natural sucrose table sugar is dextrorotary while I The amount of rotation is known as the specific rotation This is the ratio of the measured rotation divided by the path length of the cell and the concentration of the molecule It is now known that all chiral molecules are optically active while achiral molecules are not I 94 Pasteur s Discovery of Enantiomers O The fact that molecules could exist in mirror image forms was first hinted at by work done by Pasteur Upon crystallizing ammonium tartrate a byproduct of wine productionihe was French after all Pasteur discovered that two different crystal forms were obtained I The crystals were mirror images of each other I He separated crystals of each form The two crystal forms have equal but opposite optical rotations A 11 mixture of the two crystals was optically inactive however We now know that Pasteur had separated the two enantiomers of tartaric acid by crystallization Enantiomers have equal but opposite specific rotations I 95 Sequence Rules for Specifying Configuration of Chirality Centers 0 Since we can have two different arrangements for a chirality center we need a way to describe them I In the old literature L and D or and were used but these depended on a measured quantity the specific rotation and could not be predicted before hand I A systematic system has been developed using the R and S designations R comes from rectus which is right in Latin S comes from sinister which is left in Latin The IVS designation is somewhat analogous to EZ Assigning IVS configurations I Assign priorities to the 4 substituents on the chirality carbon The priorities are assigned in the same way as EZ designations Place the lowest priority substituent in the back by rotating the molecule if necessary Consider the 3 higher priority substituents If you draw a line from 1 to 2 to 3 you ll get a circle If the path goes clockwise right the chirality center has an R configuration If the path goes counterclockwise left the chirality center has an S configuration If the low priority substituent is in the front you don t necessarily have to move it to the back You can determine the direction of the substituents but reverse how you assign R and S In this case clockwise is S and counterclockwise is R If the low priority substituent is in the plane of the page you must reorient the molecule to put the low priority substituent in the back or front to determine R or S I 9 6 Diastereomers 0 So far we ve considered molecules with only one chirality center However molecules can have many chirality centers Glucose for example has 4 chirality centers 0 A molecule with n stereocenters will have 2n stereoisomers although some of these could be identical Glucose is one of 16 possible stereoisomers o A molecule with 2 stereoisomers could have 4 possible stereoisomeric structures For example 2amino3hydroxybutanoic acid has 4 possible structures one of which is the amino acid threonine The 4 possible structures are 2R3R 2S3S 2S3R and 2R3S 2R3R and 2S3S are enantiomers of each other as are 2S3R and 2R3S Enantiomers have opposite configuration at all chirality centers How are 2R3R and 2R3S and the other combinations related They are diastereomers Diastereomers are stereoisomers that are not mirror images of each other while enantiomers are mirror images Note that E and Zforms of alkenes are also diastereomers Thus the 4 stereoisomers of 2amino3hydroxybutanoic are made up of 2 pairs of enantiomers For any chiral molecule there will be a maximum of 2quot2 enantiomeric pairs where n is the number of chirality centers I 97 Meso Compounds 0 Tartaric acid is another example of a molecule with 2 chirality centers but in this case each chirality center has the same groups attached to it As in the case above there are 4 possible configuration combinations 2R3R 2S3S 2S3R and 2R3S 2R3R and 2S3S are enantiomers of each other but what about 2S3R and 2R3S I 2S3R and 2R3S are actually the same compound If you rotate one by 180 it will be identical to the other I If we look there is a mirror plane of symmetry that runs between the two middle carbons of the 283R form of tartaric acid Thus it is actually achiral I A molecule that has chirality centers but is not chiral due to a mirror plane of symmetry is known as a meso compound I A meso compound occurs when the two or more chirality centers have the same substituents but opposite con guration 0 Instead of 4 there are only 3 stereoisomeric forms of tartaric acid The enantiomeric pair and the meso compound The meso compound is a diastereomer of both enantiomers of tartaric acid I 98 Racemic Mixtures and Resolution of Enantiomers o A 5050 mixture of two enantiomers is known as a racemic mixture This mixture is not optically active because the optical activity of the two enantiomers cancels each other out o Separating enantiomers is very difficult because they have identical properties in most cases They have the same solubility melting point boiling point and polarity These are the properties most commonly used to separate molecules 0 Enantiomeric compounds only have different properties when interacting with other chiral compounds I Pasteur was able to separate enantiomers because each enantiomeric form of tartaric acid only wants to crystallize with itself Thus the RR form made one set of crystals and the 88 form as different set 0 Most often enantiomers are separating by reacting them with a single enantiomer of another compound I The resulting mixture of products are diastereomers For example if we react and R and S mixture of enantiomers with the R form of a different compound the products will be RR and SR I Diastereomers have completely different properties and can usually be separated easily 0 An commonly used strategy to separate enantiomeric carboxylic acids is to react them with a single enantiomer of a chiral amine I The acidic proton is transferred to the amine to give a mixture of diastereomeric salts ie RR and SR I The diastereomeric salts can then be separated This is usually done by crystallization due to one diastereomer being less soluble than the other I This process is quite important Naproxen the generic name for Aleve is a chiral carboxylic acid It is made as a racemic mixture and then resolved by reacting with a chiral amine to allow the enantiomers to be separated I 99 Review of Isomers o All isomers are related by having the same molecular formula o Constitutional isomers have different bond connections ie cyclopentane and l pentene o Stereoisomers are the same constitutional isomers but different 3D arrangement of atoms I Enantiomers mirror image isomers I Diastereomers nonmirror image isomers I 910 Stereochemistry of Reactions Addition of H20 to an Achiral Alkene 0 Now that we known about chirality we can go back and consider the stereochemical outcome of reactions we know 0 When an achiral alkene is hydrated to give the normal Markovnikov product two enantiomeric alcohols are formed I The two enantiomers are formed as a 5050 mixture racemic mixture 0 When two achiral compounds react the product if chiral will always be formed as a racemic mixture I In the reaction the chirality is formed when water adds to the carbocation I The carbocation is sp2 hybridized so it is at Water can add from the top or bottom I The two transition states are enantiomers so they have identical energy I Therefore there is no preference for which enantiomer is produced and a statistical mixture is obtained I 911 Addition of H20 to a Chiral Alkene o What happens if we use a chiral starting material such as R4methyllhexene o The products will now be diastereomers The original R stereocenter remains unchanged but the new alcohol stereocenter can be R or S so we ll get RR and RS products I The carbocation intermediate is still planar and the water can add from either face I The transition states are now diastereomers however Diastereomers have different stabilities so one transition state will be more stable than the other Therefore one product will be preferred The difference could be large or small but there will be a difference 0 Reaction of a chiral molecule with an achiral reagent will generally produce an uneven mixture of stereoisomer products I Alkene stereochemistry o In additions to alkenes the alkene stereochemistry E or Z also affects the product stereochemistry o If we add bromine to Z 2butene the 88 and RR enantiomeric products will be formed 0 If we start with the E 2butene stereoisomer a meso RS stereoisomer is formed I 912 Chirality at Other Atoms Carbon is not the only atom that can be chiral Any tetrahedral atom can be chiral if 4 different things are attached One of the substituents can be a lone pair An amine with H CH3 and ethyl attached would have two enantiomeric forms Although these forms are chiral they rapidly interconvert because amines undergo rapid inversion that interconverts the R and S forms If the amine is quaternary where there is no lone pair then the R and S forms can be isolated Phosphines do not invert rapidly They can be isolated as pure enantiomers The lone pair is one of the substituents and has the lowest priority when assigning IVS con gurations Sulfonium salts R3S can also be isolated as pure enantiomers I 914 Chirality in Nature 0 Chirality is critically important in biochemistry of all living things Sugars proteins DNA RNA are all chiral molecules that are found almost exclusively as single enantiomers in nature The chirality is critically important for their function Many biochemical processes involve the interaction of molecules ie an enzyme and a drug molecule This interaction can be thought of as a lock and key mechanism where the drug molecule must fit exactly into a pocket on the enzyme This can only occur if the right 3D arrangement of atoms is present chirality Most modern drugs are chiral molecules although in some cases they are sold as racemic mixtures Often only one enantiomer is active biologically In most cases the other enantiomer is inactive Thalidomide is an example where the wrong enantiomer had tragic consequences I Thalidomide is a sedative that is not habit forming or fatal when overdosed I It was used in Europe to treat morning sickness associated with pregnancy I It was soon discovered that use of thalidomide resulted in deformities in new borns where limbs were missing or malformed I It was eventually discovered that one enantiomer of thalidomide S is a safe effective sedative I The other enantiomer R is teratogenic rather than being a sedative I Although thalidomide can be prepared as a pure S enantiomer in the body it is converted back to a mixture of R and S forms
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