Stereochemistry: Enantiomers, Chirality, and Optical Activity - Prof. Yu-Lin Jiang, Study notes of Organic Chemistry

Download Stereochemistry: Enantiomers, Chirality, and Optical Activity - Prof. Yu-Lin Jiang and more Study notes Organic Chemistry in PDF only on Docsity! 9. Stereochemistry Based on McMurry’s Organic Chemistry, 6th edition 2 Stereochemistry  Some objects are not the same as their mirror images (they have no plane of symmetry)  A right-hand glove is different than a left-hand glove (See Figure 9.1)  The property is commonly called “handedness”  Many organic molecules (including most biochemical compounds) have handedness that results from substitution patterns on sp3 hybridized carbon CH.X CH,XY CHXYZ @ 2004 Thomson/Brooks Cole ie +i 4 6 9.1 Enantiomers and the Tetrahedral Carbon  Enantiomers are molecules that are not the same as their mirror image  They are the “same” if the positions of the atoms can coincide on a one-to-one basis (we test if they are superimposable, which is imaginary)  This is illustrated by enantiomers of lactic acid © 2004 Thomson/Brooks Cole HO™ H So Mismatch OH 7 ieee Mismatch CH, CN ~ CO,H Ht be (b) 10 9.2 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 (See Figure 9.4 for examples) | | | © 2004 Thomson/Brooks Cole. CH,CH,CO,H Propanoic acid (achiral) NOT symmetry plane CH, H~4—on | CO.H OH | CH,CHCO.H Lactic acid (chiral) 11 12 Chirality  If an object has a plane of symmetry it is necessarily the same as its mirror image  The lack of a plane of symmetry is called “handedness”, chirality  Hands, gloves are prime examples of chiral object  They have a “left” and a “right” version 7 a i a a H 5-Bromodecane (chiral) Substituents on carbon 5 —H —Br — CH,CH,CH,CH; (butyl) ___ sds —~CH,CH,CH,CH,CHs (pentyl) 15 16 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 1 2 Oo 6 2 3 5 3 4 6 4 5 Methylcyclohexane 2-Methylcyclohexanone (achiral) (chiral) © Thomson - Brooks Cole 17  Solution: (a) + CH,CH,CH; Cr H Coniine (poison hemlock) Menthol (flavoring agent) Dextromethorphan (cough suppressant) ©2004 Thomson - Brooks/Cole 20 21 9.3 Optical Activity  Light restricted to pass through a plane is plane-polarized  Plane-polarized light that passes through solutions of achiral compounds remains in that plane  Solutions of chiral compounds rotate plane- polarized light and the molecules are said to be optically active  Phenomenon discovered by Biot in the early 19th century 22 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 25 A Simple Polarimeter  Measures extent of rotation of plane polarized light  Operator lines up polarizing analyzer and measures angle between incoming and outgoing light 26 Specific Rotation  To have a basis for comparison, define specific rotation, []D for an optically active compound  []D = observed rotation/(pathlength x concentration) = /(l x C) = degrees/(dm x g/mL)  Specific rotation is that observed for 1 g/mL in solution in cell with a 10 cm path using light from sodium metal vapor (589 nanometers) 27 Specific Rotation and Molecules  Characteristic property of a compound that is optically active – the compound must be chiral  The specific rotation of the enantiomer is equal in magnitude but opposite in sign (or direction). 30 Relative 3-Dimensionl Structure  The original method was a correlation system, classifying related molecules into “families” based on carbohydrates  Correlate to D- and L- glyceraldehyde  D-erythrose is the mirror image of L-erythrose  This does not apply in general 31 32 9.5 Sequence Rules for Specification of Configuration  A general method applies to the configuration at each chirality center (instead of to the the whole molecule)  The configuration is specified by the relative positions of all the groups with respect to each other at the chirality center  The groups are ranked in an established priority sequence (the same as the one used to determine E or Z) and compared.  The relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule 35 Examples of Applying Sequence Rules  If lowest priority is back, clockwise is R and counterclockwise is S  R = Rectus  S = Sinister Practice Problem 9.2 (R)-2-Chlorobutane 1 H 2 H Gla ~CH,CH; I l H,C’/ ~CH,CH, CH, Cl 3 = a 36  Problem 9.8: Assign RorS XC CL Hod ~CO,H H,C~ VCO, (c) NH, MN (7CHs \ ‘ \ CN 37  | Problem 50: Same structure or Enantiomers? (a) r qn H,C-7°—cn H7°~cH, H Br (c) : = on H7°~oH H-7°~cH,CH, CH,CH, H,C ©2004 Thomson - Brooks/Cole @) CO Br _-- CC _-- CC H d Br H Vi CN CN CO,H (d) CH ung H7°~co,H Hs0-7°~H HN HN 40 41 9.6 Diastereomers  Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers  In addition they can have stereoisomeric forms that are not mirror images, called diastereomers  See Figure 9-10 2R,3S 2S,3R 2R,3R 2S,3S Mirror COOH COOH H NH> H»Nw | pH \c7 \c7 C Cc H~ OH HO” ; “H CH; CH; COOH Hw. | .NH>2 ce HO~ ; \H CH3 COOH H~ | “OH CH; +42  Problem 9.11: Assign configurations (a) Br (b) CH, BAM win | EP | | non H,07 | SH CH, OH ©2004 Thomson - Brooks/Cole (c) Bro HH” CH; Cc CN OH | -H 45 46 Problem 9.46: R or S? ‘Problem 9.12: Assign RorS H NHCOCHCI, O.N Chloramphenicol 50 9.7 Meso Compounds  Tartaric acid has two chirality centers and two diastereomeric forms  One form is chiral and the other is achiral, but both have two chirality centers  An achiral compound with chirality centers is called a meso compound – it has a plane of symmetry Practice Problem 9.3: Meso? Symmetry plane H.C CH, 1 2 Mson - Brooks Cole 51 52 Problem 9.46: R or S? Solution: ©2004 Thomson - Brooks/Cole Morphine 55  Problem 9.47: R or S? 5° ‘CH,CH,CH,CH,CO,- Biotin ©2004 Thomson - Brooks/Cole HO H Prostaglandin E, 56  Solution: S” “CH,CH,CH,CH,CO,- Biotin ©2004 Thomson - Brooks/Cole HO H Prostaglandin E, 57 60 9.10 Racemic Mixtures and Their Resolution  To separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent)  This gives diastereomers that are separated by their differing solubility  The resolving agent is then removed (R) LC HO HA -CHs | CO,H (S) Racemic lactic acid (50% R, 50% S) ® 2004 Thomson/Brooks Cole NH, ae (R)-1-Phenylethylamine H fn H - A a Se, An R,R salt \ Diastereomers 61  9.11 A Brief Review of Isomerism Isomers Constitutional isomers | | Stereoisomers | | Enantiomers Diastereomers mirror-image) |(non-mirror-image) | Cis—trans diastereomers Configurational diastereomers 62  Enantiomers (nonsuperimposable mirror-image stereoisomers) Diastereomers (nonsuperimposable, non-mirror-image stereoisomers) Configurational diastereomers © Thomson - Brooks Cole ‘i _C H,c’/ ~OH H (R)-Lactic acid CO,H Eis, | pee | C H® | “oH CH; 2R,3R-2-Amino-3- hydroxybutanoic acid HOw C. HO~ VCH, H (S)-Lactic acid CO.H HANI | o HO” | ~H CH; 2R,3S-2-Amino-3- hydroxybutanoic acid 65  Cis—trans diastereomers (substituents on same side or opposite side of double bond or ring) ©2004 Thomson - Brooks/Cole \ iv \ C=C d C=C yo = fo \ H CH; H H trans-2-Butene cis-2-Butene HC H HC CH, ( <c H; and H “H trans-1,3-Dimethy]- cis-1,3-Dimethyl- cyclopentane cyclopentane Note: these are also configurational diastereomers 66 67 9.12 Stereochemistry of Reactions: Addition of HBr to Alkenes  Many reactions can produce new chirality centers from compounds without them  What is the stereochemistry of the chiral product?  What relative amounts of stereoisomers form? . f ~ CHaCHsCH CH; " : 1-Butene = i, -H Be CHC SSeS 4 J , Carbocation intermediate (achiral) os ae CH; Br top Bottom butane 8 (50%) ™ CH CH3CH2—¢-H Br (8)-2-Bromo- butane (50% } (5)-2-Bromo- 70 71 Mirror Image Transition States  Transition states are mirror images and product is racemic Br 72 9.13 Stereochemistry pf Reactions: Addition of Br2 to Alkenes  Stereospecific Forms racemic mixture  Bromonium ion leads to anti (trans) addition 75 9.14 Stereochemistry of Reactions: Addition of HBr to a Chiral Alkene  Gives diastereomers in unequal amounts.  Facial approaches are different in energy 76 9.15 Chirality at Atoms Other Than Carbon  Trivalent nitrogen is tetrahedral  Does not form a stable chirality center since it rapidly inverts 77 9.16 Chirality in Nature  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  See Figure 9-19 80 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 81 Prochiral distinctions, paired atoms or groups  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 was increased 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 H. re face (clockwise) | | H,C— oo OH (S)-2-Butanol $s 4 HOH, si face (counterclockwise) Hat Cc OH (R)-2-Butanol | H ©2004 Thomson - Brooks/Cole 82  H | H/ oN VS CH, on a: o H CO2H Penicillin V (2S,5R,6R configuration) ©2004 Thomson - Brooks/Cole 85 H CO,H ‘of Cc A (S)-Ibuprofen (an active analgesic agent) 86 87 Prilosec (omeprazole): Chiral Sulfur Racemic (at sulfur); the S enantiomer is physiologically active