LECTURE #09 Thurs., March 06, in Lect.07 s notes actually Biological relevance of chirality

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1 EM 221 section 52 LETURE #09 Thurs., March 06, 2008 ASSIGNED READINGS: TDAY S LASS: in Lect.07 s notes actually 5.21 Biological relevance of chirality Drawing & naming enantiomers & diastereomers Measuring chiral compounds in the lab Separating enantiomers NEXT LASS: finish h.5, start h.9, 10 (1) Reality check: why care about stereochemistry? Many naturally occurring compounds are IRAL All natural amino acids have same handedness (LEVRTATRY) proteins/enzymes IRAL too! RESULT: Mirror image molecules can behave quite differently in biological systems The interaction between is superficially analogous to SUBSTRATE & ENZYME AND & GLVE ne enantiomer fits ther enantiomer DES NT (2)

2 5.21 Discrimination of enantiomers by biological molecules Interactions between enzyme & substrate = stereospecific only 1 stereoisomer fits So?! (3) orrect enantiomer interacts in all necessary places Incorrect enantiomer does not BUT might interact unexpectedly with other biomolecules! Enantiomers have SAME physical properties SAME reactivity with achiral substances NLY difference = way they interact with other chiral things! 5.4, 5.6 Drawing enantiomers To draw a molecule s enantiomer: 1. Draw perspective drawing: show all 3D info. for asymmetric atoms (*) 2. Imagine reflecting molecule in a mirror configuration of EVERY asymmetric atom will be inverted 3. heck: is this really a different compound? original & mirror image are enantiomers only if nonsuperimposable 3 3 rotate 3 * * Draw its configuration opposite enantiomer mirror to original Shortcut: to draw a chiral (i.e., *) with opposite configuration, detach any 2 groups from that * & switch their places (4)

3 Perspective drawings vs. Fisher projections Fisher projections: a short-hand often used by biologists (will not test ) each chiral looks like a planar cross, but REALLY means this: horizontal lines: aimed towards you (out of page) vertical lines: aimed away from you (into page) Rotate (~ 90º) perspective drawing Fisher projection (intuitively meaningful) (use carefully!) This molecule s enantiomer: BEWARE: a Fisher projection does look flat, but it is NT flat Thus: if rotate by 180 º still represents same molecule if rotate by 90º no longer represents the same molecule! (5) 5.7 Assigning configuration of chiral centres: the R,S system 1. Assign priority to 4 groups attached to asymmetric centre. use ahn-ingold-prelog rules: higher atomic # higher priority (same as for E/Z ) 2. Picture molecule with LWEST priority group aimed AWAY from you 3. Trace a circle through other 3 groups from highest lowest priority: lockwise = (R) rectus (Latin right) ounterclockwise = (S) sinister (Latin left) e.g., F l l F Traces in a clockwise direction R Like turning right on a steering wheel (6)

4 3 3 clockwise 4 2 (R) configuration Rectus = right The (R) enantiomer of bromochlorofluoromethane (S) configuration Sinister = left counterclockwise 4 The (S) enantiomer of bromochlorofluoromethane (7) an only invert R vs S configuration by breaking/making bonds 5.7 & 5.13: IUPA naming of stereoisomers Geometric isomery: l using cis/trans (Z/E for double bonds) at front of name, followed by dash: cis-1-chloro-3-methylpent-2-ene or Z-chloro-3-methylpent-2-ene onfiguration of chiral atoms: add R/S after position #, in brackets, followed by dash: l (3S, 5S)-3-bromo-5-ethyloctane (8) If more than one chiral, use comma between #-letter combinations

5 5.3, 5.5 Stereocenters & stereoisomers: terms & #s stereogenic centre stereocentre = atom that gives rise to stereoisomers if two groups attached to it are interchanged (via breaking & making bonds ) NE TYPE F STEREENTRE: asymmetric centre = atom bonded to chirality centre 4 different groups chiral centre (i.e., no symmetry!) ow many stereoisomers possible? n stereocentres max. 2 n stereoisomers (9) ow are different stereoisomers related? Relationship Enantiomers Diastereomers Structural difference ALL stereocentres opposite config. Not ALL stereos opposite config. Physical properties identical different cis /trans isomers are diastereomers Practical implications nly distinguishable in chiral environments Separable by distillation, crystallization, chromatography vs. Total # stereoisomers? Are any of them enantiomers? (10) NT mirror images at this point ( s with same configuration) Mirror images at this point ( s with opposite configuration) Each has horizontal internal mirror plane & superimposable on own mirror image achiral (neither has an enamtiomer)

6 Molecules with asymmetric centres: if molecule is chiral: will have an enantiomer if >1 chiral centre: will also have diastereomers AND For each molecule below... ow many stereocentres vs. asymmetric centres? ow many stereoisomers possible? ow are they related? (11) 5.8-9: hiral compounds are optically active i.e., they rotate the plane of plane-polarized light Enantiomers: same physical properties, different handedness interact differently with plane-polarized light (chiral!) rotate the plane of PPL to same extent, but in opposite directions (clockwise vs. counterw) optical rotation A 3 3 B A B bp o solubility [α] D (12) So: and: What IS plane-polarized light? ow is it chiral?

7 1 st : Refresher on the nature of light electric vector In a light beam: many randomly oriented waves like this one magnetic vector Light = a wave with oscillating electric & magnetic fields that are perpendicular to each other and the direction of propagation (13) PAY ATTENTIN T TE ELETRI VETR NLY i.e., picture an arrow that maps out the amplitude of the electric field s oscillation Unpolarized beam of light Pass light through a PLARIZING FILTER Plane-polarized light beam RANDMLY RIENTED electric field vectors removes all orientations except for one Electric field vector oscillates IN SAME PLANE for all waves NLY light waves with their direction of vibration aligned PARALLEL T TE FILTER S SLITS can pass through!! (14)

8 If we have two polarizers in a row light passes through if they are aligned (both at 0 ) unpolarized light Polarizing filter (0 ) Plane-polarized light Polarizing filter (0 ) Plane-polarized light (15) If not aligned: less light passes through N LIGT passes if polarizers are crossed (oriented at 90 to each other) (16) see demonstration

9 So, how is PPL chiral? Plane-polarized light = made up of two chiral light waves! (right PL) + (left PL) ircularly polarized light (PL) propagates through space as helices, either right-handed or left-handed i.e., IRAL light beams! (17) own & Foote (on reserve) Figure 3.6 Remember: right hands fit better into right gloves i.e., interactions of chiral species are hand-specific When plane-polarized light interacts with chiral molecules, rotation of the plane of polarization occurs. right PL & left PL are each chiral interact to different extents with chiral molecules! result: one PL gets slowed down more than other net rotation of polarization plane lockwise rotation: (+) dextrorotatory species ( dor D) e.g., (d)-methionine ounterclockwise: (-) levorotatory species ( l or L) e.g., (l)-methionine A polarimeter: used to measure rotation of polarized light substance of interest placed between two polarizers (18)

10 USING A PLARIMETER chiral sample rotates plane less light passes YU turn one polarizer until appears bright again angle polarizer rotates = sample s optical rotation (α) IRAL SAMPLE (19) Similar: uice Fig.5.2 Rotation of Plane Polarized Light -α +α Direction of the electric vector of plane-polarized light Plane rotated counterclockwise: angle of rotation = - α ompound is levorotatory (-) or l Plane rotated clockwise: angle of rotation = + α ompound is dextrotatory (+) or d For a pair of enantiomers: one is (+), other is (-) magnitude of rotation is identical racemic mixture : 50/50 mixture of enantiomers +/- rotations equal no net rotation! (20)

11 * * A 3 3 B A and B are chiral optically active A and B are enantiomers opposite optical rotation bp o solubility [α] D A B A racemic mixture of A & B would have α = 0 (rotations cancel) (21) ENANTIMERS ARE EQUAL BUT PPSITE: If optical rotation for one enantiomer is known other enantiomer has same degree of rotation, but in opposite direction. Knowing the absolute configuration (R/S) of a compound does NT let us predict the sign of the optical rotation, d(+) or l(-) Likewise, absolute configuration ANNT be determined from the sign of the optical rotation. BUT: if sign of rotation of one enantiomer IS known the other enantiomer will have opposite sign. (R)-(-)-alanine N N 3 Dextrorotatory (S)-(+)-alanine (22) NTE: cannot predict rotation direction, but if known, can specify in compound s name

12 Quantifying optical rotation: an extensive property ow much the plane of polarized light is rotated depends on: compound s identity & its concentration temperature, length of sample tube, wavelength of light Specific rotation = [α] T D D line of sodium spectrum Temperature = α l c Tube length in decimeters measured rotation (concentration, solvent) concentration in g/ml & we specify the solvent (23) EX: A solution (100 ml) of 16.5 g of (l )-camphor in ethanol has an optical rotation of at 20, using a 10 cm sample tube and a sodium lamp. What is its specific rotation? Specific rotation = [α] 20 D = [α] 20 D = = α lc dm x 16.5 g/100 ml (0.165; ethanol) onc. g/ml solvent (24)

13 5.10 ptical purity & enantiomeric excess Enantiomers rotate PPL in opposite directions thus: net rotation depends on how much of each is present A racemic mixture (racemate): contains equal #s of molecules of two enantiomers ( optical isomers ) shows N optical rotation. WY? equal concentration of molecules that rotate plane polarized light clockwise and counterclockwise. In a non-racemic mixture of optical isomers: one enantiomer A is present in larger amount (excess) rotation due to enantiomer B will be cancelled out by A s rotation net rotation observed: due to the excess quantity of A Enantiomeric excess (e.e.) or optical purity Measured specific rotation of the mixture Specific rotation of the pure enantiomer x 100 = % enantiomeric excess (25) Ex: Describe the composition of an unequal mixture of enantiomers, with measured optical rotation: [α]= 10 o if optically pure (+) enantiomer has: [α] = 20 o TUS: (10º / 20º) 100 = 50% optical purity or, 50% enantiomeric excess measured rotation has + sign means (+) enantiomer is in excess! What is the ratio of optical isomers present in the mixture? What is the true meaning of optical purity / enantiomeric excess? If 50% is optically pure, then the remaining 50% is racemic (+/- or d / l ) %d %l 50 % d l % d total d d : l = 75 : 25 = 3 : 1 (26)

14 5.14: Rxns of cmpds with asymmetric carbons Does the configuration at asymmetric centres change? depends on whether or not bonds to asymmetric atom are broken during the reaction 1.) If no bonds to * broken: relative configuration same i.e., no change in relative positions of groups BUT: might have changed one of the substituents enough that priority of group changes! i.e., absolute configuration might change l Same relative & absolute configurations (27) = Pd / 3 3 Same relative & but inverted absolute configuration Does the configuration at asymmetric centres change? depends on whether or not bonds to asymmetric atom are broken during the reaction 1.) If no bonds to * broken: relative configuration unchanged 2.) If a bond to * is broken: configuration MAY change depends on mechanism of reaction! Y Z z z 3 + Y - Same relative pposite relative configuration configuration as reactant to reactant oming soon: mechanisms of this type of reaction! (28)

15 5.16: Resolution of racemic mixtures = separating enantiomers (using clever tricks! ) 1. BRUTE FRE: Pasteur resolved crystals of sodium ammonium tartrate (from wine) viewed crystals under microscope: left- vs. right-handed crystals separated them by hand. 2. BILGIAL RESLUTIN: stereoselective rxn feed a racemic mixture to a biological system only converts one enantiomer to another product leaves behind the other enantiomer unchanged (= the one you want?) 3. PREPARATIN F DIASTEREMERS: reversible rxn chemical rxn: modify enantiomers so they stop being enantiomers separate diastereomeric products (different physical properties!) undo the rxn: convert separated products back into reactants e.g., acid-base chemistry (easily reversible) (29) Using reversible chemistry to resolve enantiomers: step 1 (R)-(-)-amphetamine 2 (30) Racemic mixture [α] D = 0 (S)-(+)-amphetamine * * N N 3 N 3 (R)(2R,3R) salt More soluble (knew they d be different ) React with in 3 2 diastereomers DIFFERENT PYSIAL PRPERTIES! ** (2R,3R)-(+)-2,3- dihydroxybutanedioic acid = optically pure (+)-tartaric acid = resolving agent 3 N 3 2 (S)(2R,3R) salt Less soluble can separate via crystallization

16 Using reversible chemistry to resolve enantiomers: step 2 Filter off crystals of the less soluble of the two diastereomeric salts recrystallize to purify it! 3 N (S)(2R,3R) salt 3 2 K (31) K/ 2 treat with base to deprotonate the ammonium ion regenerate amine! K ARGED! soluble in water (deprotonated form of the resolving agent) 2 N 3 2 insoluble in water (the desired cmpd) (S)-(+)-amphetamine, [α] D = : Meso ompounds Picture a molecule with two asymmetric centres that have identical groups on them Depending on their configurations, the molecule overall can have an INTERNAL plane of symmetry. Molecule overall is AIRAL called a meso compound own & Foote Fig. 3.4 (textbook on reserve) Nice pictures in uice too IMPLIATIN: optically inactive stereocentres in SAME molecule are mirror images cancel out each other s optical rotation like a racemic mixture inside one molecule! (32)

17 MES MPUNDS: contain mirror-image stereocenters 3 l 3 l At first glance, these look like enantiomers l 3 l 3 Internal plane of symmetry AIRAL molecule mirror-images but. superimposable identical! A MES MPUND The molecule is not chiral 3 has no optical activity Like a racemic mixture l within one molecule! 3 l Aside: in 5.9, see erythro vs. threo to describe isomers with >1 * If can rotate to have similar groups on same side of chain: erythro If config. Makes similar groups remain on opposite sides: threo BUT YU ARE NT STRITLY RESPNSIBLE FR TIS! (33) 2,3-dichlorobutane: 2 stereocentres max. 2 2 stereoisomers, but actually only 3 different cmpds since 1 is a meso cmpd l 3 3 l (2R,3R)-2,3-dichlorobutane enantiomers 3 l l 3 (2S,3S)-2,3-dichlorobutane diastereomers diastereomers (34) 3 l 3 l A meso compound (2S,3R)-2,3-dichlorobutane? (2R,3S)-2,3-dichlorobutane? Must have a unique name. Which name is correct? For meso compounds: stereocenter with lower # designated as R configuration

18 Disubstituted cycloalkanes: many have a meso diastereomer enantiomers (1S,2S)-1,2-dibromocyclopentane (1R,2R)-1,2-dibromocyclopentane diastereomers diastereomers (1R,2S)-1,2-dibromocyclopentane a meso compound NTE: convince yourself of this: all symmetrically disubstituted cyclopentanes have meso isomers both 1,2- and 1,3-substituted BUT not the case for all disubstitution patterns of cycloalkanes! don t always have asymmetric s!? (35) ASSIGNED READINGS BEFRE NEXT LETURE: Read: h.5 (all) Practice: assigning R/S configuration identifying enantiomers & diastereomers DRAWING & NAMING stereoisomers products/mechanisms of alkene reactions try thinking about stereochemistry too (covered next class) (36)