Are mirror images identical ( symmetric) , or different ( asymmetric - PowerPoint PPT Presentation

Are mirror images identical ( symmetric) , or different ( asymmetric )?

Left hand mirror Right hand the left and right hands are nonsuperimposable

A molecular case: the amino acid alanine Symmetric or asymmetric?

Molecules with the same constitution that differ only by the relative positions of their atoms in space: 1 stereoisomers! Molecular stereoisomers that are nonsuperimposable mirror images are called enantiomers 1 An enantiomer possesses the property of molecular chirality . • Enantiomers Usually have 4 different functional groups bonded to an sp 3 -hybridized atom. That atom is • referred to as a 1 Stereogenic center 1 Stereocenter 1 Chiral center • Have identical physical properites save for one: they cause exactly opposite rotations of plane-polarized light and so are said to exhibit optical activity . 1 A clockwise rotation is d ° ° ° (+) dextrorotatory 1 A counterclockwise rotation is l ° ° ° (-) levorotatory

Light: electromagnetic radiation Electric field Electric wave Magnetic Magnetic wave field Oscillating orthogonal electric and magnetic fields of a beam of light

Plane-polarized light and its consequences 1st polarizing 2nd polarizing filter filter observer sees maximum light source plane- polarized light observer sees no light plane- polarized light

Polarimeter: An instrument to measure optical activity

Defining a physical constant: Specific rotation [ α ] E C D = 100 α cl " = the observed rotation of plane-polarized light in degrees c = the concentration in g / 100mL l = the pathlength (always 1 dm) Enantiomeric purity ( % e.e. ): % e.e. = * [(+)-enantiomer] - [(-)-enantiomer] * x 100 [(+)-enantiomer] + [(-)-enantiomer] % e.e. = α x 100 [ α ] E C D Note: a 50 : 50 mixture of enantiomers has no " . It appears to be achiral . Such mixtures are called racemates .

SO WHAT? Is molecular chiralty important? Consider: • Gloves • Smells • Drug-receptor interactions Different stereoisomers like enantiomers interact with one another in different ways!

Stereochemical theory of odor

H H O O ( S )-(+)-CARVONE ( R )-(-)-CARVONE smells like caraway seeds smells like spearmint gum H H ( R )-(+)-LIMONENE ( S )-(-)-LIMONENE smells like citrus fruit smells like turpentine

Some drugs that exist as enantiomers and why this matters OH H O O O (-)-ibuprofen (+)-ibuprofen [ α ] D 25 = - 20.6 E (c 1.00, ethanol) [ α ] D 25 = + 58.5 E (c 2.00, ethanol) Advil, Motrin OTC for arthritis, fever; general anti-inflammatory analgesic (+)-enantiomer is the active isomer (-)-enantiomer is inactive the enzyme 2-arylpropionyl-CoA epimerase converts (-)-enantiomer to the (+)-enantiomer (Zhao, X.; Eur. J. Med. Chem . 2006 , 41 , 1352-1358; Piccolo, O.; J. Org. Chem . 1985 , 50 , 3945-3946.)

Some drugs that exist as enantiomers and why this matters O O O O N N N H H N O O O O ( - )-thalidomide ( + )-thalidomide 25 = - 64.6 E (DMF) 25 = + 64 E (DMF) [ α ] D [ α ] D teratogen antiemetic enantiomers are interconvertable (undergo racemization) in vivo racemate is immunomodulator used to treat erythema nodosum leprosum (in combination with dexamethasone) newly diagnosed multiple myeloma actinic prurigo (Ellis, G.P.; West, G.B. Progress in Medicinal Chemistry , Elsevier: New York, 198, p 170)

Some drugs that exist as enantiomers and why this matters H H N N Cl Cl O O ( - )-ketamine ( + )-ketamine [ α ] D 25 = - 91.88 E (c 2.00, H 2 O) [ α ] D 25 = + 92.48 E (c 2.00, H 2 O) analgesic racemate used to induce general anesthesia ( + )-enantiomer (Ketanest S) is more potent ( - )-enantiomer is more hallucinogenic: may cause nightmares (Marrietta, M. P.; Way, W.L.; Castagnoli, N. Jr.; Trevor, A.J. J. Pharmacol. Exp. Ther . 1977 , 202 , 157-165.)

The Alan Baxter story 2002 Salt Lake City Winter Olympics bronze medalist in downhill skiing (slalom) failed IOC routine drug test: + for methamphetamine source of + : Vicks nasal spray U.S. version contains the legal enantiomer of methamphetamine: H H N N (+)-methamphetamine (-)-methamphetamine (decongestant) (crank) IOC test did not differentiate between enantiomers Baxter cleared, but lost his medal – now IOC explicitly bans both enantiomers 2006 Turin Winter Olympics Baxter finishes 16 th

The R , S system of naming chiral centers: • Use the Cahn-Ingold-Prelog “Priority Rules” 1. Rank the priorities of the 4 atoms attached to the chiral center, according to atomic number. 2. If 2 or more atoms attached are identical, rank the atoms attached to those atoms, two bonds away from the chiral center. Priority of the entire substituent is determined by the first point of difference . The highest priority substituent is assigned a 1, the next, 2, then 3, and the lowest, 4. 3. Position the molecule so that your line of sight is from the chiral center, directly back to the priority 4 substituent. 4. If priority groups 1, 2, and 3 are arranged clockwise in descending rank, the chiral center is assigned the stereodesignator R 4. If priority groups 1, 2, and 3 are arranged counterclockwise in descending rank, the chiral center is assigned the stereodesignator S

For comparison purposes, identical atoms must be compared in the same hybridization state: • The “Phantom atom” Rules 1. For naming purposes, a π bonded atom is considered to replicated by a phantom σ bond to a phantom atom. 2. Rule 1 is applied to both atoms of the π bond. 3. Rules 1 and 2 apply to each π bond of multiply bonded atoms. 4. All other things being equal, phantom atoms rank below real atoms of the same atomic number. X C Y Y C X C X Z Z

An example: Cl Is this an R or an S molecule? H 1 1 H H H H Cl Cl Cl 3 Cl C C H H H H 4 4 C C C H C 2 H H C So, it is R .

What ways are there to draw enantiomers? 1. Hatched and wedged line projections (most popular) H CH 3 H 3 C H are these these enantiomers, or just different hatched and wedged line projections of the same molecule? 2. Sawhorse projections could be used, too: H H H

Remember carvone and limonene? Do these have R or S configurations? H H O O H H

What ways are there to draw enantiomers? 3. Newman projections CH 2 CH 3 CH 2 CH 3 H CH 3 CH 2 H H H 3 C H H CH 3 CH 2 CH 3 H Are these anti-staggered and gauche staggered conformations of the same molecule?

1 What ways are there to draw enantiomers? CH 3 4. Fisher projections 2 C H 3 H 2 C Br \ H 3 C 4 a. Orient your point of view so that your body lines up with the parent chain of the molecule and your line of sight bisects the bond angle formed by the remaining two substituents of the chiral center . CH 3 b. Draw the molecule as it appears to you Br C H using wedged and hatched lines: CH 2 CH 3

c. The Fisher convention replaces wedged and hatched lines with regular ones. • The vertical lines of a chiral center are always pointing away from you • The horizontal lines of a chiral center are always pointing towards you CH 3 Br H CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 H O H H OH CH 3 CH 2 CH 2 CH 2 OH CH 2 CH 2 CH 2 CH 3 CH 2 CH 2 CH 2 CH 3 H Two of these Fisher projections of different conformations of the same configuration. Which two?

Draw ( R )-2,3-dimethylheptane as a wedged and hatched line structure and as a Fisher projection:

A molecule with 2 chiral centers and 4 stereoisomers 2,3-dihydroxybutanoic acid, also called tartaric acid: OH O * * OH OH • Draw all four R , S isomers of this molecule

A molecule with 2 chiral centers and 4 stereoisomers O O CO 2 H CO 2 H H H H O OH OH H OH H O H H O H OH H O H enantiomers H H CH 3 H 3 C H O OH CH 3 CH 3 (2 R ,3 R ) (2 S ,3 S ) diastereomers O O CO 2 H H H CO 2 H H O OH H OH OH H O H O H H O H H O H OH OH enantiomers CH 3 H 3 C CH 3 H H CH 3 (2 R ,3 S ) (2 S ,3 R )

A molecule with 2 chiral centers and 3 stereisomers: one isomer is a meso isomer OH OH Consider with 2 chiral centers and (not counting conformational isomers) 2 2 = 4 possible stereoisomers, but there are only 3! CH 3 CH 3 H H CH 3 H 3 C H O OH H OH H O H H OH H O H the same H H CH 3 H 3 C H O OH CH 3 CH 3 (2 S ,3 R ) = meso (2 R ,3 S ) = meso diastereomers diastereomers CH 3 H H CH 3 CH 3 H 3 C H O OH H OH H O H H O H H O H OH OH enantiomers CH 3 H 3 C CH 3 H H CH 3 (2 S ,3 S ) (2 R ,3 R )

OH Cl Cl O H O OH O HO O OH Cl sucralose (Splenda™) 400-800 times as sweet as sugar OH OH O OH H O H O O HO O OH OH sucrose

How many chiral centers does Splenda have? nine What is the theoretical maximum number of stereoisomers can this sugar substitute have? 2 n , where n = number of stereogenic groups: 2 9 = 512 OH Cl Cl O H O OH O HO O OH Cl

Are the configurations of Splenda’s indicated chiral centers R or S ? Cl C Cl O C O H C R O C R O O C C C H H OH C Cl O 1 Cl O 3 H O OH O 4 2 HO O 2 1 3 OH Cl 4