Stereochemistry – Mechanisms - Notes | CHEM 6311, Study notes of Mechanics

Download Stereochemistry – Mechanisms - Notes | CHEM 6311 and more Study notes Mechanics in PDF only on Docsity! 26 2. Stereochemistry A. Basic definitions; this is an area where we need to make precise definitions. Once they are understood, a 3-D percep- tion (with perhaps some molecular models at first) and a little practise is all that is needed to master this field. At an el- ementary level we define isomers - compounds with the same number & kinds of atoms and using the following flowchart: Isomers Do they differ in connectivity? stereoisomers constitutional isomers C2H6O vs C2H6O C2H5OH vs CH3OCH3Are they interconverted by rotation around σ bonds? conformational isomers configurational isomers yes yes yes no no no Are they mirror images of each other? diastereomers enantiomers CC H H H O H H H CC H H H O H H H vs CC H D O H H CC D H O H H CC H T D O D H H C C H DTO DH H vs vs - or - OH D CH3 H OH DH3C H vs The property which differentiates one enantiomer from another is called chirality, derived from the Greek word for hand (χειρ). Chirality is literally: “handedness” B. Enantiomers 1. Enantiomers can be differentiated only by chiral meth- ods: note: if there is steric hindrence to rotation then conformational isomers become configurational 27 a. Effect on plane polarized light b. NMR chemical shifts in a chiral solvent c. Reaction rates in a chiral solvent or with another chiral reagent In each case each enantiomer interacts differently with another chiral compound. We will see why later. 2. It is easier to define what are the necessary elements that will make a compound achiral (i. e. not possessing chirality) than it is to do the reverse. a. The necessary elements for achirality are: i ) A mirror plane of symmetry H CH3 H Cl F Cl F Cl center of inversion mirror plane H H ii ) An inversion center b. An Sn axis of symmetry is the rigorous definition of achirality. i ) Sn = rotation by 360° /n, followed by reflection in a plane perpendicular to the rotation axis. ii ) For the above two cases: H CH3 H Cl F Cl F Cl S1 = mirror plane S2 = center of inversion 30 iv ) There are several others, particularity from the inorganic field, which we will not discuss. C. Configuration 1. This is the arrangement of atoms in space (without regard to facile rotations about bonds). Many experiments can differentiate between one enantiomer and the other, but it is not easy to tell which enantiomer has which particular configuration. 2. The assignment of absolute configuration can be deter- mined by special methods in x-ray crystallography. a. Often it is easier to determine a compound’s con- figuration by converting it to a compound of known configuration, using reactions of known stereochemis- try. b. Enantiomers are named according to some ac- cepted system of conventions. One such is the Cahn-Ingold-Prelog (R, S system. Please review it for yourself. CH2OH CH3 D H Ph NH2 D H R [α]D = +0.32 o S [α]D = +0.71 o 2.10 c. Remember. assigning an R or S name (configura- tion) to an enantiomer has nothing to do with whether the compound rotates plane polarized light in a clockwise (+) or anticlockwise (-) fashion. It also bears no fixed relation to the D, L name used for many biological molecules. 3. The representation of configuration a Some standard representations: Ph OH H3C H H HH OH H Ph OH H Ph H HH CH3 OH H Ph CH3H OH Ph wedge and dash sawhorse Newman projection Fisher projection useful for viewing multiple chiral centers 2.11 31 D. Diastereomers 1. These are stereoisomers which do not have a mirror image relationship. 2. They can usually be differentiated by most physical methods - e.g. differences in chemical shifts, boiling points, melting points, reaction rates, solubility, etc. 3. Examples: a. Stereoisomers around a double bond H3C H CH3 H H3C H H CH3 vs. cis trans Z E 2.12 b. Stereoisomers in a cyclic compound cis trans CH3 H H H3C H H H CH3 H H3C H H 2.13 note: the compound on the right is chiral, but that is immaterial for this discussion c. Molecules with more than one chiral carbon B C1 C2 Y DA ZX possible configurations 1 2 3 4 C1 = R S R S C2 = R S S R enantiomers enantiomers diastereomers 2.14 4. Enantiomers can be resolved by a chiral agent a They form diasteromeric cornplexes with the chiral agent. i ) Consider AR and AS to be two enantiomers. ii ) BR may be a chiral solvent, a chiral sub- strate, or even just plane polarized light that propagates in a clockwise (or an anticlockwise) direction. A R and A S + B R ⇒ A R •B R and A S •B R these are diastereomers 32 b. Diastereoisomeric interactions are used to separate enantiomers. If, for example, A is a race- mic acid and B is a chiral base (a natural product), the salts that are produced can be expected to have different solubility properties. 5. For a compound with n chiral centers there will be a maximum of 2n different configurations. How- ever, a special circumstance may reduce this number: Y C1 C2 Y ZX ZX possible configurations 1 2 3 4 C1 = R S R S C2 = R S S R enantiomers identical (meso compound) diastereomers 2.15 The meso compound always has a mirror plane of symmetry or an inversion center, therefore, it can never be chiral. E. Stereotopicity compares identical atoms or groups within a molecule. 1. An atom (center) is prochiral if the exchange of one of its equivalent substitutents for something else would create a chiral center. Ha C Hb CH3HO substitute D for Ha substitute D for Hb D C Hb CH3HO Ha C D CH3HO R S enantiomers prochiral center 2. Ha and Hb in the molecule above are said to be enantiotopic. a. Substitution of Ha leads to the R form, hence it is the pro-R group. 35 4.4 4.0 2.8 2.4 CO2H OH HR HR HS HS CO2H H2 H2 JHR- HSJH2- HS JHR- H2 JHS- H2 JHR- H2 D M SO 0 90 180o o o JH - H Karplus Relationship ppm 2.19 favored conformation of malic acid iv ) Suppose we had a racemic mixture of R and S malic acid - how many signals would we see for the methylene protons? (a) In an achiral solvent: Note: Do not confuse the # of lines with the # of signals in an NMR spectrum HR Hs HR Hs R S enantiomeric 2.20 We would therefore still see two signals for the methylene protons. (b) In a chiral solvent we would see all 4 signals. 4. If substitution of equivalent groups leads to identical molecules, the groups are homotopic. a Example one, ethane: 36 H3C C H Ha Hb H3C C H D H H3C C H H D identical 2.21 b. Example two, ethylene glycol: HO OH Hc Hd Ha Hb 2.22 Ha and Hb are enantiotopic along with Hc and Hd Ha and Hc are homotopic along with Hb and Hd 5. Stereotopic faces a. Sometimes faces, regions in a molecule where there are no atoms, can have stereotopic relationships. e.g. H3C C OH Nuc:- Nuc:- re face si face Nuc O-H H3C O- NucH H3C enantiomers 2.23 i) The si and re faces of acetaldehyde are enantiotopic. (a) A chiral nucleophile will react with these faces at different rates. (b) The two transition states (with a chiral nu- cleophile) are diastereomers. ii) Likewise it is easy to show for the following examples: C CH O CH3 H2N H H CH O diastereotopic faces homotopic faces 37 6. Generalized Rigorous Rules for Stereotopicity Are the groups related by a symmetry operation? Are they related by a Cn axis? yes yes yes no no no Do they have identical connectivity? Compare identical groups in a molecule homotopic enantiotopic diastereotopic heterotopic 7. A “real” example of steretopicity: the enzymatic oxida- tion of ethanol to acetylaldehyde a. The reaction CH3CH2OH + N R + (NAD+) NH2 O O H H3C E + N R NH2 O starches H H + H+ (NADH)cofactor ✷✤✧FAT ✷✤✧ 2.26 R = N NN N NH2 O HOH HH H CH2 H OPO O O P O O O OH OH H R' H OH H2C b. The catalytic site: NH CH C C H2 O O S NH CH C C H2 O O N NH H Zn+2 HN CH C C H2 O OS H O HH3CH2C cysteinecysteine histidine 2.27 note methylene hydrogens E = liver alcohol dehy- drogenase, a Zn2+ metalloenzyme (a protein) with ~375 amino acids