有机化学 ORGANIC CHEMISTRY For Undergraduates in biological science 王俊儒 理学院应化系有机化学教研室 理科楼2层C206室 87092187(O)

Chapter 6 Stereochemistry Organic Chemistry, 6th Edition L. G. Wade, Jr. Chapter 6 Stereochemistry

Chapter 6 Stereochemistry Organic Chemistry, 6th Edition L. G. Wade, Jr. Chapter 6 Stereochemistry Key Notes Chiral enantiomers; Chirality & Chiral center; Optical rotations; R /S ，D/L; Diastereomers ; meso forms; Resolution of enantiomers;

Contents Molecular Chirality & Chiral carbon Absolute and Relative Configuration Stereoisomers without chiral carbons Properties of Enantiomers & Diastereomers Resolution of Enantiomers

Biological Significance of Chirality

Biological Significance 比旋光度 mp 肌肉运动---乳酸是右旋体，（+）-乳酸 + 3.82° 53℃ 糖发酵---乳酸 是左旋体，（﹣）- 乳酸 - 3.82° 53℃ 牛奶变酸---外消旋体， （±）- 乳酸 无旋光性 18℃

Biological Discrimination 生物鉴别 used in medicine as a heart stimulant, vasoconstrictor, and bronchial relaxant. 白色到褐色之间的晶体化合物.用作心脏兴奋剂、血管收缩剂和支气管肌松弛剂 肾上腺素

手性药物chiral drugs Why to resolve the racemic mixtures to obtain the single enantiomer?

Many pharmaceuticals are chiral! * Ibuprofen (Advil) Thalidomide: used as a sedative and anti-nausea drug *

Other times, the different interaction of enantiomers with chiral biological molecules is serious. The two enantiomers of Thalidomide: beneficial sedative and anti-nausea drug * Caused serious birth defects when taken by pregnant women! *

手性药物 ※Why to resolve the racemic mixtures to obtain the single enantiomer? thalidomide 镇静 反应停

Chiral pharmaceuticals Dramatic examples of how a change in chirality can affect the biological properties of a molecule are seen in many drugs Fluoxetine, a heavily prescribed medication sold under the trade name Prozac Racemic fluoxetine is an effective antidepressant but has no activity against migraine偏头痛 The pure S enantiomer works well in preventing migraine

药 物 作用 有效成分 另一对映体作用 反应停 镇静 S R 致畸 乙胺丁醇 抗结核 SS RR 导致失明 心得安 心脏病 S R 抑制性欲 药 物 作用 有效成分 另一对映体作用 反应停 镇静 S R 致畸 Thalidomide 乙胺丁醇 抗结核 SS RR 导致失明 心得安 心脏病 S R 抑制性欲 Propranolol 氯霉素 抗菌 S R 抗菌活性低 萘必洛尔 治疗高血压 右旋 左旋 舒张血管 酮基布洛芬 抗炎 S R 防治牙周病 ketoprofen

100 million $ Chem. & Eng. News, 2001, Vol. 79, No. 40, pp79 350 452 614 812 1330 706 934 1180 300 600 900 1200 1500 1993 1994 1995 1996 1997 1998 1999 2000 100 million $ Worldwide sales of chiral drugs

胰岛素

Chirality in Nature Enantiomers of a chiral molecule Have same physical properties Usually have different biological properties (+) enantiomer of limonene has the odor of oranges (–) enantiomer of limonene has the odor of lemons

Sometimes the differing interaction of enantiomers with chiral biological molecules is relatively benign, such as a difference in taste and/or smell. The two enantiomers of carvone: * * Caraway(苋蒿，香菜) rye bread spearmint

Sec 1 Chirality “Handedness”: right glove doesn’t fit the left hand. Mirror-image object is different from the original object.

Chirality 2

Chirality A molecule is chiral if its two mirror image forms are not superposable upon one another. A molecule is achiral if its two mirror image forms are superposable. 3

Bromochlorofluoromethane is chiral It cannot be superposed point for point on its mirror image. Br Cl H F H Cl Br F To show nonsuperposability, rotate this model 180° around a vertical axis. 4

Bromochlorofluoromethane is chiral Cl H F H Cl Br F 4

Enantiomers: Nonsuperimposable mirror images, different molecules with different properties. 23

Chlorodifluoromethane is achiral The two structures are mirror images, but are not enantiomers, because they can be superposed on each other. 9

Chirality in Molecules The cis isomer is achiral. The trans isomer is chiral. Enantiomers: nonsuperimposable mirror images, different molecules.

Stereocenters Any atom at which the exchange of two groups yields a stereoisomer. Examples: Asymmetric carbons Double-bonded carbons in cis-trans isomers

The Stereogenic Center a carbon atom with four different groups attached to it also called: Chiral center Asymmetric center Stereocenter w x y z C 12

Chiral Carbons Tetrahedral carbons with 4 different attached groups are chiral. If there’s only one chiral carbon in a molecule, its mirror image will be a different compound (enantiomer).

手性和对称因素 手性(chirality)：物质的分子与其镜像不能重合的性质，是产生旋光性的充分和必要条件。 (1)、对称面(Mirror)

(2)、对称中心 图8-8 p对称中心 (3)、对称轴 (4)、更替对称轴

对称中心

Plane of symmetry A plane of symmetry bisects a molecule into two mirror image halves. Chlorodifluoromethane has a plane of symmetry. 21

Plane of symmetry A plane of symmetry bisects a molecule into two mirror image halves. 1-Bromo-1-chloro-2-fluoroethene has a plane of symmetry. 21

Mirror Planes of Symmetry If two groups are the same, carbon is achiral. (animation) A molecule with an internal mirror plane cannot be chiral.* Caution! If there is no plane of symmetry, molecule may be chiral or achiral. See if mirror image can be superimposed.

Center of symmetry A point in the center of the molecule is a center of symmetry if a line drawn from it to any element, when extended an equal distance in the opposite direction, encounters an identical element. 21

手性与分子结构关系 手性、对称性与旋光性 手性碳与手性分子二者关系 构型与旋光性 对称性、不对称性与手性: 有反映对称性的分子：物象重合，不具有旋光性，非手性分子 无对称性的分子：物象不重合，有旋光性，手性分子 手性碳与手性分子二者关系 有手性碳的分子不一定就是手性分子 手性分子并不一定就含有手性碳 只有一个手性碳的分子一定就是手性分子 构型与旋光性 分子结构的不对称性导致，物象不重合；二者主要差异在于构型不同； 对称性、不对称性与手性: 对称因素：对称面（）；对称中心(i) 凡是没有反映对称性的分子称为手性分子 不对称性：找不到任何一个对称因素的分子；手性是不对称性之一种

The ancient Egyptians had less care for the chirality of hands Pharaohs, with two left hands or two right hands—they just didn’t seem to notice.

Fischer Mirror Images Easy to draw, easy to find enantiomers, easy to find internal mirror planes. Examples:

Fischer (R) and (S) Lowest priority (usually H) comes forward, so assignment rules are backwards! Clockwise 1-2-3 is (S) and counterclockwise 1-2-3 is (R). Example: (S) (S)

Diastereomers Stereoisomers that are not mirror images. Geometric isomers (cis-trans). Molecules with 2 or more chiral carbons.

Alkenes Cis-trans isomers are not mirror images, so these are diastereomers. o o

Ring Compounds Cis-trans isomers possible. May also have enantiomers. Example: trans-1,2-dimethylcyclopentane

Summary Stereoisomers Optical Isomers Geometrical Isomers Conformers Enantiomers Diastereomers Configurational Diastereomers Cis-trans Isomers

Sec 2 Absolute and Relative Configuration Different molecules (enantiomers) must have different names. Usually only one enantiomer will be biologically active. Configuration around the chiral carbon could be specified.

Sec 2 Absolute and Relative Configuration 相对构型 Relative configuration compares the arrangement of atoms in space of one compound with those of another. until the 1950s, all configurations were relative 绝对构型 Absolute configuration is the precise arrangement of atoms in space. we can now determine the absolute configuration of almost any compound 15

Relative configuration Pd CH3CHCH OH CH2 CH3CHCH2CH3 OH [a] + 33.2° [a] + 13.5° No bonds are made or broken at the stereogenic center in this experiment. Therefore, when (+)-3-buten-2-ol and (+)-2-butanol have the same sign of rotation, the arrangement of atoms in space is analogous. The two have the same relative configuration 16

Relative Configuration D/L CHO CHO H OH HO H CH2OH CH2OH （+）－甘油醛 （-）－甘油醛 D L D －（+）－甘油醛 L－（-）－甘油醛 常用来确定糖、氨基酸等构型

D and L Assignments * * *

相对构型(Relative Conformation) D -（+）- 甘油醛 L -（-）- 甘油醛 化学关联法： D-（+）-甘油醛 D-（-）-甘油酸 D-（-）-乳酸

Absolute Conformation 1970 IUPAC R/S 标记任何一个手性碳(或手性分子) 明确与手性碳相连的4个不同基团的优先次序 用手模型法或透视法判断其构型 Which is which? E. Fisher 1891; 1954 x-ray证实 R -（+）- 甘油醛 S -（-）- 甘油醛

Cahn-Ingold-Prelog Rules Assign a priority number to each group attached to the chiral carbon. Atom with highest atomic number assigned the highest priority #1. In case of ties, look at the next atoms along the chain. Double and triple bonds are treated like bonds to duplicate atoms.

绝对构型(Absolute Conformation) IUPAC(1970) R、S构型系统命名法： 1>2>3>4

Assign Priorities 2 4 3 3 4 1 2 1 3 expands to 4 1 2

Assign (R) or (S) Working in 3D, rotate molecule so that lowest priority group is in back. Draw an arrow from highest to lowest priority group. Clockwise = (R), Counterclockwise = (S)

A Enantiomers of 2-butanol C OH H3C H CH3CH2 C HO CH3 H CH2CH3 (S)-2-Butanol (R)-2-Butanol 8

Rules for Fischer projections Cl Br Cl Br F F Arrange the molecule so that horizontal bonds at stereogenic center point toward you and vertical bonds point away from you 13

Chiral drugs Ibuprofen is chiral, but normally sold as a racemic mixture. The S enantiomer is the one responsible for its analgesic and antiinflammatory properties. CH2CH(CH3)2 H H3C C O HO 13

B 2,3-Dihydroxybutanoic acid 4 Combinations = 4 Stereoisomers CH3CHCHCOH HO OH 3 2 What are all the possible R and S combinations of the two stereogenic centers in this molecule? Carbon-2 R R S S Carbon-3 R S R S 4 Combinations = 4 Stereoisomers 6

2,3-Dihydroxybutanoic acid CH3CHCHCOH HO OH 3 2 enantiomers: 2R,3R and 2S,3S 2R,3S and 2S,3R Carbon-2 R R S S Carbon-3 R S R S 6

S R R S S R [a] = -9.5° [a] = +9.5° HO CO2H CH3 H OH CO2H CH3 H HO OH enantiomers diastereomers CO2H H CH3 HO R S CO2H CH3 H OH R S enantiomers [a] = +17.8° [a] = -17.8° 12

Fischer projections CO2H CH3 OH H 13

C Stereogenic center in a ring H H3C R —CH2C=C > —CH2CH2 > —CH3 > —H 11

D Two stereogenic centers in a ring trans-1-Bromo-1-chlorocyclopropane nonsuperposable mirror images; enantiomers 16

Two stereogenic centers in a ring cis-1-Bromo-1-chlorocyclopropane nonsuperposable mirror images; enantiomers 16

Two stereogenic centers in a ring cis-1-Bromo-1-chloro- cyclopropane trans-1-Bromo-1-chloro- cyclopropane stereoisomers that are not enantiomers; diastereomers 16

Cyclic compounds R chiral meso S R There are three stereoisomers of 1,2-dichloro- cyclopropane; the achiral (meso) cis isomer and two enantiomers of the trans isomer. 22

黑麦草内酯loliolide (also calendin) 中等免疫抑制活性 具有强的细胞毒活性

E Achiral Molecules with Two Stereogenic Centers (有2个手性中心的非手性分子) It is possible for a molecule to have stereogenic centers yet be achiral. 10

2,3-Butanediol 2 3 CH3CHCHCH3 HO OH Consider a molecule with two equivalently substituted stereogenic centers such as 2,3-butanediol. 6

Three stereoisomers of 2,3-butanediol OH CH3 HO CH3 OH H HO H CH3 OH 2R,3R 2S,3S 2R,3S chiral chiral achiral 6

Three stereoisomers of 2,3-butanediol meso form these two are enantiomers 2R,3R 2S,3S 2R,3S chiral chiral achiral 6

Three stereoisomers of 2,3-butanediol OH CH3 HO CH3 OH H HO H CH3 OH 2R,3R 2S,3S 2R,3S chiral chiral achiral 6

4 stereogenic centers 16 stereoisomers O HOCH2CH—CH—CH—CHCH OH Example

HO OH H H3C CH2CH2CO2H CH3 Cholic acid 11 stereogenic centers 211 = 2048 stereoisomers one is "natural" cholic acid a second is the enantiomer of natural cholic acid 2046 are diastereomers of cholic acid 26

How many stereoisomers? Maximum number of stereoisomers=2n where n = number of structural units capable of stereochemical variation Structural units include stereogenic centers and cis and/or trans double bonds Number is reduced to less than 2n if meso forms are possible 24

How many stereoisomers? 3-Penten-2-ol R E E S HO H H OH Z R Z S HO H H OH 27

Chirality of Conformers If equilibrium exists between two chiral conformers, molecule is not chiral. Judge chirality by looking at the most symmetrical conformer. Cyclohexane can be considered to be planar, on average.

Mobile Conformers Nonsuperimposable mirror images, but equal energy and interconvertible. Use planar approximation.

without chiral carbons SEC 3 Stereoisomers without chiral carbons (1)、丙二烯型化合物 2、3 - 戊二烯的对映异构体 手性轴

2,3-Pentadiene Is Chiral 80

(2)、单键旋转受阻的化合物 手性轴

Nonmobile Conformers If the conformer is sterically hindered, it may exist as enantiomers.

(3)、把手化合物（Ansa-compounds）

(4)、含其他手性原子的化合物 胺 季胺盐 五价磷化合物 锍盐

Sec 4 Properties of Enantiomers & Diastereomers 旋光异构体的物性比较 旋光性的测定

Sec 4 Properties of Enantiomers & Diastereomers Same boiling point, melting point, density Same refractive index Different direction of rotation in polarimeter Different interaction with other chiral molecules Active site of enzymes is selective for a specific enantiomer. Taste buds and scent receptors are also chiral. Enantiomers may have different smells.

Properties of Diastereomers Diastereomers have different physical properties, so they can be easily separated. Enantiomers differ only in reaction with other chiral molecules and the direction in which polarized light is rotated. Enantiomers are difficult to separate. Convert enantiomers into diastereomers to be able to separate them. 87

差别： 1、对平面偏振光的旋转方向不同 2、在手性环境中的反应速度不同  表 2-甲基-1-丁醇对映体物理性质比较  化合物 沸点（℃） 密度 折射率 （20 ℃） 比旋光 度[] (+)-2甲基-1-丁醇 128 0.8193 1.4102 +5.756 (-)-2-甲基-1-丁醇 -5.756 一般条件下，对映体性质完全相同 差别： 1、对平面偏振光的旋转方向不同 2、在手性环境中的反应速度不同

Racemic Mixtures Equal quantities of d- and l- enantiomers. Notation: (d,l) or () No optical activity. The mixture may have different b.p. and m.p. from the enantiomers!

 表 酒石酸的物理性质  酒石酸 熔点/℃ 比旋光度[]D25水溶液 溶解度/（g/100g水） 密度 g/ml，20 ℃ pKa1  表 酒石酸的物理性质  酒石酸 熔点/℃ 比旋光度[]D25水溶液 溶解度/（g/100g水） 密度 g/ml，20 ℃ pKa1 pKa2 左旋体 170 +12° 139 1.760 2.93 4.23 右旋体 -12 ° 内消旋体 140 不旋光 125 1.667 3.11 4.80 外消旋体 206 20.6 1.680 2.96 4.24

History 1848 巴黎师范大学 Lewis Pasteur 化学成绩中等 Besanson皇家学院 重复结晶学实验 280C以下结晶， 酒石酸钠铵

Polarized light Ordinary (nonpolarized) light consists of many beams vibrating in different planes. Plane-polarized light consists of only those beams that vibrate in the same plane. 5

Plane-Polarized Light Polarizing filter – calcite crystals or plastic sheet. When two filters are used, the amount of light transmitted depends on the angle of the axes.

Rotation of plane-polarized light Nicol prism Polarization of light a 7

Optical Activity Rotation of plane-polarized light Enantiomers rotate light in opposite directions, but same number of degrees.

Polarimetry Rotation of plane-polarized light Enantiomers rotate light in opposite directions, but same number of degrees. Use monochromatic light, usually sodium D Movable polarizing filter to measure angle Clockwise = dextrorotatory = d or (+) Counterclockwise = levorotatory = l or (-) Not related to (R) and (S)

产生旋光的原因 两种圆偏振光

旋光性的测定 左旋和右旋 ( - ) and ( + ) ( laevorotatory and dextrorotatory ) α = [α]tD x c X l 钠光D:5893A 影响α的因素：溶剂；温度；C；l；；［α］； 比旋光度 ( specific rotation) [α]tD= α/ ( c ╳ l) 外消旋体 ---- 一对对映异构体的等量混合物 Racemic mixture, racemate

有旋光性的化合物一定能测出旋光度吗？ 比旋光度(Specific Rotation)  [  ]t = L(dm) ×C(g/ml)  t ：温度   ：光源波长  L：样品管长度  C：样品浓度   ：旋光度 右旋酒石酸的比旋光度为：[  ]D = +3.79 °(乙醇，5%） 有旋光性的化合物一定能测出旋光度吗？ （CH2）3CH3 CH3（CH2）5 CH2CH3 CH2CH2CH3 1965 制两个纯品 无旋光度 0.0000010

Resolution of Enantiomers React a racemic mixture with a chiral compound to form diastereomers, which can be separated.

Chromatographic Resolution of Enantiomers

Problem 1 : R or S?

Molecules with More Than Two Chirality Centers 胆固醇

Problem2: Chirality centers?

Solution

Problem 3 Draw a correct structure of (2R, 5R)-1,1,5-trichloro-2-propylcycloheptane Solution:

REVIEW Home work 6-22; 6-23:1; 6-24; Constitutional isomers Chair Conformation:e bond, a bond Configuratiion: Z/E, R/S, D/L Optical isomers Molecular Chirality, Chiral Carbons, Chirality centre Enatiomers, Diastereomers Home work 6-22; 6-23:1; 6-24;