bài giảng hóa học lập thể

• Same connections, different spatial arrangement of atoms – Enantiomers nonsuperimposable mirror images – Diastereomers all other stereoisomers... • Some objects are not the same as the

Stereochemistry

A Brief Review of Isomerism

Constitutional Isomers

• Different order of connections gives different

carbon backbone and/or different functional

groups

• Same connections, different spatial arrangement of

atoms

– Enantiomers (nonsuperimposable mirror images)

– Diastereomers (all other stereoisomers)

Sự quay xung quanh một liên kết σσσσ là được phép

(CONSTITUTIONAL ISOMERS)

ĐỒ NG PHÂN CẤU TRẠNG

Có thể có nhiều cách sắp xếp trong không gian

khác nhau của các nguyên tử trong phân tử H 2 O 2

Cấu trạng (Conformation): Là bất kỳ cách sắp xếp

PHÉP CHIẾU NEWMAN

Công thức phối cảnh

Công thức phối cảnh

ETHANE

PROPANE

Quy tắc Cahn–Ingold–Prelog

• Bậc nguyên tử càng lớn thứ tự ưu tiên càng

lớn: I > Br > Cl > H

• Nguyên tử đầu tiên giống nhau: Xét tiếp

nguyên tử kế tiếp cho đến khi thấy được sự

khác biệt: CH2OH > CH(CH3)2 > CH3

• Liên kết đôi: bằng hai liên kết đơn,…

COOH > CHO > CH OH

DANH PHÁP E–Z

ĐỒNG PHÂN CIS-TRANS

HỢP CHẤT MẠCH VÒNG

HỢP CHẤT NHỊ VÒNG

ĐỒNG PHÂN CIS-TRANS

• 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

– The property is commonly called “handedness”

• Organic molecules (including many drugs) have

handedness that results from substitution patterns

Enantiomers – Mirror Images

• Molecules exist as three-dimensional

objects

• Some molecules are the same as their

mirror image

• Some molecules are different than their

mirror image: These are stereoisomers

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

• This is illustrated by enantiomers of lactic acid

Examples of Enantiomers

• Molecules that have one carbon with 4 different

substituents have a nonsuperimposable mirror

image – enantiomer

Mirror-image Forms of Lactic Acid

• When H and

OH substituents match up,

COOH and CH 3 don’t

• when COOH and CH 3

coincide, H and OH don’t

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

• 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

Plane of Symmetry

• The plane has the

same thing on both

sides for the flask

• There is no mirror

plane for a hand

Chirality Centers

• A point in a molecule where four different groups

(or atoms) are attached to carbon is called a

chirality center

• A chiral molecule usually has at least one chirality

center

Chirality Centers in Chiral Molecules

• Groups are considered “different” if there is any

structural variation

• In cyclic molecules, we compare by following in

each direction in a ring

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

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 [α]

• Clockwise rotation is called dextrorotatory

• Anti-clockwise is levorotatory

Measurement of Optical Rotation

• A polarimeter measures the rotation of

plane-polarized that has passed through a solution

• The angle between the entrance and exit planes is

the optical rotation

Specific Rotation

Specific rotation : [αααα] D

[α]D= observed rotation/(pathlength x concentration)

= α/(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)

28 mg of mandelic acid was dissolved in 1

cm3 of ethanol and the solution placed in a

10 cm long polarimeter cell An optical

rotation α of –4.35° was measured at 20°C

with light of wavelength 589 nm What is

the specific rotation of the acid?

Enantiomeric excess

• A 50:50 mixture of two chiral compounds that are

mirror images does not rotate light: called a

racemic mixture.

• A racemic mixture has zero net rotation.

• The composition of a mixture of enantiomers is

given by the enantiomeric excess (e.e): the

percentage excess of the major enantiomer over

the minor enantiomer

ee = % Major−% Minor

The optical purity

• An older term, is numerically identical to

enantiomeric excess

• It represents the observed rotation, relative to the

rotation of the pure enantiomer

The optical purity

Example: (S)-(+)-2-Bromobutane has an observed specific

Pasteur’s Discovery of Enantiomers (1849)

• Louis Pasteur discovered that sodium ammonium

salts of tartaric acid crystallize into right handed

and left handed forms

• The optical rotations of equal concentrations of

these forms have opposite optical rotations

Relative 3-Dimensional Structure

• The original method was a

correlation system,

classifying related molecules

into “families” focused on

Rules for Specification of Configuration

• A general method applies to the configuration at eachchirality center (instead of to the the whole molecule)

• The configuration is specified by the relativepositions of all the groups with respect to each other

at the chirality center

• The groups are ranked in an established prioritysequence and compared

• The relationship of the groups in priority order inspace determines the label applied to the

Sequence Rules (IUPAC)

• Assign each group priority according to the

Cahn-Ingold-Prelog scheme with the lowest priority group

pointing away, look at remaining 3 groups in a plane

• Clockwise is designated R (from Latin for “right”)

• Counterclockwise is designated S (from Latin word

for “left”)

R-Configuration at Chirality Center

• Lowest priority group is pointed away and

direction of higher 3 is clockwise, or right turn

Examples of Applying Sequence Rules

Đồ ng phân đố i quang hay

của cùng một chất?

và

và

Tương đương với

VẼ CẤU TRÚC ĐỒNG PHÂN ĐỐI QUANG:

CÔNG THỨC FISCHER

C H

(R))))−−−−((((−−−−)-Lactic acid

C COOH

Y

X Z

PHÉP

CHIẾU

FISCHER

C H

CH 3 HOOC NH 2

H

CH 3 HOOC NH 2 1 =

2

3

4

1 2

3 (S)-Alanine

C

CHO

H HO

CHO

H HO

1

2

Giữ cố định

FISCHER PROJECTION

FISCHER PROJECTION

Cấu hình R hay S ?

Molecules with More Than Two

Chirality Centers

• Molecules can have many chirality centers

• Each point has two possible permanent

arrangements (R or S), generating two possible

stereoisomers

• So the number of possible stereoisomers with n

chirality centers is 2n

• 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,

2R,3R 2S,3S

 Are stereoisomers that are not enantiomers

 The physical and chemical properties of a pair

of diastereoisomers are different

Số đồng phân lập thể = 22

Diastereoisomers

2S,3R 2R,3S 2S,3S 2R,3R

Diastereoisomers

Đồng phân lập thể của 2-chloro-3-hexanol ?

 Diastereoisomers can be chiral or achiral

CHIRAL AND ACHIRAL DISUBSTITUTED CYCLOALKANES

Meso Compounds

• Tartaric acid has two chirality centers and two

diastereomeric forms

• An achiral compound with chirality centers is

called a meso compound – it has a plane of

symmetry

HỢP CHẤT MESO

HỢP CHẤT MESO

Physical Properties of Stereoisomers

• Enantiomeric molecules differ in the direction in

which they rotate plane polarized but their other

common physical properties are the same

• Daistereomers have a complete set of different

common physical properties

Racemic Mixtures and Their Resolution

• A 50:50 mixture of two chiral compounds that are

mirror images does not rotate light: called a

racemic mixture.

• To separate components of a racemate: 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

Representation of Resolution through Separation

of Diastereomeric Derivatives

RESOLUTION

Resolutions by chromatography on chiral material

Resolutions by chromatography on

chiral material

KINETIC RESOLUTION

Stereochemistry of Reactions:

Addition of HBr to Alkenes

• Many reactions can produce new chirality centers

• What is the stereochemistry of the chiral product?

• What relative amounts of stereoisomers form?

Achiral Intermediate Gives

Racemic Product

• Addition via carbocation

• Top and bottom are equally accessible

Mirror Image Transition States

• Transition states are mirror images and product is

racemic

Br

Stereochemistry of Reactions:

Addition of Br2 to Alkenes

• Stereospecific: Forms racemic mixture

• Bromonium ion leads to trans addition

Addition of Bromine to Trans 2-Butene

• Gives meso product (both are the same)

Stereochemistry of Reactions:

Addition of HBr to a Chiral Alkene

• Gives diastereomers in unequal amounts

• Facial approaches are different in energy

• A molecule that is achiral but that can become

chiral by a single alteration is a prochiral molecule

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.

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

Homotopic, Enantiotopic, Diastereotopic

When two hydrogens attached to a single

carbon, they can have three different types of

relationships:

 Homotopic

 Enantiotopic

 Diastereotopic

Homotopic Hydrogens

Enantiotopic Hydrogens

Enantiotopic Hydrogens

Tâm C mang 2 H và 2 nhóm thế khác nhau: Prochiral

H a hoặc H b : Enantiotopic Hydrogens

Thay H a hoặc H b bằng một nhóm thế khác sẽ tạo ra một tâm C*.

Pro-R và pro-S tương đương về mặt hóa học:

► Phản ứng như nhau đối với tác nhân achiral nhưng

Enantiotopic Hydrogens

FORMATION OF ENANTIOMERS

FORMATION OF ENANTIOMERS

Diastereotopic Hydrogens

Diastereotopic Hydrogens

Diastereotopic Hydrogens

Ha và Hb không tương đương hóa học

Phản ứng khác nhau đối với tác nhân achiral.

FORMATION OF DIASTEREOMERS

meso

• homotopic protons have the exact same

chemical shift.

• enantiotopic protons have the same chemical

shift in the vast majority of situations.

However, if they are placed in a chiral

environment (e.g a chiral solvent) they will

have different chemical shifts.

Homotopic, Enantiotopic, Diastereotopic

TÂM NITROGEN BẤT ĐỐI XỨNG

Sự khác nhau về năng lượng giữa hai cấu hình rất

Sự khác nhau về năng lượng giữa 2 cấu hình của

hợp chất phospho là 30 kcal/mol

Sự khác nhau về năng lượng giữa 2 cấu hình của

hợp chất lưu huỳnh là 35 kcal/mol

Có thể cô lập 2 dạng đồng phân quang học

BIOACTIVITY

BIOACTIVITY

CHIRAL DRUGS