Based on McMurry’s Organic Chemistry, 7th edition

Dr Morteza Mehrdad

University of Guilan, Department of Chemistry,

Rasht, Iranm-mehrdad@guilan.ac.ir

Stereochemistryاستریوشیمی

9

Stereochemistry

Some objects are not the same as

their mirror images (technically, they

have no plane of symmetry)

A right-hand glove is different

than a left-hand glove. The

property is commonly called

“handedness” «دستواره »به استفاده از یکعادت }:از نظر معنی لغت

{دیگردست پیش از دست

Organic molecules (including many

drugs) have handedness that results

from substitution patterns on sp3

hybridized carbon2

Why this Chapter?

Handedness is important in organic and biochemistry

Other types of stereoisomers besides cis/trans

Molecular handedness makes possible specific interactions between enzymes and substrates—effecting metabolism and pharmaceuticals

3

Examples of Enantiomers انانتیومر Molecules that have one carbon

with 4 different substituents have

a non-superimposable mirror

image تصویر آیینه ای انطباق ناپذیر

Enantiomers =

non-superimposable mirror

image stereoisomers

Enantiomers have identical

physical properties (except

for one)

Build molecular models to see this4

Chirality کایرالیته If an object has a plane of symmetry it’s the same as its mirror image

A plane of symmetry divides an entire molecule into two pieces that are exact mirror images

Achiral ناکایرال means that the object has a plane of symmetry

Molecules that are not superimposable with their mirror images are chiral (have handedness)

Hands, gloves are prime examples of

chiral object

They have a “left” and a “right” version

5

Organic molecules can be Chiral or Achiral

Chiral Centers مرکزهای کایرالیته

A point in a molecule where four different groups (or atoms)are attached to carbon is called a chiral center کایرالیتهمرکز

Such carbons are referred to as chirality centers, althoughother terms such as stereocenter فضاییمرکز , asymmetric

center تقارنبیمرکز , and stereogenic center فضازامرکزhave also been used.

A chiral molecule usually has at least one chiral center

6

Chiral Centers in Chiral Molecules

Groups are considered “different” if there is any structural

variation (if the groups could not be superimposed if

detached, they are different)

In cyclic molecules, we compare by following in each

direction in a ring

7

صفحه تقارن ندارد و کایرال است

9.3 Optical Activity فعال نوری

8

راست گردان چپ گردان

Light restricted to pass through a plane is plane-polarized قطبیده مسطح

A polarimeter

measures the

rotation of

plane-polarized

light that has

passed through

a solution

Rotation, in degrees, is []

Clockwise (+) = dextrorotatory; Anti-clockwise (-) = levorotatory

Plane-polarized light that passes through solutions of achiral

compounds remains in that plane ([] = 0, optically inactive)

Solutions of chiral compounds rotate plane-polarized light and the

molecules are said to be optically active

Measurement of Optical Rotation چرخش نوری

The more molecules of a chiral sample are present the greater the rotation of the light = concentration dependent

To have a basis for comparison, define specific rotation, []Dfor an optically active compoundچرخش مخصوص

Specific rotation is that observed for 1 g/mL in solution in a cell with a 10 cm path using light from sodium metal vapor (589 nm)

The specific rotation of the enantiomer is equal in magnitude but opposite in sign (+)-lactic acid = +3.82; (-)-lactic acid = -3.82

9

ClD

g/ml)in tration dm)(concenin h (pathlengt

degrees)in rotation (observed][

9.4 Pasteur’s Discovery of Enantiomers

Louis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms

The solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes – such an event is rare

A (50:50) racemic mixture مخلوط راسمیک of both crystal

types dissolved together was not optically active

The optical rotations of equal concentrations of these forms have opposite optical rotations

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THALIDOMIDE تالیدومید

• One asymmetric carbon atom, exists as 2 enantiomers

R-Enantiomer TeratogenS-Enantiomer → sedativeمسکن جنینکنندگیناقصعامل

آرام بخشداروییکعنوانبهتالیدومیدشرکتیکتوسطمیالدی50دههاواخردر

شددتولیگروننتالنامبهآلمانیداروسازیتهوعدرمانبرایداروایناز.آمدبازاربهو

بیبیخوامشکالتوباردارزنانصبحگاهی.می شداستفاده

Sequence Rules for Specification of Configurationقواعد ترتیب برای مشخص کردن پیکربندی

A general method applies to determining the

configuration at each chiral center (instead of to

the whole molecule)

The configuration is specified by the relative

positions of all the groups with respect to each

other at the chiral center

The groups are ranked in an established priority

sequence and compared—use the same priority

ranking as we did for E/Z names

The relationship of the groups in priority order in

space determines the label applied to the

configuration, according to a rule

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13

Ranking Priorities:

Cahn-Ingold-Prelog Rules

[REVIEW CH. 6]

RULE 1

Must rank atoms that are connected at comparison point

Higher atomic number gets higher priority

Br > Cl > S > P > O > N > C > H

14

RULE 2

If atomic numbers are the same, compare at next connection point at same distance

Compare until something has higher atomic number

Do not combine – always compare

Extended Comparison

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RULE 3

Substituent is drawn with connections shown and no double or

triple bonds

Dealing With

Multiple Bonds:

17

rectus راست sinister چپ

Method

• Assign each group priority 1-4 according to Cahn-Ingold-Prelog

• Rotate the assigned molecule until the lowest priority group (4) is in

the back, look at remaining 3 groups in a plane

• Clockwise 1-2-3 movement is designated R (from Latin for “right”)

• Counterclockwise is designated S (from Latin word for “left”)

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9.6 Diastereomers دیاسترومرها Molecules with more than one chiral center have mirror image

stereoisomers that are enantiomers

In addition they can have stereoisomeric forms that are not mirror

images, called diastereomers

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یداس

ک یی

نووتا

ی بس

وکدر

هی 1

2

3

Diastereomers Diastereomers are similar, but they aren’t mirror images

Enantiomers have opposite configurations at all chiral centers;

Diastereomers are opposite at some, but not all chiral centers

Diastereomers have different physical properties

Epimers اپیمر are diastereomers different at only 1 chiral center

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9.7 Meso Compounds ترکیبات مزو Tartaric acid has two chiral centers and two diastereomeric forms

One form is chiral and one is achiral, but both have two chiral centers

An achiral compound with chiral centers is called a meso compound

– it has a plane of symmetry

The two structures on the right in the figure are identical so the

compound (2R, 3S) is achiral

Identical substitution on both chiral centers

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9.8 Racemic Mixtures and The Resolution of Enantiomers تفکیک انانتیومرها

A 50:50 mixture of two chiral compounds that are mirror images does not rotate light – called a racemic mixture (named for “racemic acid” that was the double salt of (+) and (-) tartaric acid

The pure compounds need to be separated or resolved from the mixture (called a racemate)

To separate components of a racemate (reversibly) we 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

22

23

Using an Achiral amine doesn’t change the relationship of the

products Still can’t separate the Enantiomeric Salts

24

Using a Chiral amine changes the relationship of the products

Now we can separate the Diastereomeric Salts

9.9 A Review of Isomerism The flowchart summarizes the types of isomers we have

seen

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Constitutional Isomersایزومرهای ساختمانی Different order of connections gives different carbon

backbone and/or different functional groups

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Stereoisomers استریوایزومرها Same connections, different spatial arrangement of atoms

Enantiomers

(nonsuperimposable

mirror images)

Diastereomers

(all other stereoisomers)

Includes cis, trans and

configurational

diastereomers

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9.10 Stereochemistry of Reactions:

Addition of H2O to Alkenes

Many reactions can produce new chiral centers from

compounds without them

What is the stereochemistry of the chiral product?

What relative amounts of stereoisomers form?

Example addition of H2O to 1-butene

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Achiral Intermediate Gives Racemic Product Addition via carbocation

Top and bottom are equally accessible

Achiral reactant + Achiral reactant = Optically Inactive Product

Optical Activity doesn’t come from nowhere

فعالیت نوری از ناکجاآباد نمی آید

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Addition of H2O to a Chiral Alkene

What is the sterochemical result of the addition of H2O to a chiral

alkene R-4-methyl-1-hexene

Product has 2 chiral centers

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-Chiral + Achiral = Optically Active

-Chiral Intermediate has different top

and bottom sides

-Amounts of the two products will be

different

-Product will have optical activity

9.12 Chirality at Nitrogen, Phosphorus,

and Sulfur

N, P, S commonly found in organic compounds, and can have chiral centers

Trivalent nitrogen is tetrahedral

Does not form a chiral center since it rapidly flips

Individual enantiomers cannot be isolated = Achiral

32

Also applies to phosphorus but it flips more slowly

Can isolate individual enantiomers = Chiral

Trivalent Sulfur Cations are also Chiral

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9.13 Prochirality پروکایرالیته A molecule that is achiral but that can become chiral by a single alteration

is a prochiral molecule

Re and Si are used to describe the faces of the prochiral sp2 reactant

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د و اگر مولکولی ناکایرال باشرال فقط با یک دگرگونی کای

پروکایرالگردد، مولکول نامیده می شود

Prochiral distinctions, paired atoms or groups

An sp3 carbon with two groups the same is also a prochiral

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

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Prochiral Distinctions in Nature

Biological reactions often involve making distinctions between prochiral faces or or groups

Chiral entities (such as enzymes) can always make such a distinction

Example: addition of water to fumarate

36

Chirality in Nature and Chiral Environments Enantiomers have same physical properties, different biological ones

Stereoisomers are readily distinguished by chiral receptors in nature

Properties of drugs depend on stereochemistry

Think of biological recognition as equivalent to 3-point interaction

Enzymes can make only one enantiomer from an achiral reactant

In the chiral environment, pro-R and pro-S are chemically different

37

هنگامی که یک مولکول پروکایرال در محیط کایرال قرارمی گیرد، دو استخالف قرمز رنگ قابل تمیز خواهند بود

ت محیط کایرال دسدر -ناکایرال = فنجان قهوهفقط از یک طرف می توان قهوه را نوشید

Biological Molecules

RULE - Enzymes are chiral reagents because their binding site is chiral

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