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Based on McMurry’s Organic Chemistry, 7th edition
Dr Morteza Mehrdad
University of Guilan, Department of Chemistry,
Rasht, [email protected]
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
10
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
12
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
15
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”)
18
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
19
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
20
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
21
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
26
Constitutional Isomersایزومرهای ساختمانی Different order of connections gives different carbon
backbone and/or different functional groups
27
Stereoisomers استریوایزومرها Same connections, different spatial arrangement of atoms
Enantiomers
(nonsuperimposable
mirror images)
Diastereomers
(all other stereoisomers)
Includes cis, trans and
configurational
diastereomers
28
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
29
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
30
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
31
-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
33
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
34
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
35
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
39