Transcript Orbitals - drjosephryan.com

John E. McMurry
http://www.cengage.com/chemistry/mcmurry
Chapter 5
Stereochemistry at
Tetrahedral Centers
Richard Morrison • University of Georgia, Athens
Handedness
Right and left hands are not identical
• Right and left hands are mirror images of each
other – they are nonsuperimposable mirror
images
• Almost all the molecules in the human body are
handed
• Handedness primarily arises from the tetrahedral
stereochemistry of sp3-hybridized carbon atoms
5.1 Enantiomers and the Tetrahedral
Carbon
Molecular handedness
• Molecules CH3X and
CH2XY are identical to
their mirror images
•
•
Molecular images can
superimpose on their
mirror images
Molecule CHXYZ is not
identical to its mirror
image
• Molecular image can
not superimpose on its
mirror image
Enantiomers and the Tetrahedral Carbon
Enantiomers
• From the Greek enantio, meaning “opposite”
• Stereoisomers in which molecules are not identical to
their mirror images
• Result whenever a tetrahedral carbon is bonded to four
different substituents CHXYZ (one need not be H)
• Lactic acid (2-hydroxypropanoic acid) has four different
groups (-H, -OH, -CH3, -CO2H) bonded to the central
carbon atoms and exists as a pair of enantiomers
Enantiomers and the Tetrahedral Carbon
Enantiomers of lactic acid
•
•
(+)-lactic acid
• Occurs in muscle tissue
• Found in sour milk
(-)-lactic acid
• Found in sour milk
Enantiomers and the Tetrahedral Carbon
A molecule of (+)-lactic acid can not superimpose on a
molecule of (-)-lactic acid
Regardless of how the molecules are oriented, they are not
identical
•
•
When the –H and –OH substituents match up, the –CO2H and
the CH3 substituents do not
When –CO2H and the CH3 match up, -H and –OH do not
5.2
The Reason for Handedness in Molecules:
Chirality
Chiral
• From the Greek cheir meaning “hand”
• Molecules that are not identical to their mirror images, and
thus exist in two enantiomeric forms
• A molecule is not chiral if it has a plane of symmetry
Plane of symmetry
• A plane that cuts through the middle of an object (or
molecule) so that one half of the object is a mirror image of
the other half
The Reason for Handedness in Molecules:
Chirality
a)
b)
A laboratory flask has a
plane of symmetry
•
One half of the flask
is a mirror image of
the other half
A hand does not have a
plane of symmetry
•
One half of the hand
is not a mirror image
of the other half
The Reason for Handedness in Molecules:
Chirality
Achiral
• A molecule that has a plane of
symmetry in any of its possible
conformations must be
identical to its mirror image
•
Propanoic acid, CH3CH2CO2H
• Has a plane of symmetry
and so must be achiral
The Reason for Handedness in Molecules:
Chirality
•
Lactic Acid
• Has no plane of
symmetry in any
conformation and is
chiral
The Reason for Handedness in Molecules:
Chirality
Chirality center
• Most common cause of chirality in an organic molecule is
the presence of a carbon atom bonded to four different
groups
•
•
The central carbon atom in 5-bromodecane
Chirality is a property of the entire molecule
The Reason for Handedness in Molecules:
Chirality
Methylcyclohexane
•
Achiral because there is no
carbon atom in the molecule
that is bonded to four
different groups
• Has a plane of symmetry
passing through the methyl
group and through C1 and
C4 of the ring
The Reason for Handedness in Molecules:
Chirality
2-Methylcyclohexanone
•
Chiral because C2 is bonded
to four different groups: a –
CH3 group, an –H atom, a
–COCH2– ring bond (C1) and
a –CH2CH2– ring bond (C3)
• Has no plane of symmetry
The Reason for Handedness in Molecules:
Chirality
• Note: Carbons in –CH2, –CH3, C=O, C=C, and C≡C groups
cannot be chirality centers
• * denotes a chirality center
Worked Example 5.1
Drawing the Three Dimensional Structure of a
Chiral Molecule
Draw the structure of a chiral alcohol.
Worked Example 5.1
Drawing the Three Dimensional Structure of a
Chiral Molecule
Strategy
• An alcohol is a compound that contains the –OH functional
group
• To make an alcohol chiral, we need to have four different
groups bonded to a single carbon atom, say –H, –OH, –
CH3, and –CH2CH3
Worked Example 5.1
Drawing the Three Dimensional Structure of a
Chiral Molecule
Solution
5.3 Optical Activity
Stereochemistry
• Study originated in the early 19th century during the
investigations by the French physicist Jean-Baptiste Biot
into the nature of plane-polarized light
•
A beam of ordinary light consists of electromagnetic waves
that oscillate in an infinite number of planes at right angles to
the direction of light travel
Optically active organic substances
• Biot observed that when a beam of plane-polarized light
passes through a solution of certain organic molecules,
the plane of polarization is rotated
Optical Activity
Polarimeter
• Measures the amount (angle) of rotation
•
•
•
•
•
A solution of optically active organic molecules is placed in a
sample tube
Plane-polarized light is passed through the tube
Rotation of the polarization plane occurs
Light goes through a second polarizer called the analyzer
• The new plane of polarization and degree of rotation can
be found by rotating the analyzer until the light passes
through it
Angle of rotation is denoted a and is expressed in degrees
Optical Activity
Rotation
•
The amount of rotation observed in a polarimetry experiment
depends on the number of optically active molecules
• Number of optically active molecules depends on sample
concentration and sample pathlength
• the pathlength is the length of the sample tube
Assigning direction of rotation
•
Levorotatory molecules
•
•
•
Optically active molecules that rotate polarized light to the left
(counterclockwise)
Given the symbol (-) as in (-)-morphine
Dextrorotatory molecules
•
•
Optically active a molecules that rotate polarized light to the right
(clockwise)
Given the symbol (+) as in (+)-sucrose
Optical Activity
The specific rotation, [a]D
•
•
Optical rotation expression under standard conditions
The observed rotation when light of 589.6 nanometer (nm; 1
nm = 10-9 m) wavelength is used with a sample pathlength l of 1
decimeter (dm; 1 dm = 10cm) and a sample concentration C of 1
g/mL
•
Light of 589.6 nm, sodium D line, is the yellow light emitted from
common sodium lamps
Observedrotation(degrees)
a
[a ]D 

3
Pathlength, l (dm) Concentration,c (g/cm ) l  c
Optical Activity
When optical rotation data are expressed in the standard way the
specific rotation, [a]D , is a physical constant characteristic of a
given optically active compound
• (+)-lactic acid has [a]D = +3.82
• (-)-lactic acid has [a]D = -3.82
•
Two enantiomers rotate the plane-polarized light to exactly the
same extent but in opposite directions
Worked Example 5.2
Calculating an Optical Rotation
A 1.20 g sample of cocaine, [a]D = -16, was dissolved in 7.50
mL of chloroform and placed in a sample tube having a
pathlength of 5.00 cm. What was the observed rotation?
Worked Example 5.2
Calculating an Optical Rotation
Strategy
a
Since [a]D 
l c
T hena  l  c  [a]D
where [a]D = -16
l = 5.00 cm = 0.500 dm
and C = 1.20 g/7.50 mL = 0.160 g/mL
Worked Example 5.2
Calculating an Optical Rotation
Solution
a  l  c [a ]D
a = (0.500) x (0.160) x (-16) = -1.3º
5.4 Pasteur’s Discovery of Enantiomers
Louis Pasteur discovered
enantiomers in 1848 when he
began his study of crystalline
tartaric acid salts derived
from wine
• He observed that two distinct
kinds of crystals precipitated
from a concentrated solution
of ammonium tartrate
• The two kinds of crystals
were mirror images
• Pasteur separated the
crystals into piles of “lefthanded” crystals and “righthanded” crystals
Pasteur’s Discovery of Enantiomers
Solution of ammonium tartrate
• The original mixture, a 50 : 50 mixture of right and left,
was optically inactive
• Solutions of crystals from each of the sorted piles
were optically active
•
Their specific rotations were equal in amount but
opposite in sign
• Enantiomers, also called optical isomers
• Have identical physical properties, such as melting and
boiling point
• Differ in the direction in which their solutions rotate
plane-polarized light
5.5
Sequence Rules for Specifying
Configuration
Configuration
•
The three-dimensional arrangement of substituents
at a chirality center
Sequence rules to specify the configuration of a chirality
center:
Look at the four atoms directly attached to the chirality center
and assign priorities in order of decreasing atomic number
1.
•
•
The atom with the highest atomic number is ranked first; the
atom with the lowest atomic number (usually hydrogen) is ranked
fourth
Heavier isotopes of the same element rank higher than the
lighter isotopes
Sequence Rules for Specifying Configuration
2.
If a decision cannot be reached by ranking the first atoms
in the substituents, look at the second, third, or fourth
atoms outward until a difference is found
Sequence Rules for Specifying Configuration
3.
Multiple-bonded atoms are equivalent to the same
number of single-bonded atoms
Sequence Rules for Specifying Configuration
Sequence Rules for Specifying Configuration
Stereochemical configuration around the carbon
•
Once priorities have been assigned to the four groups attached
to the chiral carbon, orient the molecule so that the group of
lowest priority (4) points directly back
• Look at the three remaining substituents
• R configuration
If a curved arrow drawn from highest to lowest priority (1→2→3)
through substituents is clockwise
S configuration
• If a curved arrow drawn from highest to lowest priority (1→2→3)
through substituents is counterclockwise
•
•
Sequence Rules for Specifying Configuration
Sequence Rules for Specifying Configuration
(-)-Lactic acid
Rule 1
•
-OH has priority 1
-H has priority 4
•
Rule 2
•
-CO2H is higher in priority
than –CH3
•
O (the highest second
atom in –CO2H)
outranks H (the highest
second atom in –CH3)
Sequence Rules for Specifying Configuration
(-)-Glyceraldehyde
• S configuration
(+)-Alanine
• S configuration
Both have the S configuration, although one is levorotatory and the other is
dextrorotatory
•
The sign of optical rotation, (+) or (-) is not directly correlated to the R,S
designation
Sequence Rules for Specifying Configuration
Absolute configuration
• The exact three-dimensional structure of a chiral
molecule
• They are specified verbally by the Cahn-IngoldPrelog R,S convention
• In 1951, an X-ray spectroscopic method for
determining the absolute spatial arrangement of
atoms in a molecule was found
•
Based on these results, it can be said with a
certainty that the R,S conventions are correct
Worked Example 5.3
Assigning Configuration to Chirality Centers
Orient each of the following drawings so that the lowest-priority
group is toward the rear, and then assign R or S
configuration:
Worked Example 5.3
Assigning Configuration to Chirality Centers
Strategy
• Start by indicating where the observer must be
located–180º opposite the lowest-priority group
• Then imagine yourself in the position of the
observer, and redraw what you see
Worked Example 5.3
Assigning Configuration to Chirality Centers
Solution
• In (a) you would be located in front of the page toward the
top right of the molecule, and you would see group 2 to
your left, group 3 to your right, and group 1 below you.
This corresponds to an R configuration
Worked Example 5.3
Assigning Configuration to Chirality Centers
• In (b), you would be located behind the page toward the top
left of the molecule from your point of view, and you would
see group 3 to your left, group 1 to your right, and group 2
below you. This corresponds to an R configuration
Worked Example 5.4
Drawing the Three-Dimensional Structure of an
Enantiomer
Draw the tetrahedral representation of
(R)-2-chlorobutane.
Worked Example 5.4
Drawing the Three-Dimensional Structure of an
Enantiomer
Strategy
• Begin assigning priorities to the four substituents bonded to
the chirality center:
•
(1) –Cl, (2) –CH2CH3, (3) –CH3, (4) –H
• To draw a tetrahedral representation of the molecule, orient
the lowest-priority –H group away from you and imagine that
the other three groups are coming out of the page toward
you
• Place the remaining three substituents such that the
direction of travel 1→2→3 is clockwise (right turn), and tilt
the molecule toward you to bring the rear hydrogen into
view
Worked Example 5.4
Drawing the Three-Dimensional Structure of an
Enantiomer
Solution
5.6 Diastereomers
Molecules with more than one chirality center
• A molecule with n chirality centers can have up to 2n
stereoisomers (although it may have fewer)
• Amino acid threonine (2-amino-3-hydroxybutanoic acid)
CH3CH(OH)CH(NH2)COOH
•
•
Two chirality centers (C2 and C3)
Four possible stereoisomers
Diastereomers
The four stereoisomers of 2-amino-3-hydroxybutanoic acid
Diastereomers
The four stereoisomers of 2-amino-3-hydroxybutanoic acid can
be grouped into two pairs of enantiomers
• The 2R, 3R stereoisomer is the mirror image of 2S, 3S
• The 2R, 3S stereoisomer is the mirror image of 2S, 3R
Diastereomers
• Stereoisomers that are not mirror images
•
•
•
Enantiomers have opposite configurations at all chirality
centers
Diastereomers have opposite configurations at one or more of
the chirality centers but the same configuration at others
2R, 3R stereoisomer and 2R, 3S stereoisomer are
diastereomers because they have the same configuration at
C2 but different configurations at C3.
Diastereomers
• Of the four stereoisomers of threonine, only the 2S,
3R isomer [a]D = -28.3 occurs naturally in plants and
animals and is an essential human nutrient
• Most biological molecules are chiral, and usually only
one stereoisomer is found in nature
Diastereomers
Epimers
• Two diastereomers that differ at only one chirality center but
are the same at all the others
•
Cholestanol and coprostanol are both found in human feces
and both have nine chirality centers
• Eight of the nine chirality centers are identical, but the one at
C5 is different
• Cholestanol and coprostanol are epimeric at C5
5.7 Meso Compounds
Tartaric acid
• A compound with more than one chirality center
Meso Compounds
• 2R, 3R and 2S, 3S structures represent a pair of
enantiomers because they are not identical
• 2R, 3S and 2S, 3R structures are identical
•
•
The molecule has a plane of symmetry
Achiral
Meso Compounds
Meso compounds
• Molecule that are achiral, yet contain chirality centers
• Tartaric acid exists as only three stereoisomers: two
enantiomers and one meso form
Meso Compounds
The (+)- and (-)-tartaric acids
•
Have identical melting points, solubilities, and densities
• Differ in sign of their rotation of plane-polarized light
• The meso isomer is diastereomeric with the (+) and (-) forms
• It has no mirror-image relationship to (+)- and (-)-tartaric acids
• Is a different compound
• Has different physical properties
Worked Example 5.5
Distinguishing Chiral Compounds from Meso
Compounds
Does cis-1,2-dimethylcyclobutane have any chirality centers?
Is it chiral?
Worked Example 5.5
Distinguishing Chiral Compounds from Meso
Compounds
Strategy
• To find a chiral center, look for a carbon atom bonded to
four different groups
• To see whether the molecule is chiral, look for the
presence or absence of a symmetry plane
• Not all molecules with chirality centers are chiral overall –
meso compounds are an exception
Worked Example 5.5
Distinguishing Chiral Compounds from Meso
Compounds
Solution
•
•
A look at the structure of cis-1,2-dimethylcyclobutane show that both
methyl-bearing ring carbons (C1 and C2) are chirality centers
Overall the compound is achiral because there is a symmetry plane
bisecting the ring between C1 and C2
•
Cis-1,2-dimethylcyclobutane is a meso compound
5.8 Racemic Mixtures and the Resolution of
Enantiomers
Racemate or racemic mixture
• Denoted by either the symbol (±) or the prefix d,l to
indicate an equal mixture of dextrorotatory and
levorotatory forms
• Show no optical rotation because the (+) rotation form one
enantiomer exactly cancels the (-) rotation from the other
• Pasteur started with a 50 : 50 mixture of the two chiral
tartaric acid enantiomers
•
He was able to resolve, or separate, the racemic tartaric
acid into its (+) and (-) enantiomers
Racemic Mixtures and the Resolution of
Enantiomers
The most common method of resolution uses an acid-base reaction
between the racemate of a chiral carboxylic acid (RCO2H) and an
amine base (RNH2) to yield an ammonium salt
•
Reaction of the
racemate of a chiral
acid, lactic acid, and
an achiral amine base,
methylamine, CH3NH2
•
The product is an
unresolvable 50 : 50
mixture of
methylammonium (+)lactate and
methylammonium
(-)-lactate
Racemic Mixtures and the Resolution of
Enantiomers
Reaction of the racemate of lactic acid and a single enantiomer of a
chiral amine base (R)-1-phenylethylamine
• (+)- and (-)-lactic acids react with (R)-1-phenylethylamine to give an
R,R ammonium salt and an S,R ammonium salt
•
Ammonium salts are separated as two different diastereomers with
different chemical and physical properties
Worked Example 5.6
Predicting the Chirality of a Product
We’ll see in Section 16.3 that carboxylic acids (RCO2H) react
with alcohols (R′OH) to form esters (RCO2R′). Suppose
that (±)-lactic acid reacts with CH3OH to form the ester,
methyl lactate. What stereochemistry would you expect
the product(s) to have? What is the relationship of the
products?
Worked Example 5.6
Predicting the Chirality of a Product
Solution
• Reaction of a racemic acid with an achiral alcohol such as
methanol yields a racemic mixture of mirror-image
(enantiomeric) products:
5.9 A Review of Isomerism
Isomers are compounds that have the same chemical formula
but different structures
A Brief Review of Isomerism
Two fundamental types of isomers:
1.
Constitutional isomers
•
Compounds whose atoms are connected differently
•
Kinds of constitutional isomers
•
•
•
Skeletal isomers
Functional isomers
Positional isomers
A Brief Review of Isomerism
Stereoisomers
2.
•
Compounds whose atoms are connected in the same
order but with a different geometry
•
Enantiomers
A Brief Review of Isomerism
•
Diastereomers
• Cis-trans isomers are non-mirror-image
stereoisomers
5.10 Chirality at Nitrogen, Phosphorus, and
Sulfur
The most common cause for chirality is the presence of four
different substituents bonded to a tetrahedral atom
•
•
The atom does not necessarily have to be a carbon
A nonbonding pair can be a substituent
•
Nitrogen, phosphorus and sulfur can all be chiral centers
Trivalent nitrogen
compounds
•
Undergo a rapid umbrellalike inversion that
interconverts enantiomers
• Except for in special cases,
individual enantiomers
cannot be isolated
Chirality at Nitrogen, Phosphorus, and Sulfur
Trivalent phosphorus compounds or phosphines
• The inversion at phosphorus is substantially slower than
inversion at nitrogen
• Stable chiral phosphines can be isolated
•
(R)- and (S)-methylpropylphenylphosphine are
configurationally stable at 100 ºC
Chirality at Nitrogen, Phosphorus, and Sulfur
Trivalent sulfur compounds called sulfonium salts (R3S+) can be chiral
• Undergo relatively slow inversions
• Chiral sulfonium salts are configurationally stable and can be isolated
• Coenzyme S-adenosylmethionine is involved in many metabolic
pathways as a source of CH3 groups
• The “S” in S-adenosylmethionine stands for sulfur and means
that the adenosyl group is attached to the sulfur atom of
methionine
• The molecule has (S) stereochemistry at sulfur, its (R)
enantiomer is also known, but has no biological activity
5.11 Prochirality
Prochiral molecule
• A molecule that can be converted from achiral to chiral in a
single chemical step
•
An unsymmetrical ketone, butan-2-one, is prochiral because it
can be converted to the chiral alcohol butan-2-ol by addition
of hydrogen
Prochirality
The enantiomer formed depends upon which face of
the planar sp2-hybridized carbonyl group
undergoes reaction
• The stereochemical descriptors Re and Si are
used to distinguish possibilities
1.
2.
Assign priorities to the three groups attached to the
trigonal, sp2-hybridized carbon
Imagine curved arrow from the highest to secondhighest to third-highest priority substituent
Prochirality
•
•
Re designator is used on the face where the arrows curve
clockwise
• Addition of hydrogen from the Re faces gives (S)-butan-2-ol
Si designator is used to the face where the arrows curve
counterclockwise
• Addition of hydrogen from the Si faces gives (R)-butan-2-ol
Prochirality
Compounds with tetrahedral, sp3-hybridized atoms can also be
prochiral
Prochirality center
• An atom in a compound that can be converted into a chirality center
by changing one of its attached substituents
• An sp3-hybridized atom is a prochirality center if changing one of its
attached groups makes it a chirality center
•
-CH2OH carbon atom
of ethanol
• Changing one of its
attached –H atoms
converts it into a
chirality center
Prochirality
Distinguishing between two identical atoms (or groups) on a
prochirality center
•
Imagine raising the priority of one atom over the other without affecting
its priority with respect to other attached groups
• On the –CH2OH carbon of ethanol, imagine replacing one of the 1H
atoms (protium) by 2H (deuterium)
• The atom whose replacement leads to an R chirality center is
said to be pro-R
• The atom whose replacement leads to an S chirality center is
said to be pro-S
Prochirality
Many biological reactants involve prochiral compounds
• One of the steps in the citric cycle is the addition of H2O to
fumarate to give malate
•
Addition of –OH occurs on the Si face of fumarate and gives
(S)-malate as product
Prochirality
• Alcohol dehydrogenase occurs during the reaction of
ethanol with coenzyme NAD+ catalyzed by yeast
•
Occurs with exclusive removal of the pro-R hydrogen from
ethanol and with addition only to the Re face of NAD+
5.12 Chirality in Nature and Chiral
Environments
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
Chirality in Nature and Chiral Environments
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
The pure S
enantiomer works
well in preventing
migraine
Chirality in Nature and Chiral Environments
To have a biological effect, a substance typically must fit into
an appropriate receptor that has an exactly complementary
shape
• Biological receptors (such as enzymes) are chiral
•
Only one enantiomer of a chiral substrate can fit into the
receptor
• The mirror-image enantiomer (b) will be a misfit
Chirality in Nature and Chiral Environments
The reaction of ethanol with NAD+ catalyzed by yeast alcohol
dehydrogenase
• The reaction occurs with exclusive removal of the pro-R
hydrogen from ethanol and with addition only to the Re face
of NAD+