# Organic Chemistry/Chirality

## Introduction

**Chirality** (pronounced kie-RAL-it-tee) is the property of
*handedness*. If you attempt to superimpose your right hand on top of
your left, the two do not match up in the sense that your right hand\'s
thumb overlays your left hand\'s pinky finger. Your two hands cannot be
superimposed identically, despite the fact that your fingers of each
hand are connected in the same way. Any object can have this property,
including molecules.

An object that is **chiral** is an object that can not be superimposed
on its mirror image. Chiral objects don\'t have a *plane of symmetry*.
An achiral object has a plane of symmetry or a rotation-reflection axis,
i.e. reflection gives a rotated version.

**Optical isomers** or **enantiomers** are stereoisomers which exhibit
chirality. Optical isomerism is of interest because of its application
in inorganic chemistry, organic chemistry, physical chemistry,
pharmacology and biochemistry.

They are often formed when asymmetric centers are present, for example,
a carbon with four different groups bonded to it. Every stereocenter in
one enantiomer has the opposite configuration in the other.

When a molecule has more than one source of asymmetry, two optical
isomers may be neither perfect reflections of each other nor
superimposeable: some but not all stereocenters are inverted. These
molecules are an example of **diastereomers**: They are not enantiomers.
Diastereomers seldom have the same physical properties. Sometimes, the
stereocentres are themselves symmetrical. This causes the
counterintuitive situation where two chiral centres may be present but
no isomers result. Such compounds are called **meso compounds**.

!Chiral
relationship.{width="300"}

A mixture of equal amounts of both enantiomers is said to be a **racemic
mixture**.

It is the symmetry of a molecule (or any other object) that determines
whether it is chiral or not. Technically, a molecule is achiral (not
chiral) if and only if it has an axis of improper rotation; that is, an
n-fold rotation (rotation by 360°/n) followed by a reflection in the
plane perpendicular to this axis which maps the molecule onto itself. A
chiral molecule is not necessarily dissymmetric (completely devoid of
symmetry) as it can have, e.g., rotational symmetry. A simplified rule
applies to tetrahedrally-bonded carbon, as shown in the illustration: if
all four substituents are different, the molecule is chiral.

It is important to keep in mind that molecules which are dissolved in
solution or are in the gas phase usually have considerable flexibility
and thus may adopt a variety of different conformations. These various
conformations are themselves almost always chiral. However, when
assessing chirality, one must use a structural picture of the molecule
which corresponds to just one chemical conformation -- the one of lowest
energy.

## Chiral Compounds With Stereocenters

Most commonly, chiral molecules have point chirality, centering around a
single atom, usually carbon, which has four different substituents. The
two enantiomers of such compounds are said to have different absolute
configurations at this center. This center is thus stereogenic (i.e., a
grouping within a molecular entity that may be considered a focus of
stereoisomerism), and is exemplified by the α-carbon of amino acids.

The special nature of carbon, its ability to form four bonds to
different substituents, means that a mirror
image of the carbon with four different bonds will not be the same as
the original compound, no matter how you try to rotate it. Understanding
this is vital because the goal of organic chemistry is understanding how
to use tools to synthesize a compound with the desired chirality,
because a different arrangement may have no effect, or even an undesired
one.

A carbon atom is chiral if it has four different items bonded to it at
the same time. Most often this refers to a carbon with three heteroatoms
and a hydrogen, or two heteroatoms plus a bond to another carbon plus a
bond to a hydrogen atom. It can also refer to a nitrogen atom bonded to
four different types of molecules, if the nitrogen atom is utilizing its
lone pair as a nucleophile. If the nitrogen has only three bonds it is
**not** chiral, because the lone pair of electrons can flip from one
side of the atom to the other spontaneously.

*Any atom in an organic molecule that is bonded to four different types
of atoms or chains of atoms can be considered \"chiral\".*

If a carbon atom (or other type of atom) has four different
substituents, that carbon atom forms a *chiral center* (also known as a
*stereocenter*). Chiral molecules often have one or more stereocenters.
When drawing molecules, stereocenters are usually indicated with an
asterisk near the carbon.

**Example:**


**Left**: The carbon atom has a Cl, a Br, and 2 CH~3~. That\'s only 3
different substituents, which means this is not a stereocenter.\
**Center**: The carbon atom has one ethyl group (CH~2~CH~3~), one methyl
group (CH~3~) and 2 H. This is not a stereocenter.\
**Right**: The carbon atom has a Cl and 1 H. Then you must look around
the ring. Since one side has a double bond and the other doesn\'t, it
means the substituents off that carbon are different. The 4 different
substituents make this carbon a stereocenter and makes the molecule
chiral.

A molecule can have multiple chiral centers without being chiral
overall: It is then called a meso compound. This occurs if there is a
symmetry element (a mirror plane or inversion center) which relates the
chiral centers.

### Fischer projections

Fischer projections (after the German chemist Hermann Emil
Fischer) are an ingenious means for
representing configurations of carbon atoms. Considering the carbon atom
as the center, the bonds which extend towards the viewer are placed
horizontally. Those extending away from the viewer are drawn vertically.
This process, when using the common dash and wedge representations of
bonds, yields what is sometimes referred to as the \"bowtie\" drawing
due to its characteristic shape. This representation is then further
shorthanded as two lines: the horizontal (forward) and the vertical
(back), as showed in the figure below:

!**Principle of Fischer
projection**

#### Operations on Fischer projections

-   *in a Fischer projection, exchange two substituent positions results
    in the inversion of the stereocenter*
-   *rotation by 90° of the Fischer projection results in inversion*
-   *rotation by 180° of the Fischer projection preserves the
    configuration*

## Naming conventions

There are three main systems for describing configuration: the oldest,
the *relative* whose use is now deprecated, and the current, or
*absolute*. The relative configuration description is still used mainly
in glycochemistry. Configuration can also be assigned on the purely
empirical basis of the optical activity.

### By optical activity: (+)- and (-)-

An optical isomer can be named by the direction in which it rotates the
plane of polarized light. If an isomer rotates the plane clockwise as
seen by a viewer towards whom the light is traveling, that isomer is
labeled (+). Its counterpart is labeled (-). The (+) and (-) isomers
have also been termed d- and l-, respectively (for dextrorotatory and
levorotatory). This labeling is easy to confuse with D- and L- and is
therefore not encouraged by IUPAC.

The fact that an enantiomer can rotate polarised light clockwise (*d*-
or *+*- enantiomer) does not relate with the relative configuration (D-
or L-) of it.

### By relative configuration: D- and L-

Fischer, whose research interest was in carbohydrate chemistry, took
glyceraldehyde (the simplest sugar, systematic name
2,3-dihydroxypropanal) as a template chiral molecule and denoted the two
possible configurations with D- and L-, which rotated polarised light
clockwise and counterclockwise, respectively.

!Glycerladehyde, the starting molecule for *relative configuration*
assignent
{width="450"}

All other molecules are assigned the D- or L- configuration if the
chiral centre can be formally obtained from glyceraldehyde by
substitution. For this reason the D- or L- naming scheme is called
*relative configuration*.

+----------------------------------------------------------------------+
|   ---------------------------------------                            |
| ------------------------------------------------ ------------------- |
| -------------------------------------------------------------------- |
|                                                                      |
|                                 D-glyceraldehyde                     |
|                                                     L-glyceraldehyde |
|     !D-glyceraldehyde{width="80"}    !L-glyceraldehy |
| de{width="100"} |
|    !D-glyceraldehyde{width="150"}   !L-glyceraldehyd |
| e{width="150"} |
|     !D-glyceraldehyde{width="150"}      !L-glyceralde |
| hyde{width="150"} |
|   ---------------------------------------                            |
| ------------------------------------------------ ------------------- |
| -------------------------------------------------------------------- |
+----------------------------------------------------------------------+

An optical isomer can be named by the spatial configuration of its
atoms. The D/L system does this by relating the molecule to
glyceraldehyde. Glyceraldehyde is chiral itself, and its two isomers are
labeled D and L. Certain chemical manipulations can be performed on
glyceraldehyde without affecting its configuration, and its historical
use for this purpose (possibly combined with its convenience as one of
the smallest commonly-used chiral molecules) has resulted in its use for
nomenclature. In this system, compounds are named by analogy to
glyceraldehyde, which generally produces unambiguous designations, but
is easiest to see in the small biomolecules similar to glyceraldehyde.

!Optical isomers{width="300"} One
example is the amino acid alanine: alanine has two optical isomers, and
they are labeled according to which isomer of glyceraldehyde they come
from. Glycine, the amino acid derived from glyceraldehyde, incidentally,
does not retain its optical activity, since its central carbon is not
chiral. Alanine, however, is essentially methylated glycine and shows
optical activity.

The D/L labeling is unrelated to (+)/(-); it does not indicate which
enantiomer is dextrorotatory and which is levorotatory. Rather, it says
that the compound\'s stereochemistry is related to that of the
dextrorotatory or levorotatory enantiomer of glyceraldehyde. Nine of the
nineteen L-amino acids commonly found in proteins are dextrorotatory (at
a wavelength of 589 nm), and D-fructose is also referred to as levulose
because it is levorotatory.

The dextrorotatory isomer of glyceraldehyde is in fact the D isomer, but
this was a lucky guess. At the time this system was established, there
was no way to tell which configuration was dextrorotatory. (If the guess
had turned out wrong, the labeling situation would now be even more
confusing.)

A rule of thumb for determining the D/L isomeric form of an amino acid
is the \"CORN\" rule. The groups:

:   COOH, R, NH2 and H (where R is an unnamed carbon chain)

are arranged around the chiral center carbon atom. If these groups are
arranged clockwise around the carbon atom, then it is the L-form. If
counter-clockwise, it is the D-form.This rule only holds when the
hydrogen atom is pointing out of the page.[^1]

### By absolute configuration: R- and S-

Main article: R-S
System

The absolute configuration system stems from the Cahn-Ingold-Prelog
priority rules,
which allow a precise description of a stereocenter without using any
reference compound. In fact the basis is now the atomic number of the
stereocenter substituents.

The R/S system is another way to name an optical isomer by its
configuration, without involving a reference molecule such as
glyceraldehyde. It labels each chiral center R or S according to a
system by which its ligands are each assigned a priority, according to
the Cahn Ingold Prelog priority rules, based on atomic number.

This system labels each chiral center in a molecule (and also has an
extension to chiral molecules not involving chiral centers). It thus has
greater generality than the D/L system, and can label, for example, an
(R,R) isomer versus an (R,S) --- diastereomers.

The R/S system has no fixed relation to the (+)/(-) system. An R isomer
can be either dextrorotatory or levorotatory, depending on its exact
ligands.

The R/S system also has no fixed relation to the D/L system. For
example, one of glyceraldehyde\'s ligands is a hydroxy group, -OH. If a
thiol group, -SH, were swapped in for it, the D/L labeling would, by its
definition, not be affected by the substitution. But this substitution
would invert the molecule\'s R/S labeling, due to the fact that
sulfur\'s atomic number is higher than carbon\'s, whereas oxygen\'s is
lower. \[Note: This seems incorrect. Oxygen has a higher atomic number
than carbon. Sulfur has a higher atomic number than oxygen. The reason
the assignment priorities change in this example is because the CH2SH
group gets a higher priority than the CHO, whereas in glyceraldehyde the
CHO takes priority over the CH2OH.\]

For this reason, the D/L system remains in common use in certain areas,
such as amino acid and carbohydrate chemistry. It is convenient to have
all of the common amino acids of higher organisms labeled the same way.
In D/L, they are all L. In R/S, they are not, conversely, all S --- most
are, but cysteine, for example, is R, again because of sulfur\'s higher
atomic number.

The word "racemic" is derived from the Latin word for grape; the term
having its origins in the work of Louis Pasteur who isolated racemic
tartaric acid from wine.

## Chiral Compounds Without Stereocenters

It is also possible for a molecule to be chiral without having actual
point chirality (stereocenters). Commonly encountered examples include
1,1\'-bi-2-naphthol (BINOL) and 1,3-dichloro-allene which have axial
chirality, and (E)-cyclooctene which has planar chirality.

For example, the isomers which are shown by the following figure are
different. The two isomers cannot convert from one to another
spontaneously because of restriction of rotation of double bonds.\
![](Hexa-3,4-dien-3-ol.png "Hexa-3,4-dien-3-ol.png")\
Other types of chiral compounds without stereocenters (like restriction
of rotation of a single bond because of steric hindrance) also exist.
Consider the following example of the R and S binol molecules:

![]((R)-_and_(S)-BINOL.svg "(R)-_and_(S)-BINOL.svg"){width="200"}

![](Chiral_biphenyl.svg "Chiral_biphenyl.svg"){width="150"}

*The biphenyl C-C bond cannot rotate if the X and Y groups cause steric
hindrance.*

![](Spiroverbindung_Chiralität.svg "Spiroverbindung_Chiralität.svg"){width="200"}

*This compound exhibits spiral chirality.*

## Properties of optical isomers

Enantiomers have -- *when present in a symmetric environment* --
identical chemical and physical properties except for their ability to
rotate plane-polarized light by equal amounts but in opposite
directions. A solution of equal parts of an optically-active isomer and
its enantiomer is known as a racemic solution and has a net rotation of
plane-polarized light of zero.

Enantiomers differ in how they interact with different optical isomers
of other compounds. In nature, most biological compounds (such as amino
acids) occur as single enantiomers. As a result, different enantiomers
of a compound may have substantially different biological effects.
Different enantiomers of the same chiral drug can have very different
pharmological effects, mainly because the proteins they bind to are also
chiral.

For example, spearmint leaves and caraway seeds respectively contain
L-carvone and D-carvone -- enantiomers of carvone. These smell different
to most people because our taste receptors also contain chiral molecules
which behave differently in the presence of different enantiomers.

!Limonene enantiomers have different
smells.{width="300"}

D-form Amino acids tend to taste sweet, whereas L-forms are usually
tasteless. This is again due to our chiral taste molecules. The smells
of oranges and lemons are examples of the D and L enantiomers.

Penicillin\'s activity is stereoselective. The antibiotic only works on
peptide links of D-alanine which occur in the cell walls of bacteria --
but not in humans. The antibiotic can kill only the bacteria, and not
us, because we don\'t have these D-amino acids.

The electric and magnetic fields of polarized light oscillate in a
geometric plane. An axis normal to this plane gives the direction of
energy propagation. Optically active isomers rotate the plane that the
fields oscillate in. The polarized light is actually rotated in a
racemic mixture as well, but it is rotated to the left by one of the two
enantiomers, and to the right by the other, which cancel out to zero net
rotation.

## Chirality in biology

Many biologically-active molecules are chiral, including the
naturally-occurring amino acids (the building blocks of proteins), and
sugars. Interestingly, in biological systems most of these compounds are
of the same chirality: most amino acids are L and sugars are D. The
origin of this homochirality in biology is the subject of much debate.

!Enantiomers of amino
acids.

Chiral objects have different interactions with the two enantiomers of
other chiral objects. Enzymes, which are chiral, often distinguish
between the two enantiomers of a chiral substrate. Imagine an enzyme as
having a glove-like cavity which binds a substrate. If this glove is
right handed, then one enantiomer will fit inside and be bound while the
other enantiomer will have a poor fit and is unlikely to bind.

## Chirality in inorganic chemistry

![\[Ru(2,2\'-bipyridine)~3~\]^2+^](Delta-ruthenium-tris(bipyridine)-cation-3D-balls.png "[Ru(2,2'-bipyridine)3]2+")

Many coordination compounds are chiral; for example the well-known
\[Ru(2,2\'-bipyridine)~3~\]^2+^ complex in which the three bipyridine
ligands adopt a chiral propeller-like arrangement \[7\]. In this case,
the Ru atom may be regarded as a stereogenic centre, with the complex
having point chirality. The two enantiomers of complexes such as
\[Ru(2,2\'-bipyridine)3\]2+ may be designated as Λ (left-handed twist of
the propeller described by the ligands) and Δ (right-handed twist).
Hexol is a chiral cobalt compound.

## More definitions

-   Any non-racemic chiral substance is called **scalemic**
-   A chiral substance is **enantiopure** or **homochiral** when only
    one of two possible enantiomers is present.
-   A chiral substance is **enantioenriched** or **heterochiral** when
    an excess of one enantiomer is present but not to the exclusion of
    the other.
-   **Enantiomeric excess** or **ee** is a measure for how much of one
    enantiomer is present compared to the other. For example, in a
    sample with 40% ee in R, the remaining 60% is racemic with 30% of R
    and 30% of S, so that the total amount of R is 70%.

## Enantiopure preparations

Several strategies exist for the preparation of enantiopure compounds.
The first method is the separation of a racemic mixture into its
isomers. Louis Pasteur in his pioneering work was able to isolate the
isomers of tartaric acid because they crystallize from solution as
crystals with differing symmetry. A less common and more recently
discovered method is by enantiomer self-disproportionation, which is an
advanced technique involving the separation of a primarily racemic
fraction from a nearly enantiopure fraction via column chromatography.

In a non-symmetric environment (such as a biological environment)
enantiomers may react at different speeds with other substances. This is
the basis for *chiral synthesis*, which preserves a molecule\'s desired
chirality by reacting it with or catalyzing it with chiral molecules
capable of maintaining the product\'s chirality in the desired
conformation (using certain chiral molecules to help it keep its
configuration). Other methods also exist and are used by organic
chemists to synthesize only (or maybe only *mostly*) the desired
enantiomer in a given reaction.

## Enantiopure medications

Advances in industrial chemical processes have allowed pharmaceutical
manufacturers to take drugs that were originally marketed in racemic
form and divide them into individual enantiomers, each of which may have
unique properties. For some drugs, such as zopiclone, only one
enantiomer (eszopiclone) is active; the FDA has allowed such
once-generic drugs to be patented and marketed under another name. In
other cases, such as ibuprofen, both enantiomers produce the same
effects. Steroid receptor sites also show stereoisomer specificity.

Examples of racemic mixtures and enantiomers that have been marketed
include:

-   **Ofloxacin** (Floxin) and **Levofloxacin** (Levaquin)
-   **Bupivacaine** (Marcaine) and **Ropivacaine** (Naropin)
-   **Methylphenidate** (Ritalin) and **Dexmethylphenidate** (Focalin)
-   **Cetirizine** (Zyrtec) and **Levocetirizine** (Xyzal)
-   **Albuterol** (Ventolin) and **Levalbuterol** (Xopenex)
-   **Omeprazole** (Prilosec) and **Esomeprazole** (Nexium)
-   **Citalopram** (Celexa / Cipramil) and **Escitalopram** (Lexapro /
    Cipralex)
-   **Zopiclone** (Imovane) and **Eszopiclone** (Lunesta)
-   **Modafinil** (Provigil) and **Armodafinil** (Nuvigil) --- sulfur is
    the chiral center in modafinil, instead of carbon.

Many chiral drugs must be made with high enantiomeric purity due to
potential side-effects of the other enantiomer. (The other enantiomer
may also merely be inactive.)

Consider a racemic sample of thalidomide. One enantiomer was thought to
be effective against morning sickness while the other is now known to be
teratogenic. Unfortunately, in this case administering just one of the
enantiomers to a pregnant patient would still be very dangerous as the
two enantiomers are readily interconverted *in vivo*. Thus, if a person
is given either enantiomer, both the D and L isomers will eventually be
present in the patient\'s serum and so chemical processes may not be
used to mitigate its toxicity.

!Thalidomide
enantiomers.{width="300"}

## See also

Optical
activity


------------------------------------------------------------------------

\<\< Haloalkanes \|
Stereochemistry \| Alcohols


[^1]: <http://www.chemguide.co.uk/organicprops/aminoacids/background.html>
