Isomerism



Isomerism 3359
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The term "isomer" ( iso from the Greek meaning same and meros meaning part) describes the relationship between molecular arrangements that, although differing in chemical or physical properties, have a level of commonality (have the "same parts"). There are two distinct levels of commonality used to describe molecular structure: one that excludes and one that includes three-dimensional considerations. The level of comparison that excludes three-dimensionality is comprised of substances having the same set of atoms but differing in how they are connected. These substances are known as constitutional isomers . The constitution of molecules (number, kind, and connectivity of atoms) may be represented by a two-dimensional "map" in which the interatomic linkages are indicated. There are two constitutional isomers for the molecular formula C 2 H 6 O: ethanol and dimethyl ether. The difference in connectivity, which is not evident in the empirical formula C 2 H 6 O, can be represented by typographical line formulas, CH 3 CH 2 OH for ethanol and CH 3 OCH 3 for dimethyl ether, or in structural representations (see Figure 1). As the number and kind of atoms in substances increases, the number of constitutional isomers increases.

Chemical reactions in which one isomer is converted to another are called isomerizations. An intramolecular Diels–Alder reaction (see Figure 2) is an example of an isomerization reaction in which the level of difference is that of connectivity. An isomerization that involves a rapid equilibrium between connectivities that cannot be easily isolated from one another is called a tautomerization (see Figure 3). Note that the number and kind of atoms remains the same on both sides of the chemical equation, and that there is only one compound involved.

History

The concept of constitutional isomerism was a significant advance in the history of modern chemistry, and especially in the development of organic chemistry. By the late 1700s only a few pure substances had been isolated via the study of "animal" and "vegetable" chemistry, and many of these by a single individual, Carl Wilhelm Scheele (1742–1786). Due to the extensive variety in organic compounds, each new substance presented a new elemental composition, which matched the generalized observation from "mineral" chemistry. As the number of isolated organic compounds increased during the early 1800s, the identification of different substances

Figure 1.
Figure 1.

Figure 2–3.
Figure 2–3.

having the same elemental composition was inevitable. In his 1830 History of Chemistry, Thomas Thomson wrote (p. 302) that "[Berzelius] applied the [atomic] theory also to the vegetable kingdom by analyzing several of the vegetable acids, and showing their atomic constitution. But here a difficulty occurs, which in the present state of our knowledge, we are unable to surmount. There are two acids…that are composed of exactly the same kind of atoms.…Now how are we to account for this [striking difference inproperties]? Undoubtably by the different ways in which the atoms are arranged in each." Thomson then drew different arrangements (on paper) of the atomic symbols used at the time (those of John Dalton), as a way to explain why two acids with the same elemental composition could have different physical and chemical properties.

Up until the early nineteenth century, it was generally believed that those chemical substances found in living organisms possessed a particular vital force associated with living things, and that these substances required living systems in order to be produced. The belief was that nowhere else in nature except in living systems could one find these compounds. Friedrich Wöhler (1800–1882) is universally credited with the observation of isomerization that led to the decline of the idea of vitalism. In 1828 Wöhler synthesized a sample of urea, (NH 2 ) 2 C=O (also CH 4 N 2 O), that was

Figure 4. Constitutional isomers for C4H10 and C4H10O.
Figure 4. Constitutional isomers for C 4 H 10 and C 4 H 10 O.

indistinguishable from the urea isolated from urine. He prepared this "animal" substance from the clearly inorganic (mineralogical) starting material ammonium cyanate, NH 4 (+)NCO(−) (also CH 4 N 2 O), which results from combining ammonium chloride and silver cyanate. In The Development of Modern Chemistry, Aaron J. Ihde (p. 165) points out that the preparation of urea from inorganic starting materials had been conducted earlier, by both Wöhler, in 1824, and Humphry Davy, in 1811, but that their achievements were not recognized for what they were at the time. The concept of isomerism is central to structural chemistry, and this concept is beautifully encapsulated in the title of a book by Nobel laureate Roald Hoffmann, The Same and Not the Same.

Figure 5.
Figure 5.

Nomenclature

The early development of a systematic nomenclature for organic compounds reflected structural isomeric relationships. A few of the terms have persisted: "normal" or "n-" to indicate a straight chain of atoms; "iso" as a prefix derived from the word "isomer" to indicate the attachment of a methyl group on the penultimate carbon of a straight chain; "tertiary," "tert-," or "t-" to indicate an arrangement in which three alkyl groups are attached to a common site; and "secondary" or "sec-" to indicate that there are two alkyl groups. Examples of common usage are provided in Figure 4 (the contemporary standard usage is included parenthetically).

Stereoisomerism

The second level of isomeric comparison includes substances that have the same connectivity but differ in their three-dimensional geometrical arrangements. The study of the resulting relationships is called stereochemistry. Two categories exist for comparing different three-dimensional geometries: configuration and conformation. Because there is an empirical component to these terms, a universally unambiguous distinction between configurational stereoisomers (sometimes simply referred to as stereoisomers) and conformational stereoisomers (sometimes simply referred to as conformations or conformers) has not emerged. There is a general understanding, however, that stereoisomers are geometrical forms that are distinct enough to be isolated under normal conditions, whereas conformers are geometrical forms that interconvert under the same conditions. Some examples will help to clarify this distinction. Tetravalent atoms bearing four different atoms or atomic groupings can occur in two different geometrical forms. The carbon atom with the OH group in 2-butanol (see Figure 4) demonstrates this. The two (and only two) different arrangements of 2-butanol are shown in Figure 5. Both of these molecules have the 2-butanol connectivity, but their three-dimensionality must be additionally labeled in order to give these two different molecules different names. Using a system that is based on assigning

Figure 6.
Figure 6.

Figure 7. Schematic relationship between isomers.
Figure 7. Schematic relationship between isomers.

priorities to the four different groups, called the Cahn–Ingold–Prelog rules, one of two unique geometrical labels, namely "R" or "S," can be assigned to the three-dimensional geometry of such an atom. "R" and "S" come from the Latin terms rectus and sinester, meaning "to the right" and "to the left," respectively.

The greater the number of these tetrahedral centers with four different groups that there are in a molecule, the greater the number of stereoisomers. For the most part, this is a simple exercise in probability and statistics. With two such centers, there are four stereoisomers possible (2 geometries at the one center × 2 at the second = 4), and with three such centers there are eight stereoisomers (2 × 2 × 2 = 8).

There are other molecular subunits that can give rise to stereoisomers. Double bonds that bear different groups at both ends, for example, give rise to two distinctly different stereoisomers that do not easily interconvert under normal conditions. Using the Cahn–Ingold–Prelog rules once again, geometrical labels of "E" and "Z" can be assigned to these geometrical arrangements. "E" and "Z" come from the German terms entgegen and zusammen, meaning "apart" and "together," respect ively. In some cases, in which there is one hydrogen atom at each end, the labels "cis" and "trans" may also be used (see Figure 6).

Figure 8.
Figure 8.

Figure 9. Conformational changes.
Figure 9. Conformational changes.

Stereoisomers: Enantiomers and Diastereomers

The two categories into which stereoisomers can be placed are absolutely distinctive in definition. Two stereoisomers that are nonsuperimposable mirror images are called enantiomers. The only other category is defined negatively. Stereoisomers that are not enantiomers are called diastereomers. (See Figure 7.)

Molecules with a single stereocenter as the only source of configurational stereoisomerism can exist as one of two enantiomers; no configurational diastereomers are possible. Molecules with two dissimilar stereocenters can exist as one of four stereoisomers. Figure 8 outlines the relationships among these four stereoisomers.

Conformers

According to Ernest L. Eliel and Samuel H. Wilen in Stereochemistry of Organic Compounds (1994, p. 102), configurational stereoisomers result from "arrangments of atoms in space of a molecule with a defined constitution without regard to arrangements that differ only by rotation about one or

Figure 10.
Figure 10.

Figure 11. The chemistry of amide bonds involves restricted rotation.
Figure 11. The chemistry of amide bonds involves restricted rotation.

more single bonds, providing that such a rotation is so fast as not to allow isolation of the species so differing." Conformational stereoisomers are then taken to be the result of such single bond rotations. Every single bond that has atoms with some identifiable geometry exists in a full range of molecular geometrical shapes based on rotation around that bond. Some examples are shown in Figure 9. In the first example, the bond rotation of the central bond of butane creates a series of molecular geometries that cannot be isolated or separated from each other. On the other hand, the Eliel and Wilen definition is well illustrated by the second example. The single bond between the two benzene rings has undergone only a 180° rotation in defining the relationship between the two structures (a conformational change), yet this creates two different molecules (stereoisomers), because under normal conditions these two molecular geometries are not easily interconverted, and these two represent separable molecules. It is not easy to predict when two separable molecules are going to be possible; it is determined empirically.

The effects of the overall molecular geometry of a molecule were recognized as contributing to chemical reactivity in the 1950s. Substituted cyclohexanes were among the first systems that could be explained by conformational analysis. These structural units appear in many different (and biologically significant) molecules. Methylcyclohexane, for example, exists as a roughly 95:5 mixture of two forms differing in stability based on the bad collisional interaction that exists for the methyl group when it lies closer to the rest of the ring. Notice how this molecular shape, called a chair

Figure 12.
Figure 12.

Figure 13.
Figure 13.

conformation , recurs in the more complex cholesterol molecule (see Figure 10).

Rotamers

In general, single bonds can undergo free rotation, while double bonds cannot. Because of the resonance phenomenon, some bonds have character that puts them partially between single and double bonding. Sometimes the partial double bond is strong enough to prevent fast bond rotation but weak enough to permit both possible geometrical isomers to be present. The amide functional group , which in biochemistry is called the peptide bond in proteins, demonstrates this property (see Figure 11).

Regioisomers

Another type of isomerism is produced as a result of the different outcomes of chemical reactions in which there are different orientations or sites to choose from. For example, when addition reactions between unsymmetrical reagents and unsymmetrical double or triple bonds occur, two outcomes are possible. As part of the original observations of this chemistry, wherein one of the atoms added was a hydrogen and the other was some distinctive, nonhydrogen atom, the placement of this distinctive atom was said to occur at one region or other of the molecule, hence the formation of regioisomers (see Figure 12). Based on the mechanism of the chemical reaction, the selectivity for one of these regioisomers forming faster than the other can be predicted. With the addition of simple mineral acids, for example, the product derived from a faster protonation giving a more stable intermediate is referred to as the Markovnikov regioselectivity, after the nineteenth-century Russian chemist who made the observations (see Figure 12).

Regioselectivity in the formation of regioisomers is also observed in electrophilic aromatic substitution reactions. In the case of monosubstituted benzene derivatives, there are three possible regiosomeric products that form at different rates, based on the mechanism of the reaction (see Figure 13).

SEE ALSO Berzelius, JÖns Jakob ; Chirality ; Dalton, John ; Davy, Humphry ; Molecular Structure ; Scheele, Carl ; WÖhler, Friedrich .

Brian P. Coppola

Bibliography

Eliel, Ernest L., and Wilen, Samuel H. (1994). Stereochemistry of Organic Compounds. New York: Wiley.

Hoffmann, Roald (1995). The Same and Not the Same. New York: Columbia University Press.

Ihde, Aaron J. (1964). The Development of Modern Chemistry. New York: Harper & Row.

Thomson, Thomas (1830). The History of Chemistry. London: Colburn and Bentley.



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