Research: Science and Education
The Meaning of Meso Addison Ault Department of Chemistry, Cornell College, Mount Vernon, IA 52314;
[email protected] The recent article by Leroy G. Wade, Jr., “Precision in Stereochemical Terminology” (1), is a welcome review of several fundamental stereochemical concepts. It does, however, inspire me to offer further comments on the meaning of the word meso. The Isomeric Tartaric Acids Beilstein (2) has four entries for molecular formula C4H6O6, butandiol-(2,3)-disauren, Weinsäuren. They are
toward theoretical, or structural, definitions. Wade presented three definitions of this type in his article (1): (i) “achiral compounds with asymmetric carbons”, (ii) “achiral compounds with chirality centers”, and (iii) “achiral compounds with chiral diastereomers”. Unfortunately, since the molecules of most meso compounds, including meso-tartaric acid, are racemic mixtures of chiral conformational isomers, none of these three definitions is a true description of the molecules. Wheland was aware of this and stated (4): In a sense, therefore, meso-tartaric acid is really a racemic modification in which the two [conformational enantiomers] are interconverted so easily that they cannot be separated.
(a) Rechtsdrehende Weinsäure, Rechtsweinsäure, d-Weinsäure, gewöhnlich “Weinsäure”, and Acidum tartaricum. (b) Linksdrehende Weinsäure, Linksweinsäure, and l-Weinsäure. (c) Inactive spaltbare Weinsäure, Weinsäure, dl-Weinsäure, Traubensäure, Para-weinsäure, and Acidum racemicum. (d) Inactive nichtspaltbare Weinsäure, Weinsäure, Mesoweinsäure, and Antiweinsäure.
Entries (a) and (b) refer to the enantiomeric forms of tartaric acid. They each melt at 187 °C. Entry (c) refers to the optically inactive form, equimolar mixture of (a) and (b), that is, spaltbare (separable, resolvable). This racemic compound, or racemate, melts at 206 °C. Entry (d) refers to the optically inactive form (a pure substance), that is, nichspaltbare (not separable, not resolvable). This pure substance melts at 143 °C. The prefix meso is still used to refer to this isomer of tartaric acid, the pure substance that is not optically active. The Original Meaning of Meso
The Heart of the Problem The reason that it is hard to develop a structural definition for the word meso is that there are several different structural reasons for the existence of meso isomers. There may be some meso isomers, such as the cis form of 1,2-dichlorocyclopropane Cl
for which one imagines molecules that are truly achiral because they contain a plane of symmetry. There are other meso isomers, however, such as the cis form of 1,2-dichlorocyclohexane Cl
A corresponding definition of meso would be A meso compound is an optically inactive member of a set of stereoisomers, some of which are optically active.
An alternative definition would be A meso compound is an optically inactive member of a set of stereoisomers, at least two of which are optically active.
The alternative version is two words longer than the first version, but it is also slightly more specific. The Evolving Meaning of Meso More recent definitions of meso have moved away from purely experimental definitions, such as the two just presented,
Cl Cl
Wheland, in Advanced Organic Chemistry (3), described meso forms in this way: As with the tartaric acids, it frequently happens that a set of stereoisomers contains both optically active and optically inactive members. The inactive members of such sets are frequently distinguished from their active isomers by being called meso forms. This is, of course, the significance of the name ‘meso-tartaric acid’.
Cl
Cl
for which one must imagine the presence of a racemic mixture of rapidly interconverting conformational enantiomers that cannot be separated at room temperature. This second possibility is by far the most common reason for the existence of a meso isomer. The Isomeric Cyclooctenes In the beginning there was only one cyclooctene, and it was cis. Then, in 1949, the trans isomer was prepared and recognized.
H
H H
H
pair of enantiomers
Although even at that time the possibility of resolving the trans isomer was appreciated, it was not until 1962 that the separation was accomplished. There are now three isomeric cyclooctenes: a pair of enantiomers and a meso form. The cis isomer has become
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a meso form. The nature of the cis isomer has not changed, but its status within the set of isomers is different. We might now inquire into the reason for the lack of optical activity of the cis, or meso, form of cyclooctene. It is unlikely that the meso form has a plane of symmetry. It is most likely that the meso form is a racemic mixture of rapidly interconverting conformational enantiomers. Furthermore, it is quite likely that all the molecules, all the time, are chiral. As Mislow has pointed out, and proven by a suitable example, “racemization may proceed through intermediates or transition states which do not possess reflection symmetry” (italics in the original) (5). We wait now for a clever experimentalist to isolate, at a lower temperature, the conformational enantiomers of cis-cyclooctene. There will then be four stereoisomeric forms, two pairs of enantiomers. All of this without a change in structure. The Isomeric 4,12-Dibromo-[2.2]-paracyclophanes A final example is the stereoisomeric forms of 4,12-dibromo-[2.2]-paracyclophane. Br
Br
Br
Br
Br pair of enantiomers
Br meso form
There are, again, three stereoisomeric forms of this compound: a pair of enantiomers and a meso form. Both the pair of enantiomers, as the racemic mixture, and the meso form were prepared by Reich and Cram (6). Reich and Cram also reported that both the pure racemate and the pure meso form can be thermally converted to the same mixture of racemate and meso form, indicating that all three forms are conformational isomers of one another. More recently, kinetic resolution has produced a sample of the (R) enantiomer (left enantiomer) with an enantiomeric purity of greater than 99.9% (7). The indications are clear: the term meso, from the beginning, refers to a relationship within a set of stereoisomers. Efforts to redefine meso in structural terms have not been successful and will probably never be successful. Consider the last example. There are no stereogenic atoms in the molecule, yet it can exist in three stereoisomeric forms. The Bottom Line The word meso should be used to indicate a relationship, not particular structural features. The meso relationship is “An optically inactive member of a set of stereoisomers, at least two of which are optically active.” Pedagogy When I teach structure in first-semester organic chemistry, I present the subject as the four C’s of structure: composition, constitution, configuration, and conformation.
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Composition Composition is a representation of the number of each kind of atom in a substance; it is the molecular formula. Constitution Constitution is a representation of the connectivity of the atoms of the substance. We allow students to believe that constitution is fixed even though we are aware of exceptions such as bullvalene (8). The level of skill we expect at this point is some ability to enumerate and represent, by figure and name, all possible constitutional isomers for a given composition. Configuration Configuration is a representation of the “permanent” shape of the molecules of a substance. I use this quotation from Wislicenus, 1869, as a preface: This is the first definitely verified case [the lactic acids] in which the number of isomers can exceed the constitutional possibilities. Facts such as these will force us to explain differences between isomeric molecules with the same constitutional formula by different arrangements of these atoms in space, and to look for definite ideas on these arrangements.
The points I make about configuration are that tetravalent carbon is tetrahedral, trivalent carbon is trigonal, and divalent carbon is linear. I also present Pasteur’s conception of the possibility of molecular handedness through his connecting handed (chiral) crystals to optical activity (9). The level of skill that we expect at this point is some ability to enumerate and represent, by figure and name, all possible configurations for a given constitution. To help students do this we introduce the concept of “stereogenic features”. We start with “chiral stereocenters on carbon” and continue later with “stereogenic carbon–carbon double bonds”. We point out that when a molecule has only one stereogenic feature, either one, the substance can exist in exactly two stereoisomeric forms. In the case of one chiral stereocenter on carbon the two forms will have the enantiomeric relationship. In the case of one stereogenic carbon–carbon double bond the two forms will have the diastereomeric relationship. We emphasize that these are the only possible stereoisomeric relationships other than identity. We then move on to two chiral stereocenters, differently substituted, and persuade everyone that there now can exist four stereoisomeric forms: two pairs of optically active enantiomers. If, however, the two chiral stereocenters are similarly substituted, as they are in tartaric acid, there can exist only three stereoisomeric forms: one pair of optically active enantiomers, and one stereoisomer that is not optically active. This is the point at which I present the definition of meso: “An optically inactive member of a set of stereoisomers, at least two of which are optically active.” Conformation Conformation is a representation of the “temporary” shape of a molecule of a substance. I introduce this term when we see that physical models of molecules are “floppy”. At that time I tell the students that real molecules, as well as models of molecules, are floppy, but that temporarily ignoring “floppiness”, or confor-
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Research: Science and Education
mational isomerism, will not affect our conclusions about stereochemical relationships. I tell them that we are free to choose favorable conformations when we want to determine relationships between the members of a set of stereoisomers. This helps greatly in the identification of members of sets of stereoisomers that contain a meso form (identical to its mirror image) as well as a pair of enantiomers (non-identical mirror images). A shortcut, of course, to the identification of a meso form is to find within a molecule an achievable conformation that has a plane (or center) of symmetry. A Word of Caution For this presentation to be effective, however, we must be sure to distinguish between optical activity (an experimental observation) and chirality (a theoretical construct). If we do not make this distinction we might hear ourselves saying that meso tartaric acid is not optically active because its molecules are not chiral. We realize, and might point out to students, that when the conformationally mobile molecules of a substance can achieve a conformation that has a plane (or center) of symmetry it necessarily follows that the molecules of the substance will be present mainly as equimolar mixtures of conformational enantiomers; that is, the substance will not be optically active. While we may be aware of exceptions to general statements presented above it might be better not mention all them to students who are only starting their study of organic chemistry. While we know that it is not true that the molecules of every substance have a fixed connectivity, we do not have to tell the students about, for example, bullvalene at this time. Nor do we need to mention the possibility that a chiral tetravalent carbon may racemize over geologic time, thus blurring the distinction between “permanent” and “temporary” configuration.
While it is also true that the distinction between “permanent” and “temporary” configuration is easily blurred by changes in temperature, we can save until later examples of this such as the temperature dependence of the proton NMR spectra of N,N-dimethylformamide and cyclohexane-d11 or the fact that the equatorial form of chlorocyclohexane can be crystallized from solution at ‒150 °C, isolated, redissolved, and studied spectrometrically for hours at ‒150 °C with no apparent change. More interesting phenomena that can be saved for later are the fact that butane, for example, has an appreciable population of a variety of racemic conformational enantiomers, and the fact that an S4 or higher improper axis of rotation is yet another indicator of a non-chiral species. We also might not hurry to mention that it is not a requirement that racemization pass through an intermediate that has reflection symmetry. Literature Cited 1. Wade, L. G., Jr. J. Chem. Educ. 2006, 83, 1793–1974. 2. Beilsteins Handbuch der Organischen Chemie, Dritter Band, Vierte Auflage; Edwards Brothers, Inc.: Ann Arbor, MI, 1943; pp 481, 520, 522, 528. 3. Wheland, G. W. Advanced Organic Chemistry, 2nd ed.; John Wiley & Sons, Inc.: New York, 1949; p 156. 4. Wheland, G. W. Advanced Organic Chemistry, 2nd ed.; John Wiley & Sons, Inc.: New York, 1949; p 192. 5. Mislow, K. Introduction to Stereochemistry; W. A. Benjamin, Inc.: New York, 1966; p 93. 6. Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3527. 7. Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. J. Org. Chem. 1997, 62, 6462–6463. 8. Ault, A. J. Chem. Educ. 2001, 78, 924–927. 9. Ault, A. Educ. Chem. 2005, 42, 66.
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