There is a strange, fairytale beauty to enantiomers, those evocative “mirror, mirror” molecules so nearly alike in appearance yet sometimes so dissimilar in significance: differences that reveal themselves in pharmacological activity, scent variation, and that fascinating ability to rotate a plane of polarized light in a certain direction. To study them is to bravely follow Alice through the looking-glass into a curiouser and curiouser world where a “mere” alteration in spatial position manages to simultaneously provide elegant answers to the riddles of the past while posing innumerable new conundrums for the seekers of the present.
What is an Enantiomer?
Also known as optical isomers, antipodes, or enantiomorphs, enantiomers are stereoisomers. They have the same number and type of atoms and bonds, but possess one or more chiral centers where an atom is covalently bonded to four different functional groups. These four groups are arranged differently in space around the chiral center(s) of each enantiomer in such a way so as to make them mirror images that cannot be superimposed on one another. Human hands exhibit that same peculiar property; thus the word “chiral” was taken from the Greek word meaning “hand.”
When the three heaviest functional groups are arranged around the chiral center from heaviest to lightest in a clockwise fashion, the stereoisomer is designated R (from the Latin rectus for right). Counterclockwise arrangement yields the S enantiomer (sinister for left). Although they generally exhibit the same physical properties, their asymmetry gives enantiomers an interesting variation in optical activity: One of them will rotate a plane of polarized light (light that vibrates in a single plane) to the left (named levorotatory, and designated by a minus sign in front of the isomer’s name), while the other will rotate it in an equal amount to the right (dextrorotatory, indicated by a plus sign). To add to the fun, there is no correlation between S and R and levo- and dextro- rotation. An S enantiomer can merrily rotate light to the right, and vice versa.
If equal amounts of R and S isomers are present, the result is known as a racemic mixture, named after racemic acid (a 1:1 mixture of tartaric acid and its nonsuperimposable mirror image). Racemic mixtures do not exhibit optical activity, as they rotate plane-polarized light to the right and left equally, cancelling out each enantiomer’s effect. Louis Pasteur was the first scientist to figure this out; he actually separated left- and right-handed tartaric acid salt crystals using a pair of tweezers!
Once the first-year Organic Chemistry student plays around with a molecular model set long enough, she should grasp the basic concepts of enantiomers and chirality. Hopefully, that’s just the first step in the journey, for enantiomers have amazing and appalling stories to tell. An enantiomer or its not-quite-twin may be responsible for a drug’s distressing or pleasingly consciousness-altering side effects, for blessed relief from infection or pain, for a subtle or spectacular note of glory in a well-crafted perfume, or the unrelenting horror of a severely malformed fetus.
Enantiomers in Drugs
In nature, one enantiomer may be the only form available or useful (e.g., D-glucose, L-ascorbic acid, L-amino acids), but in the lab all bets are off. Many drugs are synthesized and marketed as racemic mixtures.
The introduction of chirality may increase a molecule’s usefulness. Penicillin is not chiral, but ampicillin’s extra amine group gives it that quality, and it can kill bacteria that have developed a resistance to penicillin.
Sometimes one enantiomer is a harmful substance, the other relatively innocuous. The S form of methamphetamine is a government-controlled isomer; as useful as it is to the narcoleptic, it is too dangerous a stimulant to ever be readily available (legally, that is) again. The synthetic analgesic methadone, which was supposed to wean addicts off heroin, but too-often ended up a drug of abuse itself, also exists as enantiomers, with the R form being the active isomer.
With ketamine, the S isomer is an effective anesthesia; the R causes much the same wildly aroused behavior as PCP. Methyldopa, a treatment for high blood pressure, “owes its efficacy to the S enantiomer alone.”
In the well-known case of thalidomide, the R isomer proved an effective sedative. The S form’s sinister designation was sadly appropriate, as it turned out to be teratogenic, causing terrible birth defects including the rare (normally occurring in 1 out of 4 million births) malformation called phocomelia, where the infant’s hands and feet are attached directly to the shoulders and hips. 8000 children suffered this fate before thalidomide was taken off the market. Chemistry Nobel Prize winner Roald Hoffman points out that “the ‘harmless’ enantiomer converts into the ‘harmful’ one under physiological conditions,” so even selling pure R alone may not have prevented this tragedy.
Quite a few of the old witch’s Sabbat drugs in mandrake, nightshade, and other alkaloid-based brews were enantiomers, too. Tales of dancing with the devil and flying on broomsticks are probably attributable to the delirium caused by these substances. Modern derivatives include atropine (S isomer is more active), which dilates the eyes for surgery and can counter the effects of the deadly nerve gas, sarin, which itself happens to be S chiral around a phosphorus atom; and the “twilight sleep” anesthetic, scopolamine, which some say acts as a “truth serum.”
Enantiomers in Perfumes
17% of enantiomers do not smell the same, while 64% have identical or extremely similar odors. The rest are still to be classified. Some enantiomers alter the intensity of the scent notes: Carvone’s levorotatory isomer shouts green mint and whispers caraway, while the dextrorotatory version gives a positive blare of caraway and a muted murmur of mint. Other enantiomers have completely different odors, at least to the untrained nose. The dextro- form of citronellol is redolent of citronella, while its mirror image gives a pleasingly earthy scent reminiscent of geranium. R-gamma-ionone smells like metallic pineapple with a woody undertone; S-gamma-ionone has a much more pleasant floral/green/woody aroma.
Insects that react to chiral pheromones much prefer one enantiomer over the other; for gypsy moths, the dextrorotary isomer from Atta texana possesses about 400 times more powerful an allure than does the levo-. The male moth can detect a few hundred molecules from three miles away! It is still not known whether humans really unconsciously react to a sex pheromone; but if they do, it’s a good bet that one enantiomer of it will make an enticing, upscale-cosmetics-counter perfume, and the other create pretty much a complete bargain-basement dud.
Of course, some will argue that perfumes are scarcely as important as pharmaceuticals, yet the art/science of perfume-blending has been diligently practiced for millennia. In ancient Athens the perfumery was a thriving social hub, and distinct scents were purchased for wear on specific parts of the body. Centuries-old alchemy texts and even the Bible are replete with references to expensive perfumes that no doubt included a healthy percentage of right- and left-handed molecules.
In fact, a perfumer-poet wishing to pen a verse in praise of enantiomers might do worse than to reinterpret Psalms 145:16: “[Such chiral molecules] open [their] hand, satisfying the desire of every living thing.” After all, most cultures, while certainly needing efficacious medicines for the body, have prized and desired precious scents for reasons perhaps obscure to the mind but perfectly obvious to the spirit. So even if the mechanisms of the physical world did not so often depend upon the handy “handed” molecule, the innermost workings of the will would be a much bleaker place without them.