Chemistry 6, 9 AM section, graphic

Deconstructing Molecules: Cipro

The broad spectrum antibiotic marketed under the name Cipro® was frequently in the news during the fall of 2001 due to its effectiveness against the bacterium that causes anthrax. The active molecule in the commercial tablets of cipro is called ciprofloxacin. It is a medium sized molecule with the empirical formula C17H18FN3O3. Its molecular structure and complete chemical name (what is called the molecule's systematic name) are shown below.

Here, we will deconstruct the molecule: take it apart, analyze its bonding in detail, say as much as we can about its structure locally within the molecule, and try to understand this fairly complicated molecule on a simpler basis.

First, let's deconstruct the systematic name. The numbers in the name refer to a conventional way of finding atoms in the ring structure in the middle of the molecule:

The positions around ring structures are numbered systematically so that the molecular name can indicate what atoms or groups of atoms are bonded to the ring. Here, the convention starts numbering at the unique nitrogen atom in the ring. Note that two carbon atoms are not numbered. They are the two that cannot have anything else bonded to them.

Let's start at position 1, the N atom. The name indicates a "cyclopropyl" group is attached here, and "cyclopropyl" is based on the simplest ring hydrocarbon, cyclopropane, C3H6. Let's deconstruct this molecule. Here is a 3D view of cyclopropane itself with one H atom shaded blue to indicate the position on the cyclopropane ring that, when this H is removed, bonds to N in cipro:

The cyclopropane molecule is a ring of three carbon atoms, each bonded to the other two through s bonds and each bonded to two hydrogens, also through s bonds. Since each C has four sigma bonds, we can say the C atom hybridization is sp3. But the C–C–C bond angle, 60°, is much less than the perfect sp3 tetrahedral bond angle of about 109°. One says that cyclopropane is "highly strained" because the C–C–C bond angles are so small. This strain contributes to cyclopropane's reactivity.

Now let's remove that blue-shaded H in the picture of cyclopropane shown above and attach the cyclopropyl ring to the cipro N at position 1. While we're at it, we'll add the lone pair of electrons on the N atom:

The cyclopropane ring is bonded to the N atom at position 1 through a simple s bond. Adding the lone pair on N shows us that this atom must be sp3 hybridized: it has a steric number of 4. The lone pair occupies one of these four hybrids while the other three form single s bonds to the three surrounding carbon atoms. This tells us that the three C atoms in the cyclopropane ring are not in the same plane as the N atom, and moreover, the N and the three C's bonded to it are also not in the same plane. The atomic geometry around the N must be pyramidal.

The next part of the name simply indicates that a fluorine atom, F, is bonded to carbon number 6:

The fluorine atom at position 6 is bonded to a carbon through a simple single s bond. Adding the lone pairs to the fluorine completes its electron story. Note that we could describe the lone pairs as occupying three of the four sp3 hybrids on F. The fourth sp3 hybrid is used to form the s bond to the carbon.

The next part of the name, 1,4-dihydro, is included for a technical reason of nomenclature that you'll learn about when you take organic chemistry. It would seem to mean that there are hydrogen atoms at positions 1 and 4, but a glance at the structural formula shows that this is not the case. The meaning of this part of the name will not concern us further. Let's move on to the next part, 4-oxo. This indeed signals an oxygen atom bonded to position 4:

The oxygen atom at position 4 is bonded to a carbon through a double bond. Adding the lone pairs to the oxygen completes its electron story. Both the O and the C to which it is bonded are sp2 hybridized. The atomic geometry around C number 4 is roughly trigonal planar; all four atoms shown here lie in the same plane. The lone pairs on O occupy two of the three sp2 hybrids, while the third is used to make the s bond of the double bond to C. The "other" bond in the double bond is a p bond between p orbitals of O and C. Note how this fragment of the molecule looks like formaldehyde, H2CO.

Next in the name is a fairly complicated piece: 7-(1-piperazinyl). This tells us that at position 7, we find a thing called piperazine, C4H10N2, which, in turn, is attached at its 1 position. Here's piperazine itself:

The piperazine molecule is a six-membered ring with N atoms at two opposite corners of the ring. Each N also has one lone pair of electrons (not shown here). These atoms and the four C atoms are all sp3 hybridized, which tells us that the ring is not a flat, planar structure. All the ring bond angles should be close to the tetrahedral angle, 109°, whereas the internal angles of a flat hexagon are all 120°. The positions on the ring are numbered starting with either N, so that in cipro, the notation "7-(1-piperazinyl)" means "take piperazine, pull off one H atom from one of the N atoms, and attach the remaining fragment to the main cipro ring system at its position 7."

Last in the name is "3-quinolinecarboxylic acid." This is a mouthfull. If we break it down, we find that the first part, "quinoline," is the name of the simpler molecule upon which cipro and many other drugs are built. (The molecule quinine, which is used to treat malaria, is one such drug.) Here's quinoline itself:

The quinoline molecule is two fused six-member benzene rings with one C atom and its associated H atom replaced with a N atom and its associated lone pair. Each C atom and the N atom are sp2 hybridized, making the entire molecule planar. Each of these atoms has two single bonds and one double bond, as in the simple picture of bonding in benzene, C6H6, but we know (see page 637 in the text) that the p bonding orbitals in benzene are delocalized around the ring. In quinoline, the delocalization spreads over both rings.

If we contrast the ring bonding structure in quinoline to the ring bonding structure in cipro, we see some surprises, highlighted below in red with the delocalized double bonds in the benzene-like rings shown as red circles to emphasize the delocalization:

Note the changes in the right-hand ring system in cipro: the N at the 1 position has changed from sp2 to sp3 hybridization, and the C at the 4 position (right above the N), while still sp2 hybridized now has its double bond localized outside the ring in cipro rather than delocalized in the ring as in quinoline. (The mysterious "1,4-dihydro" part of cipro's name stems from these changes in bonding.) These changes also force a localized C–C double bond between carbons 2 and 3.

The final part of cipro, the rest of the "3-quinolinecarboxylic acid" part of the name, is the collection of atoms attached at position 3. These atoms, –COOH, are called a carboxyl group, and they represent one of the most important so-called functional groups in all of organic chemistry. Every organic acid has one or more such groups (formic acid, HCOOH, is the simplest), and it is the H atom in this group that provides the acidic proton. Here is that part of cipro in detail:

The carboxylic acid part of the molecule is the –COOH group bonded to ring C atom 3. The brown H atom is the acidic hydrogen that leaves as H+. The O atom bonded to it is sp3 hybridized (two s bonds + two lone pairs). The other two O atoms are sp2 hybridized. When the H+ leaves, the –COO group left behind has an interesting ability to delocalize the C–O p bond. See if you can start with the Lewis structure for formic acid, HCOOH, then remove the acidic proton (the last one), leaving the formate ion, HCOO. Try to draw Lewis resonance structures for this ion. The delocalization is the "superposition" of the resonance structures.

This completes our walk through the molecular structure of cipro. We were able to deconstruct this complicated molecule by carefully walking around from atom to atom, noting the type of hybridization at each atom and the atomic geometries and electron bonding patterns these hybridizations imply. If you would like to read more about Cipro, an 18 page 122 kbyte pdf document from its maker, Bayer, is available.

Go to top