Crystal X-ray diffraction is the principal tool for the study of the atomic and molecular structure of matter. Thanks to this technique we are able to understand the molecules of medicines, minerals, synthetic and natural materials, and also the structure of the macromolecules that are integral to life – nucleic acids, proteins and carbohydrates. This information helps us to understand how, for example, medicines work and how to improve them.
Would you like to know what the fundamentals of diffraction are? Have you heard about the large synchrotron facilities? Do you know how an antibiotic is designed?
Today we know the molecular structure of medicines in detail, from everyday aspirin to the modern drugs designed to combat AIDS: a carbon atom here, here and, at this distance, another; and this oxygen atom is to its left rotating 112º, etc. Thus we can build models of molecules just as we build scale models of ships and aeroplanes. This structural information at atomic level revolutionised mineralogy, chemistry, pharmacology, biochemistry, medicine and materials science forever. Such valuable information we owe to crystallography.
The power of the new technique of X-ray diffraction by crystals to reveal the structure of minerals astonished the scientific world. It was hugely important information for understanding the properties of minerals, the reactivity of chemical compounds and ultimately for relating the structure of pharmacological compounds with their therapeutic properties, and the structure of biological molecules with the function they carry out in the organism.
X-ray diffraction thus became the most powerful “microscope” available to science, the only one capable of seeing the molecular structure of crystals. It was obviously essential to have crystals of the compound. First minerals were used, the crystals provided by nature. By the end of the 1920s the structure of sulphides, garnets and silicates had been established, compounds with few different atoms. And the structures of important metal alloys were also discovered.
|A garnet||and it crystalline structure|
Soon they began to study compounds that had to be crystallized. The first organic compound whose structure was resolved by X-ray diffraction was hexamethylenetetramine. Obviously it was a simple structure with four nitrogen atoms (in blue), six carbon (in black) and twelve hydrogen (in grey).
It became an irrepressible challenge to resolve more and more complex and more interesting molecule structures. Dorothy Hodgkin stood out for determining the three-dimensional structure of the first compounds of biochemical interest, such as cholesterol in 1937, penicillin in 1945, vitamin B12 in 1954 and insulin in 1969. In 1964 she received the Nobel Prize for her research.
|Model of the structure of penicillin carried out by Dorothy Hodgkin.||The molecular structure of penicillin. Each colour represents a type of atom: green for carbon, red for oxygen, white for hydrogen, blue for nitrogen and yellow for sulphur.|
In 1925 Louis de Broglie received the Nobel Prize for Physics for his discovery of the wave nature of electrons. The idea of using them in diffraction, complementing X-rays, was established. Soon it was discovered that electron beams are also diffracted by crystals. The physics on which this diffraction is based is different to that of X-rays, but the pattern that the diffracted beams produce are the same and are interpreted in the same way. Clinton Joseph Davisson and George Paget Thomson received the Nobel Prize for Physics in 1937 due to this discovery.
|Louis de Broglie||Electron diffraction diagrams|
Plus ultra. Always onwards, always further. More complex structures, larger and with a greater number of different atoms; but there was an obstacle to completely understanding all the information that those black stains distributed harmoniously on the photographic plate contained that seemed insurmountable. It was called the phase problem.
The molecular information was there, in those spots, from whose size and blackness we could obtain the intensity, that is the amplitude, but not the other information that a wave contains, the phase. It was like recomposing a symphony from a score in which the bar numeration is missing, so it is impossible to synchronize the piano with the strings, within which each of the violins, violas and cellos are also “out of phase”… We can only appreciate the symphony when we “align” the scores in time, in other words, when we put them “in phase”.
For a long time the problem was considered not just difficult but insoluble. However, Herbert Hauptman and Jerome Karle succeeded in finding the equations that unravelled it and the method to resolve them directly. And it was Isabella Karle who converted these ideas into experimental protocol. Thus they made the tool available that enabled chemists and biochemists to dream of understanding reactions and life at molecular level: the determination of the real structure of molecules. For this admirable contribution to what were called the direct methods of structure solution, Herbert Hauptman and Jerome Karle received the Nobel Prize for Chemistry in 1985.
|Jerome and Isabella Karle||Herbert Hauptman|
|Fluoxetine (known as Prozac, its first commercial name) is an antidepressant used for treating major depressive disorders, bipolar disorder, obsessive-compulsive disorder, and bulimia nervosa. In 2012 it was discovered that it is also a powerful antiviral.||
Acetylsalicylic acid, popularly known as aspirin, is a drug from the salicylate family, used frequently as an anti-inflammatory and painkiller. Its worldwide consumption is around 25 million kilos a year. Yet its spatial arrangement, as shown in the figure, was not discovered until 1964. The molecule is formed by nine carbon atoms (in black), eight hydrogen (in grey) and four oxygen (in red).