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Chemistry 1874

Structural Formulae in Space

J. H. van 't Hoff

Carbon's four bonds point to the corners of a tetrahedron — so molecules have shape, and some come in left- and right-handed forms.

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In depth · the introduction

Why does your right hand never fit a left-handed glove — and what could that possibly have to do with a molecule of sugar?

The big idea

Chemists used to draw molecules flat, as letters joined by lines on a page. In 1874 a 22-year-old named van 't Hoff insisted that a carbon atom's four bonds actually reach out into three dimensions — toward the four corners of a tetrahedron, a little triangular pyramid, with the carbon at the centre.

That one move has a startling consequence. If the four things attached to a carbon are all different, you can build the molecule in two ways that are mirror images of each other — like a left and a right hand. No matter how you turn one, it will never sit exactly on top of the other. Such a carbon is called asymmetric, and the two mirror-image molecules are its two forms. Molecules, in other words, have a shape, and sometimes a handedness.

How it came about

The clue was a strange property of light. Some substances, in solution, twist the plane of polarised light — one to the left, another, otherwise identical, to the right. Louis Pasteur had even sorted two mirror-image crystals of a tartrate by hand under a microscope in 1848, but no one knew what, deep down, made a molecule handed. Johannes Wislicenus had sharpened the puzzle with two lactic acids that looked the same on paper yet behaved differently.

Van 't Hoff, still a student, saw that a tetrahedral carbon answered it exactly, and published a short pamphlet. In Paris, Joseph Le Bel reached the same conclusion within weeks, by a different argument. Not everyone was pleased: the eminent Hermann Kolbe publicly mocked the unknown youth for mounting "Pegasus, evidently borrowed from the Veterinary School," to fantasise about atoms in space. Van 't Hoff turned out to be right, and in 1901 received the very first Nobel Prize in Chemistry — though, as it happens, for other work.

Why it mattered

Handedness is not a curiosity; it is how life is built. The amino acids in your proteins and the sugars in your DNA are all of a single handedness, so your body tells mirror-image molecules apart with ease. That is why a medicine and its mirror twin can behave completely differently — one may heal while the other does nothing, or worse. Knowing that a molecule has a shape, and being able to predict and control which handed form you make, is now central to chemistry, biology and the entire pharmaceutical industry.

A way to picture it

Hold up your two hands. Same parts — four fingers and a thumb each — joined the same way, and yet they are mirror images: try as you might, you cannot lay your right hand on your left so that every finger matches. A carbon carrying four different groups is exactly like this. Make one of the four groups a repeat — give a hand six fingers, two of them identical and interchangeable — and the mirror trick suddenly works again: now the two versions are the same. Four different things at the corners; that is the whole condition for handedness.

Interactive stereochemistry model: choose a molecule (CHFClBr, CH₃CHClBr, CH₂ClBr, CHCl₂Br); the widget draws a central carbon with four groups on tetrahedral bonds — two plain bonds, one bold wedge toward the viewer, one hashed bond away — beside its mirror image across a dashed mirror line. When all four groups differ the carbon is asymmetric: a green ring marks it chiral and two opposing curved arrows show the left and right handedness. A repeated group makes it achiral and the arrows vanish. A button swaps two groups and flips the handedness.

Where it sits

Van 't Hoff arrived just as chemistry was learning the architecture of molecules: Kekulé had shown that carbon forms four bonds and chains into rings, and the tetrahedron now lifted those chains into space. What a bond actually is came later — Lewis's shared electron pair (lewis-1916) — and why it points where it does came later still, with quantum mechanics in Pauling's hands (pauling-1931). The thread runs straight on to the handed double helix of DNA (watson-crick-1953) and the folded shapes of proteins: the idea that a molecule's arrangement in space is the thing that matters begins here.

The original document
Original source text
J. H. van 't Hoff · pamphlet, Utrecht, 5 September 1874 · also Archives néerlandaises des sciences exactes et naturelles 9 (1874) 445–454
Carbon, lifted off the page
Van 't Hoff opens from a frustration: the flat structural formulae chemists drew on paper could not account for certain pairs of substances that share every atom and every connection yet are plainly different — above all, compounds that rotate the plane of polarised light. His proposal is to take the formula off the page. The four valencies (he calls them affinities) of a carbon atom are not arranged flat; they point toward the four corners of a regular tetrahedron, with the carbon atom at its centre.
[Annotation] From this one geometric move a definition follows. When the four groups attached to a carbon are all different, the tetrahedron and its mirror image cannot be brought into coincidence — van 't Hoff calls such a centre an asymmetric carbon atom. There are then exactly two arrangements, related as left hand to right hand.
…in cases where the four affinities of the carbon atom are saturated with four mutually different univalent groups, two and not more than two different tetrahedra can be formed, which are each other's mirror images.
[Annotation] The note's second half links the geometry to a measurement. Van 't Hoff observes that the substances known to be optically active in solution are just those whose formulae contain an asymmetric carbon, and that chemical changes which destroy the asymmetry destroy the optical activity with it. He runs through known cases — lactic acid (the puzzle Wislicenus had sharpened) and the tartaric acids whose mirror-image crystals Pasteur had separated by hand in 1848.
[Annotation] The same tetrahedral picture is extended to the carbon–carbon double bond, treated as two tetrahedra joined along an edge: rotation is locked, so a doubly-bonded pair of carbons with different groups also comes in two fixed forms — the geometric (cis / trans) isomers, such as maleic and fumaric acid.
[ … ]
[Annotation] A few weeks after this pamphlet, the French chemist J. A. Le Bel reached the same conclusion by an independent route. Van 't Hoff expanded the work the next year as La chimie dans l'espace (1875); the English text quoted here is from Richardson's 1901 collection of the founding memoirs.
J. H. van 't Hoff · Utrecht · September 1874