Field of Science

What are the top five most memorable chemistry papers that you have read?

Here's a question I have wanted to ask the chemoblogosphere for some time, just for fun: What are the most memorable chemistry papers that you have encountered in your career as a student and working chemist? I am sure many of us remember at least a few papers that reminded all of us of why we love the subject. Are there papers which are stuck in your memory as particularly elegant, revolutionary or just plain well-written (more of a rarity than we might think)? The papers need not be universally accepted as significant in the history of chemistry, they only need to have moved you in one way or another on a personal level. 

So without further ado, here's my list (of the top six, actually), in chronological order; there are others, but I find myself going back to these again and again. Being a biologically oriented organic chemist, not surprisingly I tend to gravitate toward topics dealing with synthesis, physical organic chemistry, medicinal chemistry and biochemistry. Feel free to add your own in the comments sections and on your own blogs.

1. "The total synthesis of reserpine" (Woodward, 1958): Chemistry as poetry, nothing more. This remains the leading candidate for the paper that introduced synthetic and natural products chemists to the third dimension and to stereoselective synthesis. Although Woodward had synthesized a few complex substances before, the reserpine paper was perhaps the first to incorporate solid - and exceedingly elegant - stereochemical considerations in the making of what was then a mind-bogglingly complicated molecule. More than any other Woodward paper, this one reminds me that chemistry is the science most akin to architecture.

Tetrahedron 19582, 1.

2. "Isotopic perturbation of resonance" (Saunders and Kate, 1980): For most students of chemistry today the non-classical ion controversy, waged primarily between Herbert Brown, Saul Winstein and George Olah must be ancient and forgotten history. And yet it supplies one of the best examples of both how controversy can sharpen chemical understanding and how the human factor can complicate chemical matters through emotions and acrimonious debate. The recent crystal structure of the norbornyl cation puts the controversy to rest, but for many people it was settled long before when Olah and Martin Saunders obtained irrefutable NMR evidence of a bridged, non-classical ion.

Everyone knows Olah, but few have heard of Saunders. And yet for my money, the most elegant proof of the non-classical cation came from Saunders' NMR work with deuterated norbornyl cations in which only one side of a symmetrical compound was labeled with deuterium. The idea is that the C13 chemical shift of a carbon next to a deuterium will be perturbed and therefore the usually symmetrical C13 peak will be split. However, the splitting will be too small if the structure is bridged and non-classical, while it will be noticeable if it consists of two rapidly equilabrating structures. Saunders's experiment, along with Olah's two decade-old work, clinched the deal. For me this is one of the most elegant demonstrations of how a powerful instrumental technique can be brought to bear on a fundamental chemical problem.

ReferenceJ. Am. Chem. Soc. 1980, 102, 6867.

3. "The Endiandric Acid Cascade" (Nicolaou et al. 1982): Cascade reactions have always had a special place in my heart, and this artful synthesis of endiandric acids by Nicolaou ties with Clayton Heathcock's biomimetic alkaloid synthesis as the best example of cascade reactions that I remember. The work speaks elegance and also attests to the power of electrocyclizations (rationalized by the Woodward-Hoffmann rules) to form several key bonds in a single step with absolute stereospecificity and high yield. There are few better examples I know of chemistry in motion.

Reference: J. Am. Chem. Soc. 1982, 104(20), 5558 

4. "Dominant forces in protein folding" (Dill, 1990): It's often said that scientists don't know how to write. Here's an exception to the rule. In this review Ken Dill shows us that even technical material can be an absolute pleasure to read. The review is comprehensive, extremely well-organized and lucid. It's one of those few technical articles that make for good bedtime reading, and in spite of advances in the field I keep myself going back to it quite often.

ReferenceBiochemistry199029 (31), 7133

5. "Design principles for bioactive drugs" (Navia and Chaturvedi, 1996): This is a great review because it comprehensively lays out the key properties that lead to drugs making it across biological membranes and being orally bioavailable. It was also one of the first articles that pointed out how molecules which are now regarded as "beyond rule of 5" can succeed as drugs; ironically this was only a year before Chris Lipinski came up with the much used and abused Rule-of-5 for orally active drugs.

Reference: Drug. Disc. Today, 1996, 1(5), 179

6. "Organic fluorine hardly ever accepts hydrogen bonds" (Dunitz, 1997): Here's another world-class chemist who really knows how to write. In a recent interview veteran chemist Jack Dunitz - who is past 90 and still going strong - said that by reading good literature he came to appreciate the value of clear expression (now there's something else that chemists should do more often; read fiction). Dunitz also happens to be one of the first people to have seen Watson and Crick's model of DNA.

But in any case, this paper really blew me away because until I read it I naively believed that F, being the most electronegative element, should accept hydrogen bonds with alacrity. Dunitz analyzes thousands of crystal structures and showed that there's a fraction of them, if any, which show evidence of hydrogen bonding with F. The lesson has stayed me for years, and even now I point out the article to any medicinal chemist who might want to install a fluorine in a drug molecule to enhance hydrogen bonding.

Reference: Chem. Eur. Jour. 1997, 3 (1), 89


  1. Can't remember a one except maybe that little note by Watson and Crick about the structure of DNA.

  2. Although electronegative, fluorine (at least when bonded to aromatic carbon)is more lipophilic than fluorine. Somehow, this experimental observation never seems to get mentioned when people invoke C-F dipoles to 'explain' molecular recognition phenomena. If you look at the electrostatic potential minima associated with fluorine, you'll find them to be a lot less negative than those associated with oxygen atoms. The distribution of charge 'within' atoms is an important determinant of their propensity to form hydrogen bonds.

    1. Interesting, thanks for the input; I would think high-level quantum chemistry calculations would definitely pick up on this.

    2. Actually you can 'see' these effects with HF/6-31G* which is not particularly high level these days. All in the lone pairs as Bismarck might have observed when he wasn't sending troops to invade Prussia's neighbours:

    3. Good to know that the cheap, electron correlation-ignoring HF method can make out the difference. Nice presentation on halogen bonding by the way.


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