November 22, 1934

The Rockefeller Foundation

49 West Forty-ninth Street

New York City

Gentlemen:

For three years (1932-5) my researches have been supported by a grant of ten thousand dollars per year made to the California Institute of Technology by the Rockefeller Foundation. During this time my associates and I have been engaged in developing a combined experimental and theoretical method of attack on difficult structural problems such as arise in biochemistry. This preliminary work (mainly on relatively simple molecules) has progressed very satisfactorily. We now feel, largely because of our discovery of a new and powerful x-ray method, that we are ready to make an intensive attack on the problem of the structure of haemoglobin and chlorophyll by application of these newly-developed methods.

The haemoglobin project, as described in the following pages, will be difficult and laborious. I feel confident, however, that definite and significant results can be obtained regarding the structure of haemin and related compounds, the nature of the bond to globin, and the process of addition of oxygen molecules, within three years. I accordingly make application to you for a grant of ten thousand dollars per year for three years, from July 1, 1935, to June 30, 1938, to be used in support of researches on the structure of heamoglobin and other complex molecules of biological importance.

Although we have now developed our methods to such an extent that they can be applied to complex biochemical problems with confidence, I feel that it would be very short-sighted for us to abandon entirely the fundamental investigations such as we have been carrying on, and I plan to continue these researches, on a smaller scale, with the aid of a research fund provided by the California Institute. The Trustees of the Institute have informed me, through Professor Millikan, that the Institute will provide a research fund of five thousand dollars per year during the three-year period 1935-1938, for support of researches relating to the haemoglobin investigation.

I wish again to express my belief that the projected unified attack on the problem of the structure of haemoglobin and related substances of biological importance, together with the associated fundamental researches to be supported by the California Institute, will lead to results of great interest.

Respectfully yours,

During the past year my research assistants and associates and I have devoted our efforts mainly to three methods of attach on problems of structural chemistry; namely, (1) the application of the quantum mechanics, (2) the study of the structure of gas molecules by the diffraction of electron waves, and (3) the study of the structure of crystals and other solid substances by the diffraction of x-rays.

(l) The Application of the Quantum Mechanics to Problems of Structural Chemistry. During the last year we have developed our quantum-mechanical methods (previously applied to aromatic molecules and free radicals) to make them applicable to heterocyclic molecules and other complex molecules containing nitrogen and oxygen atoms as well as carbon and hydrogen. These methods have led to the formulation of a quantitative theory of the very important phenomenon of directed substitution in the benzene ring. A thorough treatment has also been given to the simpler heterocyclic molecules, including pyrrole, an important constituent of the prophyrins and chlorins, which are characteristic constituents of haemoglobin and chlorophyll. The theoretical treatment of the porphyrins themselves has begun, and has already indicated that some of the assigned structural formulas are incorrect.

Several other theoretical studies, dealing with hybridization of bond orbitals, normal coordinates of vibrating molecules, van der Waals forces, etc., have been and are being carried on.

(2) The Study of the Structure of Gas Molecules by the Diffraction of Electron Waves. We have developed and tested the electron-diffraction method of investigating the structure of gas molecules until it rivals the spectrographic method in accuracy,* and have applied it in determining the molecular configurations and interatomic distances for about forty molecules. In particular, a study has been made of the

*The latter method is applicable only to very simple molecules, whereas the electron-diffraction method can be used in studying even complex organic substances.

configuration of the pyrrole ring and of the effect of conjugation on interatomic distances, this information being required for the formulation of the structure of haemoglobin and chlorophyll. We are installing in our apparatus a device for vaporizing substances of high molecular weight, and hop to investigate some of the porphyrins themselves.

(3) The Study of the Structure of Crystals and Other Solid Substances by the Diffraction of X-rays. Our knowledge of interatomic distances and bond angles has been increased by the determination of the structures of several crystals during the last year. More important than this, however, is the discovery of a new method of x-ray investigation. This method depends on the use of the phenomenon of anomalous dispersion; in conjunction with the Fourier series treatment developed by Warren and Patterson, it will permit the straightforward investigation of the environment of iron atoms in haemin and should permit a study to be made of the changes in this environment accompanying oxidation, addition to globin, etc. It is this powerful method which will form our principal type of experimental investigation of substances related to haemoglobin. The method is laborious, requiring very accurate measurements and extensive calculations.

Our staff includes the following research men, in addition to several graduate students.

Research Fellows on Rockefeller Fund.

Dr. J. H. Sturdivant, x-ray work.

Dr. L.O.Brockway, electron diffraction.

Dr. G.W.Wheland, quantum mechanics of organic molecules(Harvard).

Dr. J.Sherman, computers and general assistants.

Dr. S.Weinbaum, computers and general assistants.

Additional Research Fellows.

Dr. L. E. Sutton, International Fellow in Organic Chemistry (Oxford). Electron Diffraction

Dr. L. Helmholz, National Research Fellow (Johns Hopkins). Crystal Structure.

Dr. L. K. Frevel, National Research Fellow (Johns Hopkins). Crystal Structure.

Dr. H. O. Jenkins, Commonwealth Fellow (Oxford). Electron diffraction.

Dr. L. La Coste, quantum mechanics (Texas).

[2 pages of Published Papers]