Remembering Frank A. L. Anet – Professor Emeritus of Chemistry and Biochemistry (1926 – 2024)

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Prof. Frank Anet

We are sad to report that Professor Emeritus Frank Adrien Louis Anet passed away at the age of 97 on May 18, 2024.  

Frank Adrien Louis Anet was born to Gaston and Anna Anet in Doulcon, France on October 24, 1926. He was the second of four siblings. In France he helped his father in his workshop and garage, and was taught to knit by local women. At that time, the shadow of Hitler and his Nazi regime hung heavily over Europe. When Frank was ten, his father who remembered the horrors of WWI all too well, decided to migrate to Australia in 1937.

Frank Anet at work in the computer lab, circa 1995.

On arriving in Australia, Frank learned English and settled into the WWII austere life. With his brothers he built canoes from corrugated steel caulked with bitumen ‘borrowed’ from the road. Their father built a pump to extract ground water during rationing and made a telescope from a drainpipe and home-ground glass. Frank excelled at school, scoring top in physics and fifth in chemistry on state-wide exams. He progressed through school and university with scholarships and bursaries.

He received his B.Sc. with honors from the University of Sydney, winning the university medal, and completed his M.Sc. in 1950. While in Sydney, Frank published several papers on the chemistry of alkaloid natural products. He also was a water polo player, a skier, and a founding member of the Sydney University soccer club.

In 1950, Frank boarded a ship for England with his older brother, Edward. Frank was awarded two fellowships to study in England, of which he accepted the fellowship of the Royal Commission for the Exhibition of 1851 because it was more prestigious and better funded. Frank decided to study in Oxford for his Ph.D., while Edward went to Cambridge to earn his Ph.D.

Frank completed his doctoral studies in just eighteen months at Oxford under the supervision of Nobel Laureate Sir Robert Robinson. He received his Ph.D. in 1952 for work in natural products chemistry. While at Oxford, Frank performed impactful research on the chemistry of alkaloids. His observation of transannular amine-carbonyl interactions, for example, later informed Burgi and Dunitz’ identification of angular requirements in carbonyl nucleophilic addition reactions. In the area of natural products synthesis, his conversion of the Wieland-Gumlich aldehyde into strychnine was used in subsequent formal syntheses of this compound by the groups of Magnus, Stork, Overman, and others.

Frank and Ragini Phadke, whom he had met while both were doctoral students at Oxford, were married in 1955 in Bombay. The couple first resided in Ottawa, Canada where Frank was a postdoctoral researcher with the National Research Council, a position which led to his appointment as Professor of Organic Chemistry at the University of Ottawa. It was in Canada that Frank discovered the wonders of Nuclear Magnetic Resonance (NMR) spectroscopy.

In 1958, he published his first paper to include NMR data. His proton spectrum of the Lycopodium alkaloid lycodine, recorded at 40 MHz, was also featured in Pople, Schneider, and Bernstein’s classic 1959 text, High Resolution Nuclear Magnetic Resonance, as a contemporary example of structure determination using this new technique. His interest in reaction mechanisms showcased applications of partial deuteration and spin-spin decoupling to simplify complex NMR spectra. These studies joined others that investigated fundamental aspects of chemical shifts and coupling constants, as well as an investigation of “through space” nuclear Overhauser effects in organothallium compounds.

During this period, Frank also published some of his first papers in conformational analysis, using variable-temperature dynamic NMR as a principal tool. These investigations looked at cyclooctatetraene, cyclohexane and derivatives, cyclooctane, cycloheptatriene, and restricted rotation in aldehydes.

In 1962, Saul Winstein, impressed by Frank’s work as an early practitioner of NMR spectroscopy in the study of organic molecules, invited Frank to join the UCLA faculty as a visiting professor to teach a one semester graduate course in physical organic chemistry. This visit led to Frank’s moving to UCLA in 1964.

His early work at UCLA examined the effect of steric compression on chemical shifts and coupling constants, including a hydrogen bond-mediated spin-spin coupling measurement made decades before such effects were rediscovered by biomolecular NMR spectroscopists.

Frank’s most influential studies from this era revealed the utility of making NMR spectral assignments and determining molecular structures from nuclear Overhauser effects, a discovery that significantly impacted future applications of NMR. In a widely cited JACS communication, Frank presciently stated that such measurements should be “widely applicable” and “…of considerable stereochemical and conformational interest in organic chemistry.” These experiments from his early years at UCLA are described in many NMR textbooks, with applications of the nuclear Overhauser effect abounding in the chemical and structural biology literature. Indeed, for decades NOE measurements were the only basis upon which solution-state protein and nucleic acid structures could be determined.

Other work during the 1960s included measurement of the ring inversion barrier in cyclohexene using NMR measurements at −170 °C and related measurements in cyclooctane, prototropine, carbonium ions and carbanions, nitrogen inversion, restricted rotation in tert-butyl groups, and valence tautomerism in metal-olefin complexes. Another widely cited paper from this era established the kinetic parameters for cyclohexane ring inversion.

By the late 1960s, Frank often found that commercially available instrumentation was not adequate. Having taught himself electronics, he made important modifications to existing equipment, then built an entire multinuclear NMR spectrometer that operated at 251 MHz for protons, with a design that allowed for very low temperature measurements to study dynamics of medium ring compounds and other systems. The first experiments on this instrument measured the ring inversion barrier in thiepin dioxide and explored the conformational behavior of [3.3]paracyclophane.

These studies were followed by conformational investigations of cyclooctanone, semibullvalene derivatives, ketenimines, carbodiimides, 1,4-dioxane, cyclohexanone, cyclononane, tetrathiocane, oxocanes, 1,5-cyclooctadiene, solvent association/chemical shift effects, detection of the axial conformer of methylcyclohexane, and determination of conformational barriers in medium- and large-ring cycloalkanes and cycloalkanones by proton and 13C NMR.

Frank published his first paper on NMR relaxation in 1972 and his first on empirical force-field calculations in 1973. By the early to mid-1970s, Frank was publishing definitive review articles on the conformations of medium and large ring compounds, as well as high-field NMR applications of 13C NMR.

Recognizing the need for higher frequency studies, in 1976 he began construction of a 400 MHz system, including winding a 9.4 Tesla superconducting magnet. This was an ambitious goal as no superconducting magnets with sufficient field homogeneity for NMR at that high magnetic field had yet been produced. The goal was slightly exceeded, but for practical reasons the spectrometer was operated at 396 MHz for several years. A unique part of the system design was the first set of matrix shim coils, which many years later became commonly used in commercially available NMR spectrometers. Both the 251 MHz and the 396 MHz multinuclear spectrometers were heavily utilized into the mid-1980’s by the research group of Fred Hawthorne at UCLA whose research centered on boron hydride clusters. 11B NMR was not available on any other spectrometers at that time and proved to be crucial to the characterizations of the extensive compounds produced by the Hawthorne group.

From the mid-1970s to the early 1980s, Frank continued to explore conformational properties of medium and large cyclic alkanes, alkenes, alkynes, and allenes using dynamic NMR measurements and empirical force-field calculations. These included conformationally complex compounds, such as cycloundecane, cyclododecane, cyclotridecane, cyclopentadecane, as well as 1,3-cyclooctadiene, 1,4-cyclooctadiene, 1,5-cyclononadiene, 1,4,7-cyclononatriene, trans,trans,trans-1,5,9-cyclododecatriene, cyclododecyne, and cyclic allenes, such as 1,2-cyclononadiene, 1,2,6-cyclononatriene, and 1,2,6,7-cyclodecatetraene.

High-vacuum cryogenic deposition experiments, done by Frank in collaboration with Orville Chapman, used infrared and NMR spectroscopy to characterize high energy molecular conformations captured from high temperature equilibrium mixtures. One study, described in many textbooks, detected the twist conformation of cyclohexane, known then only as a theoretical possibility, and determined its relative energy and rate of conversion to the ground state chair conformation. The elusive axial conformation of methylcyclohexane and scis-1,3-butadiene were also revealed by these techniques.

In addition to extensive conformational analysis of cyclic compounds, Frank also investigated acyclic systems with restricted internal rotations. These included dynamic NMR and computational studies of the generalized anomeric effect and barrier to rotation about the O-CH2 bond in ɑ-chloroethers, barriers to C-N rotation of urea and aniline derivatives, and rotation barriers in 1,8-naphthalenes substituted by different (CH3)3X groups. Notably, the naphthalene study was done on Frank’s 396 MHz spectrometer and required measurements at −180 °C and below.

Frank collaborated with George Olah on a low-temperature NMR study to investigate the much-debated bridged nature of the 2-norbornyl cation. Completely resolved 1H and 13C spectra were recorded on Frank’s 396 MHz spectrometer. The absence of line broadening in the −80 to −160 °C temperature range indicated a symmetrically bridged cation structure or, alternately, interconversion between two asymmetrical bridged structures with a low barrier of 3 kcal/mol or less.

Several publications reflect Frank’s deep interest and expertise in molecular symmetry and its varied manifestations. In work of significant stereochemical interest, his collaboration with Kurt Mislow examined mathematical constructs of dividing finite geometric objects into isometric segments and how these constructs related to chemical fragmentation and combination of molecules. The work culminated with the self-coupling of two homochiral molecules (4-bromomethyl-6-mercaptomethyl[2,2]metacyclophanes) to give an achiral product. 

During this period, Frank also investigated intrinsic and equilibrium isotope effects. His work on 1,3-dioxanes and half-cage pentacyclododecanes demonstrated long-range intrinsic deuterium isotope effects on 1H chemical shifts. Frank attributed these effects, remarkably large in half-cage compounds, to spatial proximity of non-bonded HD atoms (estimated at 2.0 Å and 1.6 Å in dioxane and half-cage compounds, respectively) and appreciable van der Waals repulsions between them, thus proposing the term steric isotope effects. In this and related work on half-cage pentacyclododecanes with ultrashort non-bonded HH distance, Frank again demonstrated application of NMR (1H / 13C T1s and nuclear Overhauser effect) as a unique tool for quantitative structural measurements in solution.

In collaboration with Martin Saunders, Frank used NMR measurements, force-field calculations, and electronic structure calculations, to investigate equilibrium isotope effects that involve small differences in populations of two or more exchanging species. Thus, a high-field 63.1 MHz 13C NMR room temperature spectrum of 1,1,3,3-tetramethylcyclohexane with one trideuteriomethyl group demonstrated a 24 cal/mol preference for the conformation with CD3 group in axial position.

Frank Anet (second from left) at the 2016 John D. & Edith M. Roberts Inaugural Lecture at UCLA with Bill Gelbart, Jane Strouse, Mike Jung, and Yves Rubin.

Frank measured the A value for deuterium and tritium in cyclohexane using several independent techniques, firmly establishing that the mass-2 isotope prefers the equatorial position by 6-8 cal/mol. Larger equatorial isotopic preferences were observed in 1,3-dioxanes and 1,3-diazacyclohexanes and explained in terms of n-σ* hyperconjugation and weakening of the axial substituent bond, or the generalized anomeric effect. Later studies of these and related systems, including 1,3-dithianes and cycloheptatriene, utilized high-precision measurements to provide an understanding of the enthalpic and entropic origins of these isotope effects.

Single authored papers on a range of topics are found throughout Frank’s publication record. These articles sometimes corrected an erroneous result from a different laboratory, uncovered chaotic inflection points in conformational search algorithms, or proposed a general definition of the oft-used terms axial and equatorial. These papers reveal Frank in his element: curiosity-driven, able to advance fields new to him, and educate broader communities in the process. In studies of viscoelastic micellar systems, for example, Frank not only uncovered aspects of their macromolecular structure but also identified novel NMR signal behavior and relaxation effects that later gained the attention of those using NMR to solve large protein structures.

Frank’s early training as a natural products bench chemist provided the skills to creatively synthesize molecules and test a career’s-worth of predictions. These efforts were often practical and useful to others working in the field. Even late in his time at UCLA, for example, he published syntheses of deuterated feedstocks and, together with long-time collaborator Jay Siegel, disclosed the preparation of a deuterated Freon-type solvent for convenient low-temperature NMR studies.

Frank continued pursuing his deep interests in stereochemistry, conformational equilibria, physical organic chemistry and NMR in general in the latter part of his career. He showed that diastereotopic protons in a CH2D group can have different and assignable NMR chemical shifts. Working in collaboration with Heinz Floss, he extended this study to develop a tritium NMR method for assigning the configuration of so-called chiral methyl groups (CHDT), used to study the stereochemistry of biological methyl transfer reactions.

In another study with biological relevance, Frank and a UCLA undergraduate used chiral shift reagents and enzymatic deuteration to provide absolute stereochemical assignments for the four methylene hydrogens of citrate. This paper nicely complemented a 1960 publication by Frank, then in Ottawa, which confirmed the stereochemical outcome of malate synthase using a combination of chemical synthesis and NMR spectroscopy.

Frank was also interested in gas-phase NMR. One study compared gas and solution phase isotope shifts and H-D coupling constants in partially deuterated methanes. Another project commenced when an IR study appeared in the literature suggesting the barrier to ring inversion in cyclohexene was twice as high as the value Frank determined in the 1960s. Through low-temperature gas-phase NMR studies and theoretical work in collaboration with Ken Houk, he was able to provide firm additional evidence in support of his first measurement.

His expertise in stereochemistry and isotope effects facilitated a collaboration with John Baldwin in an extension of his earlier papers on semibullvalenes to determine the stereochemistry of the vinylcyclopropane to cyclopentane rearrangement. And when a proposal surfaced in the literature suggesting the theory of NMR parameter averaging needed revising, Frank carefully investigated and disproved the idea. Like many scientists of his generation, he regarded scientific literature as a venue for occasional debate, necessary for fields to advance.    

His interest in nuclear relaxation continued through the latter phase of his career. In a collaboration with Chuck Wade and Bob Johnson, Frank showed that T2 can be longer than T1. This result appeared to contradict standard textbook explanations, but he knew that certain molecules had magnetic shielding characteristics making this relaxation behavior possible. Experiments undertaken at UCLA and IBM Almaden proved him correct.

True to his identity as a physical organic chemist, Frank was interested in better understanding the aromatic properties of fullerenes such as C60 and C70. In another collaboration with Martin Saunders, he used 3He NMR to probe the interior of these molecules. He concluded there are significant differences in the ring currents in these two molecules.

Due to economic challenges in the early 1990s, the University of California offered professors near retirement age additional years of credit towards their pensions if they would retire earlier than planned. Frank accepted one such offer and transitioned to Professor Emeritus in 1991.

Frank remained active in research during retirement, using his expanded freedom to pursue other interests. He developed a method for processing data from astronomical observations of asteroids and also became deeply interested in the chemical origins of life. Frank’s immense knowledge of cyclic organic compounds and molecular symmetry had ignited his interest in the origin of nucleic acids, which contain a single handedness of ribose (in the case of RNA) or 2’-deoxyribose (in the case of DNA).

Contrary to many investigators working on the chemical origins of life at that time, Frank firmly believed that RNA could not have been the first genetic polymer of life. Further, he was convinced that the backbone of the first genetic polymers would have been heterogeneous in chemical structure and formed by readily reversible, low energy bonds (unlike those of RNA). He imagined that the homo-chiral phosphodiester backbone of RNA only appeared after a process of chemical evolution that was driven by a gradual movement towards functionally superior molecules, of which RNA and DNA could be considered the end points of backbone evolution.

Frank’s refreshing insights resulted in several publications with Nicholas Hud regarding theoretical and experimental models for the prebiotic synthesis of molecules that could have preceded RNA. He also published a single author paper on the place of metabolism in the origin of life, in which he argued against the burgeoning hypothesis that a highly developed metabolism could have preceded the formation of a genetic apparatus.

Characteristically, even in his final years when his speech was labored due to a series of strokes, Frank remained engaged in discussions of origins of life chemistry in which he continued to serve as a source of valuable critiques and fresh perspectives.

Frank published more than 200 articles over the course of a remarkable career, each inevitably a unique and definitive story. As a mentor, Frank trained many students and postdoctoral researchers who were, by all accounts, uniformly impressed by his brilliance and careful approach to the interpretation and communication of scientific results.

It is clear from the record that Frank played a leading role in advancing our fundamental understanding of organic chemistry and NMR spectroscopy. His contributions to the conformational analysis of cyclic molecules, taken alone, would be a remarkable accomplishment for any scientist. But accolades never seemed to factor into Frank’s thinking and for him, the spotlight was to be shared. Indeed, he concluded his 1996 autobiography, “A Lapsed Organic Chemist in the Wonderland of NMR,” by thanking the many collaborators with whom he shared his journey.     

His research was recognized by the UCLA Department of Chemistry and Biochemistry with the H. N. McCoy Award (1968), the H. C. Brown Lectureship at Purdue University (1994), and the Eastern Analytical Symposium Award for Outstanding Achievement in Magnetic Resonance (1999). In 1988, Frank was elected a Fellow of the American Association for the Advancement of Science, in recognition of his “Investigations of molecular conformations and molecular symmetry, especially in their dynamic aspects.”

Frank’s last years were spent in retirement living, where he still held a keen interest in science, exercised regularly, and worked on projects with hand and power tools. He missed his independence, driving, and cooking, but made the most of every day.

Frank was preceded in death by his older brother Edward in 1976, Ragini in 2003, and his younger brother Lionel in 2022. He is survived by his sister Denise, his nephews John and Peter, his nieces Julie, Susan, Judith, and Marie, and twelve great-nieces and great-nephews.

The writing of this remembrance was a labor of love for a much-revered mentor by Prof. Nicholas Hud (Georgia Tech), Prof. Dan O’Leary (Pomona College), Dr. Daron Freedberg (FDA), Dr. Max Kopelevich (UCLA), and Dr. Jane Strouse (UCLA), with input from his nephew, John Anet, for personal details.