Fluorine at a chosen carbon

Given an ordinary organic molecule and one carbon–hydrogen bond marked in advance, a written procedure replaces that hydrogen with one fluorine and does not do the same at the other carbon–hydrogen bonds. The marked carbon may be an unactivated methyl or methylene sitting next to a C–H bond the usual fluorination catalysts would prefer.

Fluorine is how a candidate’s metabolism, acidity, and conformation are tuned, and it is usually installed by building the molecule from a fluorinated starting material. A late fluorination counts only if the site was chosen. A method that fluorinates the weakest C–H bond on a steroid is useful, and it is not the same result.

Liu, Huang, Cheng, Nielsen, Goddard, and Groves reported a manganese porphyrin that fluorinates aliphatic C–H bonds with fluoride ion and a stoichiometric iodine(III) oxidant (doi:10.1126/science.1222327 (opens in a new tab)). The abstract states that simple alkanes, terpenoids, and steroids were fluorinated at otherwise inaccessible sites in 50 to 60 percent yield, and that the site of C–H cleavage is set by an oxomanganese(V) intermediate. Decalin was fluorinated predominantly at the C2 and C3 methylene positions, bornyl acetate gave the exo-5-fluoro product, and 5α-androstan-17-one was fluorinated in the A ring. The site is the one that intermediate selects. A later protocol from the same laboratory, covering the porphyrin and a manganese salen catalyst, states that isolated methylene groups and unactivated benzylic sites are accessible and that the reactions typically afford 50 to 70 percent yield of the monofluoride. Celestolide and ibuprofen gave about 50 percent isolated yield, on a few hundred milligrams, in one to eight hours (doi:10.1038/nprot.2013.144 (opens in a new tab)). Those are still the sites the method addresses, not a carbon marked in advance against a more reactive neighbor.

Wang, Ruskin, Marques, Garrison, and Lectka surveyed single-atom late-stage fluorination of natural products and drugs in 2025 and present it as a collection of methods, nucleophilic and electrophilic, each with its own substrate class (doi:10.1021/acs.chemrev.5c00363 (opens in a new tab)). Nothing opened for this problem accepts a blinded set, a carbon marked by someone else, and a procedure frozen before any experiment on that set.

An independent laboratory preregisters 12 molecules. Each has a molecular weight between 180 and 500, at least four constitutionally distinct carbon–hydrogen sites, and only the elements C, H, N, O, S, F, Cl, and Br. Fluorine already in the drawing is allowed and is not the marked site. On each structure the laboratory marks exactly one carbon that bears at least one hydrogen. The required product is the monofluoride at that carbon. A gem-difluoride, an alcohol, or a fluoride at any other carbon does not count.

At least four of the twelve marked carbons are unactivated, by a rule fixed before the structures are released. A marked carbon is unactivated only when all three of the following are true: it is a methyl or a methylene; it is not benzylic, not allylic, and not adjacent to oxygen, nitrogen, or sulfur; and the same molecule contains at least one benzylic C–H or tertiary aliphatic C–H. The attempt sees the marked structures.

The structures are revealed together. Within 24 hours, and with no experiment on any of the 12, the attempt submits one written procedure. Only the substrate changes from molecule to molecule. The laboratory runs that procedure once, as written, on 0.1 to 0.3 mmol of substrate. One backup procedure may be submitted in the same 24 hours. If it is used, it applies to every substrate or to none.

The site ratio is measured on the crude mixture, before chromatography, by fluorine NMR against a weighed internal calibrant: the integral of the specified monofluoride divided by the sum of the integrals of every other monofluoride. The specified product is then isolated. Identity is a proton spectrum, a fluorine spectrum, a carbon spectrum, and an HSQC or a fluorine–proton correlation sufficient to place the fluorine. A chemist who did not write the procedure does the placement. Purity of the isolated monofluoride is at least 95 percent by absolute quantitative proton NMR.

At least 9 of the 12 substrates give the specified monofluoride in an isolated yield of at least 30 percent, with a crude site ratio of at least 10 to 1, and at least 3 of those 9 are among the 4 unactivated sites.

The count, the 3-of-4 unactivated requirement, the 30 percent yield, the 10-to-1 ratio, and the 95 percent purity are pass marks defined here. Thirty percent is below the 50 to 60 percent yields Groves and co-workers report for sites their catalyst selects, and it is a floor for isolation rather than a record. The unactivated-site count is what a benzylic-only method cannot clear. Ten to one means the marked carbon accounts for at least about 91 percent of the monofluorinated material.

A no-reagent blank, identical except for the absence of the catalyst or fluorinating reagent named in the procedure, is run for two substrates chosen before the procedures are opened. One of the two is unactivated. The blank must not produce the specified monofluoride above 2 percent yield by the same fluorine-NMR assay. If it does, the batch is invalid.

The crude fluorine spectrum must be integrated against the calibrant, not against a chromatogram that has already discarded the other isomers. If the assigning chemist cannot place the fluorine, the substrate fails.

Any catalyst, fluoride salt, electrophilic fluorinating reagent, light source, or electrochemical cell that the written procedure names. Computation before the 24-hour clock starts is allowed. A stoichiometric oxidant is allowed if it is named in the procedure. The single backup procedure submitted with the first procedure is allowed.

Installing a halogen, a boron substituent, a diazonium salt, or a directing group on the way to the fluoride. Deoxyfluorination of an alcohol that is not already the marked carbon in the preregistered drawing. Halogen exchange at a carbon that was not the marked C–H. Counting a gem-difluoride, or a mixture of monofluorides, as the product. Screening conditions on the test substrate, or on a close analog made for the purpose, after the structures are revealed. Reporting only the eight activated sites and treating the unactivated four as optional.

At least 6 of the 12 substrates meet a 15 percent isolated yield and a 5-to-1 site ratio, at least 1 of the 6 is an unactivated site, and the blanks pass. These figures are pass marks for the lesser bar. Partial success is not a solution.

The success counts, the unactivated-site rule, the 30 percent and 15 percent yields, the site ratios, the 2 percent blank ceiling, and the 95 percent purity are pass marks defined here.

Cited measurements:

• Liu, Huang, Cheng, Nielsen, Goddard, and Groves, Science, 2012, 337, 1322–1325, doi:10.1126/science.1222327 (opens in a new tab). Aliphatic C–H fluorination in 50 to 60 percent yield at sites selected by the oxomanganese intermediate. The decalin, bornyl acetate, and androstanone descriptions are from that abstract.
• Liu, Huang, and Groves, Nature Protocols, 2013, 8, 2348–2354, doi:10.1038/nprot.2013.144 (opens in a new tab). Isolated methylenes and unactivated benzylic sites; typically 50 to 70 percent yield of the monofluoride. Celestolide and ibuprofen, about 50 percent isolated, a few hundred milligrams. Individual yields in the substrate tables were not re-tabulated here.
• Wang, Ruskin, Marques, Garrison, and Lectka, Chemical Reviews, 2025, 125, 9382–9428, doi:10.1021/acs.chemrev.5c00363 (opens in a new tab). A survey of late-stage fluorination by substrate class, not a blinded site-selection test.

Purity uses the absolute quantitative proton NMR assay of Pauli and co-workers, Journal of Medicinal Chemistry, 2014, 57, 9220–9231, doi:10.1021/jm500734a (opens in a new tab). The 50 to 70 percent sentence and the celestolide and ibuprofen figures are taken from the protocol abstract, not from a line-by-line check of every example in its tables.