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Is TMEDA inhibition a reliable test for hidden BH3 catalysis, and is any amine a better trap?

Determine the temperature range over which trapping by N,N,N',N'-tetramethylethylenediamine (TMEDA) inhibits BH3-catalysed hydroboration with pinacolborane (HBpin), and therefore over which a lack of inhibition can be read as evidence of true, non-boron catalysis; and find whether any other amine is a better trap.

Source: Hidden Boron Catalysis: A Cautionary Tale on TMEDA Inhibition (doi:10.1021/acs.orglett.4c03591). Path record: acs-tmeda-path.json. Headline outcome partial. Kinetic analyses showed that TMEDA inhibition is only applicable below 60 °C and that other amine traps are likewise ineffective. TMEDA reaction doping can still be used to indicate BH3 formation, but users should proceed with caution and rely on observing the adduct by 11B NMR spectroscopy. All graphs · Back to the pilot

How to read these graphs

A discourse graph breaks a piece of research into typed one-sentence nodes and draws how they bear on one another. The grammar is that of Discourse Graphs (Chan and Akamatsu). Read each graph left to right: a question, the experiments that addressed it, the results they produced, and the hypothesis every result is drawn against.

QUE Question: What the work set out to answer.
HYP Hypothesis: The answer the authors expected. Every result earns one edge against it.
EXP Experiment: One attempt at the question: a trial arm, an assay, a survey, an analysis.
RES Result: One finding from an experiment, with where in the source it comes from.
ISS Issue: An open question or untried branch the work leaves for someone else.

addresses: An experiment addresses the question.
produces: An experiment produces a result.
supports: A positive result that backs the hypothesis.
opposes: A negative result that counts as evidence against the hypothesis, or a refutation of an earlier claim.
informs: A partial or mixed result that bears on the hypothesis without settling it.
consistent with: A negative or inconclusive result that does not count either way: no positive control passed, or there is no sensitivity or power statement, so the absence of an effect cannot be told from a measurement that failed.
relation: A thin dotted line: a link the source itself states between two experiments, such as one being derived from another.

A dashed box marks a result the rule above counts as uninformative, or an issue. In the drawing, click a node to jump to its text below.

The graph

Read left to right. The question (QUE) is addressed by 4 experiments (EXP), each of which produces results (RES), and each result bears on the hypothesis (HYP) with one of four edges. 8 support it, 8 oppose it, 4 inform it, and 0 are merely consistent with it because the informativeness rule would not count them as evidence either way. Click a node to jump to its full text below.

supports positive finding
opposes informative negative, or refutation
informs partial finding
consistent with inconclusive or uninformative: no positive control passed, or no sensitivity statement
thin grey a relation the record itself states between two attempts
dashed box a result the informativeness rule marks uninformative, or an issue

The grammar is that of Discourse Graphs (Chan and Akamatsu): QUE, HYP, EXP, RES and ISS nodes with supports, opposes and informs edges. Every node and edge is derived from fields already in the Negative-Results Record; the edge a finding earns is decided by its outcomeClass and informativeness. Issues (ISS) hang below the graph as a strip: the open questions and untried branches the path leaves for someone else to pick up.

Nodes

Question and hypothesis

QUE: Determine the temperature range over which trapping by N,N,N',N'-tetramethylethylenediamine (TMEDA) inhibits BH3-catalysed hydroboration with pinacolborane (HBpin), and therefore over which a lack of inhibition can be read as evidence of true, non-boron catalysis; and find whether any other amine is a better trap.
HYP: If the TMEDA.(BH3)2 adduct is labile at the temperatures hydroboration catalysis is run at, TMEDA will fail to inhibit BH3-catalysed hydroboration there and a lack of inhibition cannot be read as true catalysis.

Experiments (4 attempts)

Node	Attempt	Type	Headline	JSON
EXP	TMEDA.(BH3)2 is inert at 60 °C but catalyses HBpin hydroboration at 80 and 100 °C, so the TMEDA inhibition test gives false negatives above 60 °C Alkyne: 0.3 mM/s and 4 % at 60 °C against 9.6 mM/s and 87 % for free BH3; 50 % at 80 °C and 94 % at 100 °C. Alkene: 0.02 mM/s and 3 % at 60 °C against 1.8 mM/s and >95 %; complete at 80 and 100 °C. HBpin alone decomposes to BH3 from 80 °C.	`wet-lab`	`refuted`	record
EXP	No amine tested is a better BH3 trap than TMEDA: two match its 60 °C limit, four release BH3 at room temperature Amine-borane adducts 5a and 5b resulted in reaction inhibition (product formation <5%) up to 60 °C ... All other amine-borane adducts resulted in product formation at room temperature and above. All of the amines tested did not offer an improvement over TMEDA.	`wet-lab`	`negative-not-achievable`	record
EXP	Of 633 catalysed HBpin hydroboration papers since 2010, 24 used TMEDA inhibition and 15 of those ran it above 60 °C 633 publications; 5 % tested for hidden catalysis before May 2020 and 23 % after; 24 used TMEDA inhibition, 15 of them above 60 °C and 7 on carbonyl substrates.	`evidence-synthesis`	`positive`	record
EXP	Higher TMEDA loading improves but does not complete inhibition of hidden BH3 catalysis above 60 °C Alkyne: 0.5 eq TMEDA gives less than 5 % product at 80 and 100 °C. Alkene: 70 % at 0.5 eq and 80 °C; 11, 9 and 7 % at 0.5, 0.75 and 1.0 eq at 100 °C. The authors conclude false negatives remain possible.	`wet-lab`	`partial`	record

Results (20 findings)

Node	Finding	Id	Outcome and informativeness	Edge	JSON
RES	Does the TMEDA.(BH3)2 adduct catalyse the hydroboration of phenylacetylene (1) with HBpin at 60 °C? target: TMEDA.(BH3)2 adduct; initial rate of boronic ester formation = 0.3 mM/s	`alkyne-60` in acs-tmeda-adduct-kinetics	`negative-no-effect` informative designated positive control passed; negative control clean; sensitivity or power stated	opposes HYP	record
RES	Does the TMEDA.(BH3)2 adduct catalyse the hydroboration of phenylacetylene (1) with HBpin at 80 °C? target: TMEDA.(BH3)2 adduct; initial rate of boronic ester formation = 0.6 mM/s	`alkyne-80` in acs-tmeda-adduct-kinetics	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	Does the TMEDA.(BH3)2 adduct catalyse the hydroboration of phenylacetylene (1) with HBpin at 100 °C? target: TMEDA.(BH3)2 adduct; initial rate of boronic ester formation = 4.56 mM/s	`alkyne-100` in acs-tmeda-adduct-kinetics	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	Does the TMEDA.(BH3)2 adduct catalyse the hydroboration of 4-tert-butylstyrene (3) with HBpin at 60 °C? target: TMEDA.(BH3)2 adduct; initial rate of boronic ester formation = 0.02 mM/s	`alkene-60` in acs-tmeda-adduct-kinetics	`negative-no-effect` informative designated positive control passed; negative control clean; sensitivity or power stated	opposes HYP	record
RES	Does the TMEDA.(BH3)2 adduct catalyse the hydroboration of 4-tert-butylstyrene (3) with HBpin at 80 °C? target: TMEDA.(BH3)2 adduct; initial rate of boronic ester formation = 0.19 mM/s	`alkene-80` in acs-tmeda-adduct-kinetics	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	Does the TMEDA.(BH3)2 adduct catalyse the hydroboration of 4-tert-butylstyrene (3) with HBpin at 100 °C? target: TMEDA.(BH3)2 adduct; initial rate of boronic ester formation = 0.7 mM/s	`alkene-100` in acs-tmeda-adduct-kinetics	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	Does a lack of inhibition by TMEDA demonstrate true, non-boron catalysis at the temperatures the test is used at? target: TMEDA inhibition test for hidden BH3 catalysis in HBpin hydroboration; temperature above which the trapped adduct catalyses hydroboration = 60 °C	`tmeda-test-false-negative-above-60` in acs-tmeda-adduct-kinetics	`refuted` not-applicable an affirmative refutation is judged on the refuting analysis, not on the controls of the run it refutes	opposes HYP	record
RES	Does TMEDA added to a deliberately hidden BH3-catalysed reaction inhibit it at 60 °C, and does the inhibition survive heating to 100 °C? target: TMEDA inhibition test for hidden BH3 catalysis in HBpin hydroboration; inhibition on adding 0.1 eq TMEDA at 60 °C = complete, lost at 100 °C	`hidden-catalysis-demonstration` in acs-tmeda-adduct-kinetics	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	At what temperature does pinacolborane alone decompose to BH3? target: pinacolborane (HBpin); lowest temperature at which Et3N.BH3 is observed by 11B NMR after 20 h = 80 °C	`hbpin-thermal-decomposition` in acs-tmeda-adduct-kinetics	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	Does DABCO.(BH3)2 inhibit BH3-catalysed hydroboration of phenylacetylene with HBpin, and to what temperature? target: DABCO.(BH3)2 (5a); highest temperature with less than 5 % product = 60 °C	`amine-5a` in acs-tmeda-amine-screen	`partial` not-applicable rule applies to negative and inconclusive findings only	informs HYP	record
RES	Does PMDTA.(BH3)3 inhibit BH3-catalysed hydroboration of phenylacetylene with HBpin, and to what temperature? target: PMDTA.(BH3)3 (5b); highest temperature with less than 5 % product = 60 °C	`amine-5b` in acs-tmeda-amine-screen	`partial` not-applicable rule applies to negative and inconclusive findings only	informs HYP	record
RES	Does N-methylmorpholine.BH3 inhibit BH3-catalysed hydroboration of phenylacetylene with HBpin, and to what temperature? target: N-methylmorpholine.BH3 (5c); highest temperature with less than 5 % product = none, product at 18 °C °C	`amine-5c` in acs-tmeda-amine-screen	`negative-no-effect` informative internal positive arm passed; negative control clean; sensitivity or power stated	opposes HYP	record
RES	Does DIPEA.BH3 inhibit BH3-catalysed hydroboration of phenylacetylene with HBpin, and to what temperature? target: DIPEA.BH3 (5d); highest temperature with less than 5 % product = none, product at 18 °C °C	`amine-5d` in acs-tmeda-amine-screen	`negative-no-effect` informative internal positive arm passed; negative control clean; sensitivity or power stated	opposes HYP	record
RES	Does Et3N.BH3 inhibit BH3-catalysed hydroboration of phenylacetylene with HBpin, and to what temperature? target: Et3N.BH3 (Et3N); highest temperature with less than 5 % product = none, product at 18 °C °C	`amine-Et3N` in acs-tmeda-amine-screen	`negative-no-effect` informative internal positive arm passed; negative control clean; sensitivity or power stated	opposes HYP	record
RES	Does Me3N.BH3 inhibit BH3-catalysed hydroboration of phenylacetylene with HBpin, and to what temperature? target: Me3N.BH3 (Me3N); highest temperature with less than 5 % product = none, product at 18 °C °C	`amine-Me3N` in acs-tmeda-amine-screen	`negative-no-effect` informative internal positive arm passed; negative control clean; sensitivity or power stated	opposes HYP	record
RES	Is any of the six amines tested a better in situ BH3 trap than TMEDA for the inhibition test? target: TMEDA inhibition test for hidden BH3 catalysis in HBpin hydroboration; amines inhibiting above 60 °C = 0 (n = 6)	`better-trap` in acs-tmeda-amine-screen	`negative-not-achievable` informative internal positive arm passed; negative control clean; sensitivity or power stated	opposes HYP	record
RES	How many catalysed-HBpin-hydroboration publications test for hidden boron catalysis, before and after the TMEDA method was introduced in May 2020? target: catalysed hydroboration literature with HBpin, 2010 to September 2024; publications testing for hidden boron catalysis after May 2020 = 49 publications (n = 212)	`uptake` in acs-tmeda-literature-survey	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	How many published uses of the TMEDA inhibition test were run above 60 °C, where this study shows the test gives false negatives? target: TMEDA inhibition test for hidden BH3 catalysis in HBpin hydroboration; TMEDA inhibition tests run above 60 °C = 15 publications (n = 24)	`tests-above-60` in acs-tmeda-literature-survey	`positive` not-applicable rule applies to negative and inconclusive findings only	supports HYP	record
RES	Does a higher loading of TMEDA relative to the 'catalyst' restore complete inhibition of hidden BH3 catalysis in the hydroboration of phenylacetylene at 80 and 100 °C? target: TMEDA inhibition test for hidden BH3 catalysis in HBpin hydroboration; product at 100 °C with 0.5 eq TMEDA = <5 %	`loading-alkyne` in acs-tmeda-loading	`partial` not-applicable rule applies to negative and inconclusive findings only	informs HYP	record
RES	Does a higher loading of TMEDA relative to the 'catalyst' restore complete inhibition of hidden BH3 catalysis in the hydroboration of 4-tert-butylstyrene at 80 and 100 °C? target: TMEDA inhibition test for hidden BH3 catalysis in HBpin hydroboration; product at 100 °C with 1.0 eq TMEDA = 7 %	`loading-alkene` in acs-tmeda-loading	`partial` not-applicable rule applies to negative and inconclusive findings only	informs HYP	record

Issues (5 open questions and untried branches)

ISS Is there any amine or other trap that sequesters BH3 irreversibly above 60 °C under hydroboration conditions? (open-question)
ISS Which of the published 'true catalysis' claims validated by TMEDA above 60 °C survive a re-test below 60 °C or by 11B NMR? (open-question)
ISS Rely on observing the TMEDA.(BH3)2 adduct by 11B NMR rather than on inhibition alone. (proposed-by-authors)
ISS Treat any HBpin hydroboration run at or above 80 °C as susceptible to hidden BH3 catalysis. (proposed-by-authors)
ISS Re-test the published 'true catalysis' claims whose only evidence was TMEDA inhibition above 60 °C, at or below 60 °C or by direct 11B NMR observation of the adduct. (inferred-by-ingest)