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\DOI{10.5802/crchim.416}
\datereceived{2024-10-02}
\daterevised{2025-02-11}
\dateaccepted{2025-08-29}
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\dateposted{2025-10-10}
\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{review}

\title{Activation of N-containing olefins and alkynes with superacids}

\alttitle{Activation d'ol\'{e}fines et d'alcynes azot\'{e}es en milieu
superacide}

\author{\firstname{Delphine} \lastname{Pichon-Barr\'{e}}\CDRorcid{0000-0002-2307-6388}\IsCorresp}
\address{UMR-CNRS 7285, IC2MP, Universit\'{e} de Poitiers, Poitiers
Cedex 9 86073, France}
\email[D. Pichon-Barr\'{e}]{delphine.pichon.barre@univ-poitiers.fr}

\author{\firstname{H\'{e}l\`{e}ne} \lastname{Carreyre}}
\addressSameAs{1}{UMR-CNRS 7285, IC2MP, Universit\'{e} de Poitiers, Poitiers
Cedex 9 86073, France}

\author{\firstname{Fr\'{e}d\'{e}ric} \lastname{Lecornu\'{e}}}
\addressSameAs{1}{UMR-CNRS 7285, IC2MP, Universit\'{e} de Poitiers, Poitiers
Cedex 9 86073, France}

\author{\firstname{Agn\`{e}s}\nobreakauthor\lastname{Martin-Mingot}\CDRorcid{0000-0002-2633-3714}}
\addressSameAs{1}{UMR-CNRS 7285, IC2MP, Universit\'{e} de Poitiers, Poitiers
Cedex 9 86073, France}

\author{\firstname{Bastien} \lastname{Michelet}\CDRorcid{0000-0002-3248-5781}}
\addressSameAs{1}{UMR-CNRS 7285, IC2MP, Universit\'{e} de Poitiers, Poitiers
Cedex 9 86073, France}

\author{\firstname{S\'{e}bastien} \lastname{Thibaudeau}\CDRorcid{0000-0002-6246-5829}\IsCorresp}
\addressSameAs{1}{UMR-CNRS 7285, IC2MP, Universit\'{e} de Poitiers, Poitiers
Cedex 9 86073, France}
\email[S. Thibaudeau]{sebastien.thibaudeau@univ-poitiers.fr}

\shortrunauthors

\def\thanksname{Note}

\thanks{This review expands on a previously published review
``Synthesis of fluorinated nitrogen-containing compounds through
superelectrophilic activation in superacid HF/$\mathrm{SbF}_5$''~\cite{159}.}

\keywords{\kwd{Superacid}
\kwd{Superelectrophile}
\kwd{Hydrofluorination}
\kwd{Cyclization}
\kwd{Polycyclization}}

\altkeywords{\kwd{Superacide}
\kwd{Super\'{e}lectrophile}
\kwd{Hydrofluorination}
\kwd{Cyclisation}
\kwd{Polycyclisation}}

\begin{abstract}
In superacid conditions, through the capacity to generate polycationic
species from functionalized organic substrates, original reactions can
be conducted from unsaturated nitrogen-containing compounds, ranging
from hydro- and heterofluorination to polycyclization. These strategies
allow the synthesis of elaborate enantioenriched polyfunctionalized
compounds, and their final exploitation in a late-stage modification
approach also demonstrates their synthetic potential.
\end{abstract}

\begin{altabstract}
Exploitant la capacit\'{e} de g\'{e}n\'{e}rer des esp\`{e}ces
polycationiques \`{a} partir de substrats organiques
fonctionnalis\'{e}s en conditions superacides, des r\'{e}actions
originales peuvent \^{e}tre men\'{e}es \`{a} partir de compos\'{e}s
azot\'{e}s insatur\'{e}s, allant de l'hydro- et
h\'{e}t\'{e}rofluoration \`{a} la polycyclisation. Ces strat\'{e}gies
permettent la synth\`{e}se de compos\'{e}s polyfonctionnalis\'{e}s
\'{e}nantio-enrichis \'{e}labor\'{e}s et leur exploitation finale dans
une approche de modification tardive d\'{e}montre \'{e}galement leur
potentiel synth\'{e}tique.
\end{altabstract}

\maketitle

\vspace*{1pc}

\twocolumngrid

\end{noXML}

\section{Introduction}\label{sec1}

The~hydrofunctionalization of N{-}containing alkenes and alkynes
represents an attractive, atom-economical approach to furnish linear or
heterocyclic nitrogen-containing molecules, which are widespread
moieties in the pharmaceutical and agrochemical fields~\cite{1,2,3}.
Nonetheless, applying this strategy to unsaturated amines remains
limited because of the electronic deactivation of the unsaturated C--C
bond after protonation of the amino group under acid conditions 
(Scheme~\ref{sch1}A). Over the past decades, our group has shown that
the use of superacid activation can enhance the reactivity of such
substrates, which allows us to overcome this obstacle.

\begin{scheme*}
\includegraphics{sc01}
\vspace*{1pc}
\caption{\label{sch1}N-allylamines activation in classical acidic
conditions vs {superacidic} conditions (adapted/redrawn
from~\cite{159}).}
\end{scheme*}

The term ``superacid'' was first mentioned in the literature by Hall
and Conant~\cite{4}. However, it was only in the 1960s that George Olah
brought it up to date when his work was focused on the use of highly
acidic non-aqueous systems for studying long-lived carbocations using
NMR spectroscopy~\cite{5}. The  {significant} contribution of George
Olah in carbocation chemistry has been later recognized with his
attribution of the Nobel Prize in Chemistry in 1994~\cite{6}. In 1971,
Gillespie arbitrarily defined the Br\o{}nsted superacids as non-aqueous
systems having an acidity equal or greater than that of 100~wt\%
sulfuric acid~\cite{7}. This can be quantified using the Hammett
acidity scale with $H_0$ values lower than ${-}$12~\cite{8,9}. Since
then, a wide range of superacid media have been studied including pure
liquid Br\o{}nsted superacids and their combinations with various
Br\o{}nsted or Lewis acids~\cite{5}. The strongest superacid systems
are composed of hydrogen fluoride and antimony pentafluoride
(HF/$\mathrm{SbF}_{5}$) with Hammett acidities that could reach $H_0$ values
down to ${-}$24~\cite{10}. Under these highly acidic conditions,
functionalized organic substrates can be mono- or polyprotonated
leading to original reactivity (Scheme~\ref{sch1}B). Through the
addition of a positive charge (or electron deficiency) close to them,
the generated cations show increased electron deficiency and enhanced
electrophilic character (superelectrophilic activation) allowing
reactions with poor nucleophilic \unskip\break partners~\cite{11,12,13,14}.

Although other contributions allowed the development of elegant
strategies, especially hydroarylation~\cite{15,16,17,18}, this report only
accounts for the use of superacid-promoted hydrofunctionalization to
generate fluorinated {N}-containing compounds.

\section{Hydrofluorination of unsaturated N-cont\-aining derivatives}

The use of fluorine atom(s) to enhance therapeutic efficiency and
improve pharmacological properties of a drug is a well-established
strategy as shown by the number and diversity of fluorine-containing
pharmaceuticals commercially available~\cite{19,20,21}. This success can
be directly related to the many effects that the fluorine atom(s) and
fluorinated moieties can exert on the {biological and} physicochemical
properties of a molecule~\cite{22,23}. Thanks to these benefits,
fluorine is now ``the second-favorite heteroatom'' after nitrogen in
drug design~\cite{24}, in particular in order to tune amine basicity
to play with the penetration and bioavailability of a
molecule~\cite{25, 26}. In this context, {the development of new}
synthetic pathways to further extend the scope of fluorinated
N{-}containing building blocks is of a {high} interest. 

In this effort, hydrofluorination of unsaturated amines can be
{envisaged} as a {direct} route to monofluorinated amines. However,
radical hydrofluorination compatible with a {wide range} of substrates
has never been applied to unprotected amines~\cite{27,28} and
Pd-catalyzed hydrofluorination is {inefficient} with amine
substrates~\cite{29}. Moreover, the use of Olah's reagent
(HF${\bullet}$pyridine 9:1) with unsaturated amines is limited to very
few examples in the literature with relatively modest
yields~\cite{30,31,32,33,34}, which could be directly related to the
electronic deactivation of the unsaturation after protonation of the
amino group, and neither gold catalysis~\cite{35,36} nor designed
HF-based fluorination reagents can overcome this obstacle~\cite{37}.

In superacid HF/$\mathrm{SbF}_{5}$, amine \textbf{1} can undergo a subsequent
protonation of the alkene moiety to form ammonium--carbenium dication
\textbf{A} (Scheme~\ref{sch2}). {While} the 
``non-coordinating'' properties of
fluoroantimonate anions were largely exploited in catalysis to tune
catalyst properties~\cite{38}, ammonium--carbenium superelectrophilic
activation overcomes the non-coordinating anions' properties~\cite{39}.
The electron-withdrawing effect of the proximal protonated
nitrogen-based group {enhances the superelectrophilic character of the
dication} {\textbf{A}}, allowing its trapping by $\mathrm{SbF}_{6}^{-}$ or
$\mathrm{Sb}_2\mathrm{F}_{11}^{-}$ anions~\cite{40,41}, {resulting in} {the formation
of the} corresponding fluorinated amines \textbf{2} in good
yields~\cite{42,43}.

\begin{scheme*}
\includegraphics{sc02}
\vspace*{1pc}\caption{\label{sch2}Hydrofluorination of unsaturated amines in
superacidic conditions (adapted/redrawn from~\cite{159}).}
\vspace*{-3pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc03}
\vspace*{1pc}\caption{\label{sch3}Synthesis of gem-chlorofluorinated and
gem-difluorinated N-containing derivatives in HF/$\mathrm{SbF}_{5}$
(adapted/redrawn from~\cite{159}).}
\vspace*{-8pt}
\end{scheme*}

\textit{Gem}-chlorofluorinated {N}-containing derivatives \textbf{4}
(successfully applied to amines, amides, sulfonamides {and} imides with
good yields 68--83\%) at ${-}$20~\textdegree C or the corresponding
\textit{gem}-difluorinated products \textbf{5} under more acidic
conditions at 0~\textdegree C {can be easily obtained by applying the
previously described method to chlorine-substituted olefins}
{\textbf{3}} (Scheme~\ref{sch3})~\cite{44}.

\begin{scheme*}
\includegraphics{sc04}
\vspace*{1pc}
\caption{\label{sch4}Reactivity of $N$-allyl amino esters in
HF/$\mathrm{SbF}_{5}$% (adapted/redrawn from~\cite{159})
.}
\vspace*{-8pt}
\end{scheme*}


We have recently explored this strategy for the diastereoselective
hydrofunctionalization of allylic amines derived from natural amino
acids~\cite{45}. In this case, the reaction mechanism involves the
accumulation of chiral cyclic ammonium--carboxonium dications after a
tandem diastereoselective proton transfer/intramolecular cyclization
from ${N}$-allyl substituted amino esters (Scheme~\ref{sch4}). The
latter can then react inter- or intramolecularly to furnish fluorinated
amines \textbf{7}, amino alcohols \textbf{8} or amino lactones
\textbf{8}$'$ depending on the reaction conditions. The diprotonation of
unsaturated amino esters followed by a concerted diastereoselective
proton-transfer/cyclization with full diastereocontrolled formation of
a chiral lactone \textbf{8a}$'$ from a L-proline-derived substrate
confirms the persistency of a well-tuned chiral dication \textbf{B}
which should open interesting synthetic \mbox{perspectives}.


Alternatively, the synthesis of fluorinated amine derivatives can also
be achieved from saturated substrates through the superelectrophilic
C(sp$^{3}$)--H bond fluorination of aliphatic amines in
superacid~\cite{46}. Indeed, by  {using} the hydride abstraction
{capabilities} of CCl$_{3}^{+}$ species in HF/$\mathrm{SbF}_{5}$ 
conditions~\cite{47}, we developed a direct strategy  {to fluorinate}
unactivated C(sp$^{3}$)--H bonds of terminal isopropyl moieties in
aliphatic amines with moderate to {fair} yields. This {method} was also
{used} to introduce other nucleophiles, allowing arylation, amination,
and deuteration (Scheme~\ref{sch5}A). Extended to amides and esters,
the superacid-promoted electrophilic activation can be exploited to
generate alcohols \textbf{11} in a selective {way}
(Scheme~\ref{sch5}B).


\begin{scheme*}
\includegraphics{sc05}
\vspace*{1pc}
\caption{\label{sch5}(A) Superelectrophilic C(sp$^{3}$)--H bond
functionalization of aliphatic amines in superacid; (B)
Superelectrophilic C(sp$^{3}$)--H bond hydroxylation of aliphatic
amides and esters in superacid% (adapted/redrawn from~\cite{159})
.}
\vspace*{-5pt}
\end{scheme*}

The hydrofluorination reaction in HF/$\mathrm{SbF}_{5}$ can also be applied to
alkynes. Starting from 1-bromopropargylic amines \textbf{12}, the
trifluorinated amines \textbf{13} can be synthesized with moderate to
good yields (Scheme~\ref{sch6}). On the other hand,
1-bromodifluoroamines or 2-bromo-1,1,1-trifluorinated products {may} be
isolated depending on the {amine substitution and} reaction
conditions~\cite{48}.\looseness=-1

\begin{scheme*}
\includegraphics{sc06}
\vspace*{1pc}\caption{\label{sch6}Synthesis of trifluorinated amines from
1-bromopropargylic amines in HF/$\mathrm{SbF}_{5}$% (adapted/redrawn from~\cite{159})
.}
\end{scheme*}


The \textit{gem}-difluorination reaction can also be efficiently
achieved from propargylic amines \textbf{14} in HF/$\mathrm{SbF}_{5}$ through
the successive formation of dicationic superelectrophiles \textbf{C}
and \textbf{D} to afford the \textit{gem}-difluorinated products in
good yields (Scheme~\ref{sch7}A)~\cite{49}. As an alternative method,
the \textit{gem}-difluorinated amine derivatives could also be obtained
through oxidative \textit{gem}-difluorination in the presence of
${N}$-bromosuccinimide (NBS) from allylic or haloamines
(Scheme~\ref{sch7}B).

\begin{scheme*}
\includegraphics{sc07}
\vspace*{1pc}\caption{\label{sch7}Synthesis of gem-difluorinated amines in
HF/$\mathrm{SbF}_{5}$ starting from propargylic amines (A) or from allylic and
haloamines (B) (adapted/redrawn from~\cite{159}).}
\end{scheme*}

Over the past decades, because of their singular physicochemical
features~\cite{50}, {ureas have seen a renewed interest in
chemistry-related fields} with remarkable applications
(organocatalysts~\cite{51,52}, anion chemosensors~\cite{53,54}, {and}
artificial membranes~\cite{55,56}). {Furthermore, the recent
development of urea-based anticancer compounds}~\cite{57,58}
{highlights their} potential as key structural elements and/or
pharmacophores in medicinal chemistry. Thus, generating bioisosters
from this functional group is an area of interest for the
\mbox{pharmaceutical} \mbox{industry}~\cite{59,60,61}. Considering the well-known
bioisosterism between fluoroolefins and amides~\cite{62} and the
scarcity of reported urea bioisosters in SAR studies~\cite{63,64,65},
we have developed, in collaboration with the Evano group, the first
stereoselective {hydrofluorination} of ynamides \textbf{17} in HF as an
entry to ${\upalpha}$-fluoroenamides \textbf{18}, potent urea
bioisosters (Scheme~\ref{sch8})~\cite{66}. In neat HF conditions, after
protonation,  {extremely} reactive keteniminium intermediates
\textbf{E} can be further stereoselectively \mbox{fluorinated}
(sterically-favored incoming approach of the \mbox{fluorinating} agent) to
{produce} fluoroenamides \textbf{18} in excellent yields. A similar
reaction can also {occur} in HF/pyridine systems~\cite{67}, {prompting}
us to develop a semi-empirical {approach} {to determine} the acidity of
HF/base mixtures~\cite{68}. 

\begin{scheme*}
\includegraphics{sc08}
\vspace*{.5pc}
\caption{\label{sch8}Hydrofluorination of ynamides in neat HF
(adapted/redrawn from~\cite{159}).}
\vspace*{-7pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc09}
\vspace*{.5pc}
\caption{\label{sch9}Behavior of ynamides \textbf{17e} in HF/pyridine
vs HF conditions (adapted/redrawn from~\cite{159}).}
\vspace*{-9pt}
\end{scheme*}

Surprisingly, while the targeted fluoroenamide \textbf{18e} was
{isolated} in 63\% yield from ynamide \textbf{17e} after reaction at
${-}$10~\textdegree C in HF/pyridine, the tetracyclic compound
\textbf{19e} was generated at ${-}$78~\textdegree C in neat HF as a single
{diastereomer} in 79\% yield (Scheme~\ref{sch9})~\cite{69}. With these
unexpected results in hand, various acids were screened to further
optimize the reaction conditions. The use of triflic acid (TfOH) as
well as catalytic amounts of bistriflimidic acid (Tf$_2$NH) in
CH$_2$Cl$_2$ provided selectively the polycyclic product \textbf{19e}
in 90\% yield. The method designed was exemplified to a large range of
substrates (more than 15 examples) with good yields and was
successfully applied to chiral ynamides and bis-ynamides, allowing
larger molecular diversity of the reaction.


The following mechanism was hypothesized based on a series of
experiments using deuterated substrates and reactants, as well as DFT
calculations, to justify the original cationic polycyclization of
ynamides (Scheme~\ref{sch10}). {The keteniminium ion} {\textbf{E}} {is
generated first, followed by a~\cite{1,5}-sigmatropic hydrogen shift
from the intermediate} {\textbf{F}} {(in resonance with the bis-allylic
carbocation} {\textbf{G}}). The first cycle would be generated by a
diastereoselective 4${\uppi}$ conrotatory electrocyclization, resulting
in \textbf{H}. The tetracycle and its {\textit{cis}} {ring
junction would then be formed via a final cyclization of the benzylic
cation} {\textbf{H}}.

\begin{scheme*}
\includegraphics{sc10}
\vspace*{.5pc}\caption{\label{sch10}Proposed mechanism for the polycyclization of
ynamides in HF (adapted/redrawn from~\cite{159}).}
\end{scheme*}

Having demonstrated that this polycyclization could be conducted with
catalytic amounts of bistriflimidic acid (Tf$_2$NH, 20 mol\% in
CH$_2$Cl$_2$), the method was applied to a range of ynamides
derivatives \textbf{17} (Scheme~\ref{sch11}).

\begin{scheme*}
\includegraphics{sc11}
\vspace*{.5pc}\caption{\label{sch11}Selected examples of N-containing chiral
tetracycles \textbf{19} generated from ynamides \textbf{17} in the
presence of catalytic amounts of Tf$_2$NH (adapted/redrawn
from~\cite{159}).}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc12}
\vspace*{.5pc}
\caption{\label{sch12}Synthesis of chlorofluorinated amines from
$N$-allylamines in superacid conditions (adapted/redrawn
from~\cite{159}).}
\vspace*{-.5pc}
\end{scheme*}

\section{Heterofluorination of unsaturated N-containing derivatives}

Following our interest in the synthesis of fluoroamine derivatives, we
also became interested in the halofluorination of unsaturated amines.
While electrophilic activation of alkenes {by} halonium ion addition
has been {widely employed} {to produce new} C--C, C--O, C--N, and C--X 
bonds~\cite{70,71,72,73,74,75,76}, its application to the
halofluorination of allylic amine derivatives is limited to few
examples~\cite{30,77,78,79,80,81,82}. {The combination of HF/base and}
${N}$-halosuccinimide {(NXS) reagents is particularly efficient
for the halofluorination of C${=}$C double bonds, although it is
significantly less efficient on allylic amine derivatives.} {Again, the
fundamental challenge in applying chlorofluorination to unsaturated
amines is the significant \mbox{decrease} in nucleophilicity of the double
bond after protonation of the amino group, which prohibits any
interaction with a halonium ion source}~\cite{83}. {In this regard,
tandem superelectrophilic activation of unsaturated nitrogen-containing
compounds with} {${N}$}{-chlorosuccinimide (NCS) was discovered to
be a useful alternative to address this} difficulty
(Scheme~\ref{sch12})~\cite{84}. In superacid, the classical chloronium
ion source NCS can be activated through the protonation of both
carbonyl groups as showed by low temperature NMR experiments. In these
conditions, NCS---activated as superelectrophilic species
(\textbf{I})---is reactive enough to allow the formation of chloronium
ion \textbf{J} from amine \textbf{20}. The fluorination of this
chloronium ion leads to the corresponding
${\upbeta}$-fluoro-${\upgamma}$-chlorinated amine \textbf{21}. This method
was found to be compatible with a wide range of unsaturated
nitrogen-containing substrates. 


Directed by a halogen substituent on olefins \textbf{3b} and
\textbf{3b}$'$, chlorofluorination {demonstrated} good efficiency for the
synthesis of original and high-valued polyhalogenated building blocks
in relatively good yields (Scheme~\ref{sch13}).


\begin{scheme*}
\includegraphics{sc13}
\vspace*{1pc}
\caption{\label{sch13}Extension of the method to the synthesis of
polyhalogenated compounds (adapted/redrawn from~\cite{159}).}
\vspace*{-.3pc}
\end{scheme*}

Our group has also shown that 1,2-oxyfluorination of unsaturated amines
can be performed in the presence of hydrogen peroxide. Applied to
elaborated unsaturated amines such as quinine derivatives \textbf{22},
\mbox{fluorohydrins} \textbf{23} could be synthesized along with ketones
\textbf{24} (Scheme~\ref{sch14})~\cite{85}.

\begin{scheme*}
\includegraphics{sc14}
\vspace*{.5pc}
\caption{\label{sch14}Oxyfluorination of quinine derivatives using
superacid in the presence of oxygen peroxide% (adapted/redrawn from~\cite{159})
.}
\vspace*{-.5pc}
\end{scheme*}

\section{Anti-Markovnikov hydroarylation of unsaturated N-containing
derivatives}

In the course of our work on superacid-mediated hydrofluorination of
olefins, the {unusual} formation of a ${\upgamma}$-fluorinated product
\textbf{2}$'$\textbf{e} besides the desired product \textbf{2e} from
substrate \textbf{1e} led to a {deep} mechanistic investigation
(Scheme~\ref{sch15})~\cite{86}.

\begin{scheme*}
\includegraphics{sc15}
\vspace*{.5pc}\caption{\label{sch15}Hydrofluorination of substrate
\textbf{1e} in HF/$\mathrm{SbF}_{5}$ (adapted/redrawn
from~\cite{159}).}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc16}
\vspace*{.5pc}
\caption{\label{sch16}Reactivity of $N$-allylanilines in
HF/$\mathrm{SbF}_{5}$ (adapted/redrawn from~\cite{159}).}
\vspace*{-.5pc}
\end{scheme*}

{The Markovnikov product} {\textbf{2e}} {and anti-Markovnikov product}
$\mathbf{2}'\mathbf{e}$ {may respectively result from the nucleophilic trapping
of the secondary carbocation} {\textbf{A}} {(${\upbeta}$-position) and
primary carbocation} {\textbf{L}} (${\upomega}$-position)~\cite{87},
{or from a nonclassical intermediate} {\textbf{K}}
(${\upmu}$-hydrido-bridged structure)~\cite{88,89}. {By
submitting fluorinated products} {\textbf{2e}} {and} $\mathbf{2}'\mathbf{e}$ {to
HF/SbF}$_{5}${, both compounds were found to be in a thermodynamic
equilibrium via the C--F bond activation/carbocation
formation/fluorination process under the reaction} {conditions}. As a
consequence, intramolecular trapping of the generated cationic
intermediate through stable C--C bond formation was {proposed}. As
{previously stated}, starting from ${N}$-allylic aniline
derivatives, intramolecular trapping of the generated carbocation with
aromatics {enabled} the synthesis of indolines \textbf{25} and
tetrahydroquinolines \textbf{26}, which were found to be stable under
the reaction conditions. {A significant difference in behavior was
noticed between anilines substituted with electron-donating or
electron-withdrawing groups.} For example, {the reaction of} aniline
\textbf{1j} led to a mixture of products \textbf{25j} and \textbf{26j}
in a 1:6:1 ratio {while} nitro-substituted substrate \textbf{1k}
{transformed} only {into} the tetrahydroquinoline \textbf{26k}
(Scheme~\ref{sch16}). 

\begin{scheme*}
\includegraphics{sc17}
\vspace*{.5pc}\caption{\label{sch17}Proposed superelectrophilic structures in
superacid based on DFT calculations (adapted/redrawn from~\cite{159}).}
\vspace*{-.5pc}
\end{scheme*}


This difference in reactivity prompted us to evaluate the protonation
of these substrates by DFT calculations (M06-2X level). This study
revealed that the polyprotonation of ``non-deactivated'' aniline
derivatives (anilines are partially deactivated in superacid due to
nitrogen protonation) results in the formation of dicationic
ammonium--arenium species \textbf{M} (Scheme~\ref{sch17}). {The species
formed via protonation of the nitrogen atom and the C--C double bond
has {stationary} points on the potential energy surface as well, but it
is 7.7 kcal/mol more energetic. Similar calculations using
4-nitroaniline derivative} {\textbf{1k}} {predicted the first
protonation of the nitro group and the second protonation of the amino
group. Interestingly, the computed energies suggested that further
protonation on the double bond would result in a triprotonated
carbenium ion (type} {\textbf{A}}{).} This reaction was {anticipated}
to be energetically more favorable (by over 40 kcal/mol) {than aromatic
ring protonation, implying that tetrahydroquinoline products would not
be produced by aromatic ring protonation for deactivated substrates.}
{A third protonation would result in a secondary carbenium ion of type}
{\textbf{A}}{, however a second stationary point (energy minimum) was
near in energy at +1.1 kcal/mol. The optimized} $\mathbf{K}'$
{structure (Scheme~\ref{sch17}) has a three-center two-electron bond
intermediate corresponding to a symmetrically
${{\upmu}}$-hydrido-bridged species (${{\upmu}}$-H${\cdots}$C
distances: 1.33~\AA{}, activated C${=}$C bond length: 1.39~\AA{}).}  
\looseness=-1

\begin{scheme*}
\includegraphics{sc18}
\vspace*{.5pc}
\caption{\label{sch18}Structures of the Wheland intermediates of
substrate \textbf{1k} (adapted/redrawn from~\cite{159}).}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc19}
\vspace*{.5pc}\caption{\label{sch19}Application of the method to the synthesis of
nitrojulolidine \textbf{28} (adapted/redrawn from~\cite{159}).}
\end{scheme*}

As a result, the selectivity for the production of six-membered ring
products from deactivated substrates was attributed to the relative
stabilities of Wheland intermediates {\textbf{N}} {and} $\mathbf{N}'$
{emerging from cyclization via trapping of intermediate} $\mathbf{K}'$
{(Scheme~\ref{sch18}). In the case of substrate} {\textbf{1k}}{, the
energy difference between intermediates} {\textbf{N}} {and more
strained} $\mathbf{N}'$ {is responsible for the formation of the
tetrahydroquinoline\break product.


This anti-Markovnikov process was then {used to prepare}
nitrogen-containing polycyclic molecules~\cite{90}. Starting from
substrate \textbf{1k}, through a tandem
cyclization/allylation/cyclization process, the nitro-substituted
julolidine \textbf{28} was synthesized in an overall yield of 65\%
(Scheme~\ref{sch19}).


\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc20}
\vspace*{.5pc}
\caption{\label{sch20}C--F bond activation and intramolecular trapping
of ammonium--carbenium dications in HF/$\mathrm{SbF}_{5}$ (adapted/redrawn
from~\cite{159}).}
\vspace*{-1pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc21}
\vspace*{.5pc}
\caption{\label{sch21}Selective hydrofluorination and cyclization of
$N$-allyl-benzenesulfonamides in HF/$\mathrm{SbF}_{5}$ (adapted/redrawn
from~\cite{159}).}
\vspace*{-4pt}
\end{scheme*}

As mentioned earlier, the capability of superelectrophiles to react
with poor nucleophiles can be exploited not only in hydrofluorination
reactions. Indeed, depending on the superacid conditions, C--F bonds
can be activated ($\mathrm{SbF}_{5}$ loading ${\geq}$ 13.6 mol\%), thus
displacing the equilibrium toward the formation of an
ammonium--carbenium intermediate \textbf{A}, prone to be quenched
{intramolecularly} (Scheme~\ref{sch20}).

\begin{scheme*}
\vspace*{3pt}
\includegraphics{sc22}
\vspace*{1pc}
\caption{\label{sch22}Superacid/copper-mediated multistep divergent
synthesis of 4-aminobenzenesulfo\-namides (adapted/redrawn
from~\cite{159}).}
\vspace*{-2pt}
\end{scheme*}


Since the discovery of sulfa drugs and their antibiotic and
antibacterial properties~\cite{91}, sulfonamides and sultams have
gained popularity in SAR investigations in medicinal chemistry research
with numerous} applications~\cite{92,93,94,95,96,97}. As a consequence,
\mbox{diversifying} the synthetic route for their preparation found a strong
interest~\cite{98}.

\begin{scheme*}
\vspace*{.6pc}
\includegraphics{sc23}
\vspace*{1pc}
\caption{\label{sch23}Superacid-mediated synthesis of enantioenriched
benzosultams% (adapted/redrawn from~\cite{159})
.}
\end{scheme*}

Exploiting the stability of fluorinated products (obtained from
hydrofluorination reactions) in HF/$\mathrm{SbF}_{5}$
($\mathrm{SbF}_{5}$ loading ${\leq}$ 10 mol\%), and the ability to
activate C--F bonds at higher acidity with a concomitant decrease in
the nucleophilicity of the fluoride ions, fluorinated sulfonamides
\textbf{30} and benzofused sultams \textbf{31} can be selectively
synthetized from ${N}$-allyl-benzenesulfonamides \textbf{29}
(Scheme~\ref{sch21})~\cite{99}. With this method, a large {variety} of
products \textbf{30} and \textbf{31} incorporating alkyl, halogen,
amide, ester, ketone, and other functions were generated in good
yields.


{Given that amino-benzenesulfonamide derivatives and their cyclic
analogues are interesting targets for various} therapeutic applications
(inhibition of matrix  metalloprotease~\cite{100}, carbonic
anhydrases~\cite{93, 94, 101} or HIV protease~\cite{102, 103} for
instance), the method described above was next applied to their
synthesis. A complete set of fluorinated 4-aminobenzofused sultams and
fluorinated 4-aminobenzenesulfonamides could be produced from
halogen-substituted derivatives using a combination of
superacid-mediated cyclization/hydrofluorination and Ulmann-type
coupling with amines~\cite{104}. For instance, starting from
\mbox{brominated} ${N}$-allyl-benzenesulfonamide \textbf{29d},
fluorinated 4-morpholino-benzenesulfonamide \textbf{34d} and
fluorinated 4-morpholino-benzofused sultam \textbf{36d} were
synthesized in overall good yields, confirming the synthetic potential
of this method (Scheme~\ref{sch22}).


Using the stability of benzylic carbocations and {their restricted
conformation due to} benzylic strain~\cite{105,106}, we hypothesized
that starting from simple ${N}$-(arenesulfonyl)-ephedrine
derivatives \textbf{37}, dicationic intermediate \textbf{O} could be
generated under superacidic conditions. It would react
diastereoselectively, to {afford} enantiopure benzosultams
\textbf{38}~\cite{107}. {Taking advantage of the chiral pool, a number
of optically active} {${N}$}{-(arenesulfonyl)-amino alcohols were
successfully transformed in triflic acid into enantiopure benzosultams
with a diverse range of functionalities and substitution patterns}
(Scheme~\ref{sch23}).


Pursuing our efforts to develop hydrofunctionalization methods, we also
turned our attention to organophosphorus derivatives which have found
wide application in various fields such as catalysis, medicinal
chemistry, and material science~\cite{108,109,110,111,112}. Starting
from arylated phosphine oxide derivatives \textbf{39a} in
HF/$\mathrm{SbF}_{5}$ superacid conditions, the cyclized
phosphinindoline \textbf{40a} was generated in a 2/3 mixture of
\textit{syn/anti} diastereomers (Scheme~\ref{sch24}A)~\cite{113}.  The
same substrate submitted to anhydrous HF \mbox{($H_0 \approx -11$)}\ or
CF$_{3}$SO$_{3}$H ($H_0 = -14$) remained unreactive at
${-}$20~\textdegree C. These results confirmed that activation of the
substrate is strongly dependent on the (super)acidity of the medium, a
result that is consistent with a superelectrophilic activation process.
This hypothesis was further confirmed by in-situ low-temperature NMR
experiments and single-crystal X-ray diffraction studies showing
evidences for the formation of phosphonium--carbenium dications in
HF/$\mathrm{SbF}_{5}$. The superelectrophilic character of these
species was exploited in intra- and intermolecular hydroarylation
reactions (Scheme~\ref{sch24}B).

\begin{scheme*}
\includegraphics{sc24}
\vspace*{.5pc}\caption{\label{sch24}Reactivity of phosphonium--carbenium
superelectrophiles toward hydroarylation reaction% (adapted/redrawn from~\cite{159})
.}
\end{scheme*}

\section{Cyclization/fluorination of unsaturated N-containing derivatives}

{As demonstrated in the synthesis of benzofused sultams, the
superelectrophilic nature of ammonium--carbenium dications enables
intramolecular trapping with poor nucleophiles. This reactivity was
further expanded by utilizing a C${=}$C double bond as a nucleophile. The
cyclization/fluorination of differently substituted dienes}
{\textbf{41}} {was found to be a versatile technique to obtain
fluorinated piperidines} \textbf{42} (Scheme~\ref{sch25})~\cite{114}.

\begin{scheme*}
\includegraphics{sc25}
\vspace*{.5pc}
\caption{\label{sch25}Cyclization/fluorination of $N$-dienes in superacid
HF/$\mathrm{SbF}_{5}$ (adapted/redrawn from~\cite{159}).}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc26}
\vspace*{.5pc}
\caption{\label{sch26}(A) Formation of 3- and 4-fluoropiperidines in
HF/$\mathrm{SbF}_{5}$; (B) Formation of 4-fluoropiperidine
{\textbf{41e}} from 3-fluoropiperidine {\textbf{42e}} in
HF/$\mathrm{SbF}_{5}$ (adapted/redrawn from~\cite{159}).}
\vspace*{-.5pc}
\end{scheme*}

Low-temperature experiments were {carried out} to {investigate} the
reaction mechanism. After \mbox{reaction} of amine \textbf{42e} in
HF/$\mathrm{SbF}_{5}$ (11.1~mol\% $\mathrm{SbF}_{5}$) at
${-}$78~\textdegree C, 21\% of 3-fluoropiperidine \textbf{43e} was
generated beside 4-fluoro analog \textbf{42e} (Scheme~\ref{sch26}A).
{Furthermore}, substrate \textbf{41e} was shown to {transform} only
{into} \textbf{42e} after reaction at 0~\textdegree C. Thus, milder
conditions were {required} to selectively {generate} the
3-fluoropiperidine, which indicated that this isomer might be an
intermediate of the reaction. The quantitative formation of compound
\textbf{42e} starting from 3-fluoropiperidine \textbf{43e} {validated}
this hypothesis (Scheme~\ref{sch26}B), which allowed to postulate the
following mechanism (Scheme~\ref{sch27}). 


\begin{scheme*}
\includegraphics{sc27}
\vspace*{.5pc}\caption{\label{sch27}Proposed mechanism for the
cyclization/fluorination reaction of diallylamines (adapted/redrawn
from~\cite{159}).}
\vspace*{-1.2pc}
\end{scheme*}

After {nitrogen protonation}, the superacidity of the medium allows
formation of ammonium--carbenium dication \textbf{Q}. {Proximity of the
charges greatly activates its electrophilic character, permitting
nucleophilic addition of the non-protonated alkene (despite electronic
deactivation due to the strong withdrawing influence of the proximal
ammonium ion), resulting in} intermediate \textbf{R}. A sequence of
hydride and methyl shifts favors the formation of the more stable
dication \textbf{T} through the generation of intermediate \textbf{S},
both respective precursors of \textbf{42} and \textbf{43} after
fluoride ion trapping. 


Using superelectrophilic ammonium--${\upalpha}$-chloro\-carbenium
dications allowed the direct preparation of difluorinated piperidines
by cyclization and fluorination. Starting from chlorinated
{${N}$}{-diene} {\textbf{41f}}{, the difluorinated piperidine}
{\textbf{42f}} was directly synthesized in 57\% yield 
(Scheme~\ref{sch28})~\cite{115}.


\begin{scheme*}
\includegraphics{sc28}
\vspace*{1pc}
\caption{\label{sch28}Direct synthesis of a difluorinated piperidine
through cyclization/fluorination reaction (adapted/redrawn
from~\cite{159}).}
\end{scheme*}

Alternatively, using ammonium--nitrilium dications as
superelectrophiles, unsaturated piperidinones can also be synthesized
exploiting the alkene moiety as internal nucleophile~\cite{46}. These
ammonium--nitrilium dications \textbf{U} have been observed and
characterized by single-crystal X-ray diffraction analysis and
low-temperature NMR experiments in superacid media. Taking advantage of
their superelectrophilic character, their intramolecular trapping with
poorly nucleophilic alkenes {allows} straightforward {access to}
high-valued (enantioenriched) piperidin-3-ones \textbf{45}
(Scheme~\ref{sch29}). 
\vspace*{-3pt}


\begin{scheme*}
\includegraphics{sc29}
\vspace*{1pc}
\caption{\label{sch29}Exploitation of ammonium--nitrilium dications'
reactivity in HF/$\mathrm{SbF}_{5}$ for the synthesis of 
piperidinones% (adapted/redrawn from~\cite{159})
.}
\end{scheme*}


\section{Miscellaneous applications}
\vspace*{-3pt}

\subsection{Late-stage functionalization}

{The development of new synthetic methods is essential for the
discovery of efficient and selective} pharmaceuticals~\cite{116}.
Jacquesy et al. have {shown that activation in superacid medium is a
suitable synthetic tool in this perspective, allowing the modification
of simple to highly complex molecules and thereby giving access to new
analogs}~\cite{117, 118}. The most notable example is the direct
synthesis of vinflunine from a \textit{Vinca} alkaloid through a direct
modification in a HF/$\mathrm{SbF}_{5}$ solution
(Scheme~\ref{sch30})~\cite{119,120,121}. To the best of our knowledge,
despite extensive efforts, this anti-cancer agent~\cite{122},
commercialized under the brand name Javlor{\textregistered}, cannot be
synthesized by other synthetic methods~\cite{123}.


\begin{scheme*}
\includegraphics{sc30}
\vspace*{.5pc}\caption{\label{sch30}Synthesis of vinflunine in
HF/$\mathrm{SbF}_{5}$/CCl$_{4}$ (adapted/redrawn from~\cite{159}).}
\vspace*{-6pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc31}
\vspace*{.5pc}\caption{\label{sch31}Superelectrophilic activation of
Vinca alkaloids in superacid (adapted/redrawn from~\cite{159}).}
\end{scheme*}

The vinorelbine starting material reacts with HF/$\mathrm{SbF}_{5}$ to form a
superelectrophilic ammonium--carbenium dication \textbf{V} which can be
chlorinated in the presence of CCl$_{4}$ to generate intermediate
\textbf{W} {along with} chlorocarbocation $\mathrm{CCl}_{3}^{+}$. The latter can
act as a hydride-abstracting agent (as shown above on some standard
building blocks)~\cite{47}, allowing the ionic electrophilic activation
of the C--H bond which leads to superelectrophile \textbf{Y}. Its
subsequent fluorination and halogen exchange allow delivering
vinflunine (Scheme~\ref{sch31}). A similar strategy has {also} been
applied to diverse \textit{Cinchona} alkaloids~\cite{124,125}. 

\begin{figure*}
\includegraphics{fig01}
\caption{\label{fig1}Binding of primary sulfonamide inhibitors to
carbonic anhydrase. Key interactions between a generic
benzenesulfonamide and the hCA II active site (adapted/redrawn
from~\cite{159}).}
\end{figure*}


\begin{figure*}
\includegraphics{fig02}
\caption{\label{fig2}Fluorinated tertiary benzenesulfonamides acting as
selective hCA IX nanomolar inhibitors (adapted/redrawn
from~\cite{159}).}
\end{figure*}


\subsection{Carbonic anhydrase inhibitors}

Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes
{that participate in a variety of metabolic processes involving the}
hydration/dehydration of carbon dioxide/bicarbonate~\cite{126,127,128}.
Human CAs (hCAs) present 16 isoforms, which belong to the
${\upalpha}$-class. {They differ in cellular location (cytosol,
mitochondria, and cell membrane) and catalytic activity}~\cite{93,94,95}.
They are involved in numerous cellular and physiological activities,
including respiration, electrolyte secretion, pH homoeostasis, and
biosynthetic reactions that require bicarbonate as substrate including
lipogenesis, glucogenesis, and ureagenesis, as well as tumorigenicity
among others~\cite{94}. As a consequence, CAs are well-established
therapeutic targets {for treating a variety of diseases using
inhibitors or activators}~\cite{101, 129, 130}. {Classical CA
inhibitors (CAIs) disrupt the catalytic process by complexing (as
anions) the zinc ion from the enzyme's active site}~\cite{94}. Among
the numerous families of CAIs, primary sulfonamides {are} one of the
most exploited, mainly due to the multiple interactions {that such
compounds can establish with} the hydrophobic and hydrophilic half
parts of the isoforms \mbox{(Figure~\ref{fig1})~\cite{131,132,133}}.


\begin{scheme*}
\vspace*{-1pt}
\includegraphics{sc32}
\vspace*{.5pc}
\caption{\label{sch32}Evaluation of urea bioisosters as CA 
inhibitors%(adapted/redrawn from~\cite{159})
.}
\end{scheme*}

The design of highly selective CAIs is a favored strategy to prevent
undesired side effects~\cite{134,135}. In this context, the so-called
family of ``non-zinc binding inhibitors'' have deeply increased
over the last few years~\cite{136,137,138}, especially in the quest of
potent and selective anti-cancer agents (targeting the
cancer-associated isoforms hCA IX and XII)~\cite{139,140,141,142,143}.
On the other hand, various studies have been conducted on the impact of
fluorine insertion on benzenesulfonamides inhibitors showing that
inserting fluorine atoms can {improve} specific interactions that can
strengthen the inhibition by the fluorinated benzenesulfonamides
compared to the non-fluorinated ones~\cite{144}. 

Our recent investigations on the synthesis of fluorinated compounds in
superacid led to the identification of a series of fluorinated tertiary
benzenesulfonamides \textbf{46} acting as selective hCA IX inhibitors
(Figure~\ref{fig2})~\cite{145,146}. Almost all of the proposed
compounds in this fluorinated series were shown to be highly selective
tumor-associated CAIs that did not inhibit the widespread off-target
isoform hCA II, showing a new mode of inhibition of tumor-associated
CAs by sulfonamides.


Recently, urea derivatives, and especially sulfonylurea analogs, were
found to be good inhibitors of hCA IX/XII~\cite{147,148,149}.
Exploiting our method to design new fluoroenesulfonamides as
${N}$-sulfonylurea isosters~\cite{86}, these compounds, which are
stable in solution, were evaluated as CA inhibitors
(Scheme~\ref{sch32})~\cite{150}. {This study identified a novel, highly
selective family of cancer-related transmembrane CAIs. The studied
${\upalpha}$-fluoroenamide ureidoisosters did not inhibit broadly
distributed cytosolic isoforms hCA I and II, but preferentially
inhibited transmembrane cancer-related isoforms hCA IX and XII.
Modifying the C-substituent of ${\upalpha}$-fluoroenesulfonamide}
{\textbf{47}} {and ${\upalpha}$-fluoroenimide} {\textbf{48}} {resulted
in selective hCA IX, selective hCA XII, or dual hCA IX and hCA XII
isoforms, demonstrating the potential of these novel pharmacophores.}

\begin{scheme*}
\includegraphics{sc33}
\vspace*{.5pc}\caption{\label{sch33}Direct synthesis of fluorinated sugar--azacycle
hybrids in neat HF% (adapted/redrawn from~\cite{159})
.}
\vspace*{-.7pc}
\end{scheme*}

\subsection{Carbohydrate chemistry}

Considering the weakly coordinating nature of the anions in superacid
media, as well as the ability to generate and stabilize cationic
species in HF/$\mathrm{SbF}_{5}$ solutions, {we recently contributed to the
investigation of the glycosylation mechanism in partnership with the
Bl\'{e}riot and Barbero groups. It is accepted that glycosyl
oxocarbenium intermediates play a key role in the stereochemical
outcomes of \mbox{glycosylation} reactions. Yet, their direct experimental
observation remained elusive owing to their very short lifetime in
solution. Using superacidic (non-nucleophilic) conditions, their
analysis by NMR, combined with computational methods, becomes
possible}. Thus, we have reported the use of superacid HF/$\mathrm{SbF}_{5}$
solution to generate and stabilize the glycosyl cations derived from
peracetylated 2-deoxy- and 2-bromoglucopyranose~\cite{151}.

The generation of glycosyl cations from carbohydrates in superacid was
then used for synthetic purposes in the 2-aminoglycoside series
resulting in unprecedented sugar--azacycle hybrids. {A tandem internal
C-glycosylation/fluorination reaction initiated by
2-}{${N}$}{-allyl- and 2-}{${N}$}{-propargyl-glycopyranoses
through the intermediacy of ammonium--carbenium superelectrophiles
afforded new fluorinated compounds} (Scheme~\ref{sch33})~\cite{152}.
{The reaction of} ${N}$-allyl-D-gluco- \textbf{49a} and
D-mannopyranose \textbf{49b} provided the corresponding monofluorinated
bicycles \textbf{50a} (46\%) and \textbf{50b} (53\%) {with} a
1,2-\textit{cis} relationship. {Fluoride anion trapping of the
transitory cyclic cation led diastereoselectively to the formation of a
C--F bond in ${\upbeta}$-position to the nitrogen atom. A similar
process involving alkyne derivative} {\textbf{51}} {enabled direct
synthesis of} analog \textbf{52} {incorporating a vinyl fluoride
moiety}. These sugar-based polycyclic compounds with a central
piperidine ring, amenable to further structural modification, are of
interest in a medicinal chemistry context~\cite{153}, {owing} to the
therapeutic potential {offered by both} fluorine-containing molecules
and sugar derivatives.

\begin{figure*}
\vspace*{2pt}
\includegraphics{fig03}
\caption{\label{fig3}Structure of 1-deoxynojirimycin (DNJ) and
representative derivatives% (adapted/redrawn from~\cite{159})
.}
\vspace*{.5pc}
\end{figure*}

\begin{scheme*}
\includegraphics{sc34}
\vspace*{.8pc}
\caption{\label{sch34}Synthesis of fluorinated $N$-alkyl DNJ in
HF/$\mathrm{SbF}_{5}$% (adapted/redrawn from~\cite{159})
.}
\vspace*{-.3pc}
\end{scheme*}


The replacement by a nitrogen atom of the endocyclic oxygen in
monosaccharides results in iminosugars, a class of sugar mimics with
\mbox{strong} \mbox{therapeutic} potential~\cite{154}. Its most famous
representative, 1-deoxynojirimycin (DNJ), {is} a natural
product~\cite{155} that exhibits potent ${\upalpha}$- and
${\upbeta}$-glucosidases inhibition. The alkylation of the endocyclic
nitrogen with various alkyl chains led to two approved medicines
Zavesca{\textregistered}~and Miglitol{\textregistered}~which target
Gaucher's disease~\cite{156} and type II diabetes~\cite{157},
respectively (Figure~\ref{fig3}). 


In this context, the introduction of a fluorinated chain on the
iminosugar moiety through superacid activation was explored. A small
series of \mbox{fluorinated} DNJ derivatives \textbf{54} and \textbf{56} were
successfully synthetized from ${N}$-allyl and ${N}$-propargyl
iminosugars \textbf{53} and \textbf{55} with good yields, showing the
potential of this strategy to generate potentially interesting
pharmacophores in this context (Scheme~\ref{sch34})~\cite{158}.

\section{Conclusion}

Elegantly exploited by Olah and others for studying long-lived
carbocations, superacids can be considered as especially unique media
to transform organic molecules. In the design of nitrogen-containing
fluorinated bioactive compounds, we recently demonstrated that
superacid media (e.g., HF-based media) allow original
hydrofunctionalization of \unskip\break\mbox{N{-}containing} alkenes and alkynes and
can be applied to the late-stage functionalization of elaborate
molecules ranging from natural products to active pharmaceutical
ingredients. The ability to use superelectrophilic activation for C--H
bond fluorination or for carbohydrate activation
{also} let us envisage original applications of this
chemistry in a near future.

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could \mbox{benefit} from this article, and have
declared no affiliations other than their research organizations.

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