Efficient stabilisation of a dihydrogenphosphate tetramer and a dihydrogenpyrophosphate dimer by a cyclic pseudopeptide containing 1,4-disubstituted 1,2,3-triazole moieties
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E icien s abilisa ion o a dihyd ogenphospha e e ame and a
dihyd ogenpy ophospha e dime by a cyclic pseudopep ide con aining 1,4-
disubs i u ed 1,2,3- iazole moie ies
Mungalpa a, Disha; Valkonen, A o; Rissanen, Ka i; Kubik, S e an
Mungalpa a, D., Valkonen, A., Rissanen, K., & Kubik, S. (2017). E icien s abilisa ion
o a dihyd ogenphospha e e ame and a dihyd ogenpy ophospha e dime by a
cyclic pseudopep ide con aining 1,4-disubs i u ed 1,2,3- iazole moie ies. Chemical
Science, 8(9), 6005-6013. h ps://doi.o g/10.1039/C7SC02700A
2017
Efficien s abilisa ion o a dihyd ogenphospha e
e ame and a dihyd ogenpy ophospha e dime
by a cyclic pseudopep ide con aining
1,4-disubs i u ed 1,2,3- iazole moie ies†‡
Disha Mungalpa a,
a
A o Valkonen,
b
Ka i Rissanen
b
and S e an Kubik *
a
A cyclic pseudooc apep ide 2is desc ibed con aining 1,4-disubs i u ed 1,2,3- iazole moie ies. This compound
ea u es eigh con e ging hyd ogen bond dono s along he ing, namely ou amide NH and ou iazole CH
g oups, which enable 2 o engage in in e ac ions wi h anions. While ully dep o ona ed sul a e anions exhibi
only mode a e affini y o 2, p o ona ed anions such as dihyd ogenpy ophospha e and dihyd ogenphospha e
anions a e s ongly bound. Complexa ion o he phospha e-de i ed anions in ol es sandwiching o
a dihyd ogenpy ophospha e dime o a dihyd ogenphospha e e ame be ween wo pseudopep ide ings.
X- ay c ys allog aphy p o ided s uc u al in o ma ion, while
1
H NMR spec oscopy, mass spec ome y, and
iso he mal i a ion calo ime y demons a ed ha hese complexes a e s able in solu ion (2.5 ol% wa e /
DMSO) and can e en be ans e ed wi hou decomposi ion in o he gas phase. The obse ed high
he modynamic s abili ies a e a ibu ed o he mu ual ein o cemen o he in e ac ions be ween he
indi idual complex componen s, namely, hyd ogen-bonding be ween he anions, mul iple hyd ogen
bonding in e ac ions be ween he anion agg ega es and he iazole CH and NH hyd ogen bond dono s o
2, and po en ial dispe si e in e ac ions be ween he closely a anged pseudopep ide ings. Pseudopep ide 2
hus ep esen s a p omising lead o he cons uc ion o phospha e ecep o s, whose binding selec i i y
makes use o he unique abili y o ce ain anions o assemble in o highe agg ega es.
In oduc ion
Coulomb's law s a es ha pa icles wi h a like elec ical cha ge
epel each o he .
1
As a consequence, wo isola ed ca ions o anions
a e expec ed o maximise hei dis ance hus minimising he
elec os a ic epulsion. Repulsion can be a oided i he cha ges o
he ions a e sc eened by an app op ia e ligand as in complexes o
la ge c own e he s olding a ound wo ca ions,
2
o complexes o
ce ain anion ecep o s binding o wo halides.
3
A special si ua ion
a ises in anion coo dina ion chemis y
4
i he anion is p o ona ed.
In his case, Coulomb epulsion o he anions can be compen-
sa ed by hyd ogen-bonding in e ac ions, allowing p o ona ed
anions o o m dime s o la ge agg ega es in which e e y
indi idual componen is nega i ely cha ged. While he e ecen ly
has been con o e sy in he li e a u e abou he exac na u e o he
unde lying in e ac ions,
5
such agg ega es a e gene ally belie ed o
be s abilised by a ac i e elec os a ic in e ac ions in he
hyd ogen bond ha balance elec os a ic epulsion.
6
Agg ega es o anions ha e been expe imen ally de ec ed in
he solid s a e,
7–10
and in solu ion.
11
They can be s abilised by
o ganic ligands as he examples o complexes demons a e
con aining hyd ogensul a e anions,
7a–
sul a e anions,
7g
sul a e
anions b idged by wa e molecules,
7h
o dihyd ogenphospha e
anions.
8–10
Phospha es, in pa icula , ha e been shown o
assemble in o a wide a ie y o diffe en s uc u es, anging
om dime s
8
o la ge linea
9
o cyclic oligome s.
10
The e is
ample e idence o he sup amolecula s abilisa ion o anion
agg ega es in he solid s a e, bu epo s ha demons a e he
su i al o hese complexes in solu ion a e sca ce.
11
A no able
excep ion came om he Flood g oup who showed ha hei
cyanos a ecep o s abilises he hyd ogensul a e dime .
12
NMR
spec oscopy clea ly e ealed he exis ence o he espec i e
complex in chlo o o m. The au ho s we e e en able o de ec he
signal o he b idging p o ons in he anion dime by NMR
spec oscopy and hey demons a ed he s abili y o he
complex in he gas phase by mass spec ome y. In addi ion,
a bis-calix[4]py ole ecep o has ecen ly been desc ibed by he
a
Technische Uni e si ¨
a Kaise slau e n, Fachbe eich Chemie –O ganische Chemie,
E win-Sch ¨
odinge -S aße, 67663 Kaise slau e n, Ge many. E-mail: kubik@chemie.
uni-kl.de
b
Uni e si y o Jy askyla, Depa men o Chemis y, Nanoscience Cen e , P.O. Box 35,
Jy ¨
askyl¨
a FI-40014, Finland
†In memo iam F i z V¨
og le (1939–2017).
‡Elec onic supplemen a y in o ma ion (ESI) a ailable: Syn he ic de ails, NMR
spec oscopic and MS spec ome ic cha ac e isa ion o 2, NMR spec oscopic
and mass spec ome ic binding s udies, ITC i a ions, and c ys al s uc u es.
CCDC 1555955–1555958. Fo ESI and c ys allog aphic da a in CIF o o he
elec onic o ma see DOI: 10.1039/c7sc02700a
Ci e his: Chem. Sci.,2017,8, 6005
Recei ed 16 h June 2017
Accep ed 12 h July 2017
DOI: 10.1039/c7sc02700a
sc.li/chemical-science
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Chemical
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Sessle g oup, which was shown o bind wo dihy-
d ogenphospha e anions, wo sul a e anions b idged by wa e
molecules, and wo py ophospha e anions.
13
Ou g oup ecen ly in oduced he cyclic pseudopep ide 1
con aining 1,4-disubs i u ed 1,2,3- iazole moie ies.
14
This
compound p e e s con o ma ions in solu ion wi h he p o ons on
he NH g oups and hose on he iazole moie y con e ging o he
cen e o he mac ocycle, well p eo ganised o anion binding.
Binding o oxoanions such as sul a e and dihyd ogenphospha e
(DHP) was de ec ed in 2.5 ol% wa e /DMSO, bu he binding
equilib ia we e a he complex, likely because o he inabili y o 1
o sa u a e all hyd ogen bond accep o s o he in es iga ed
anions. In he case o sul a e, we de ec ed he o ma ion o
complexes wi h wo ecep o molecules binding o one anion.
DHP ecogni ion, on he o he hand, in ol ed binding o wo
DHP anions o one ecep o in solu ion, a complex s oichiome y
consis en wi h he dime o he DHP anion ac ing as gues . The
c ys al s uc u e o he co esponding complex e ealed ha wo
molecules o 1bind o a linea DHP ime in he solid s a e,
con ming he abili y o 1 o s abilise DHP agg ega es.
He e, we show ha he highe cyclic oligome o 1, cyclic
pseudooc apep ide 2, has an e en mo e p onounced p opensi y
o s abilise such anion agg ega es. Compound 2was o iginally
syn hesised in he hope ha i would old a ound oxoanions as
some o he la ge mac ocyclic ecep o s in oduced by Ka aye
and Sessle ,
15
hus yielding simple 1 : 1 complexes. We ound,
howe e , ha 2p e e s o bind a DHP e ame and a dime o
dihyd ogenpy ophospha e (DHPP) anions by sandwiching hese
agg ega es be ween wo mac ocyclic ings. The complexes
pe sis in solu ion (2.5 ol% wa e /DMSO) and can also be
de ec ed in he gas phase. Conside ing ha he DHP complex
comp ises six indi idual componen s his s abili y is ema k-
able, clea ly illus a ing he subs an ial s abilising effec o
ecep o 2. Pseudopep ide 2 hus ep esen s a p omising lead
compound o he cons uc ion o phospha e ecep o s, whose
binding selec i i y is no go e ned by size o shape comple-
men a i y be ween he hos and indi idual anions bu makes
use o he unique abili y o ce ain p o ona ed anions o
assemble in o highe agg ega es.
Resul s and discussion
Syn hesis and s uc u al cha ac e isa ion
Syn hesis o 2was based on he s a egy de eloped o 1
(Scheme 1). I s a ed wi h building block 3o which one
po ion was TMS dep o ec ed and an equi alen po ion con-
e ed in o he azide by subs i u ion o he mesyla e g oup. The
p oduc s hus ob ained we e hen coupled unde coppe (I)-
ca alysis o affo d dime 4. This dime , which was also used o
he syn hesis o 1,
14
was now chain elonga ed o he co e-
sponding linea e ame 5by using a ela ed h ee s ep
sequence. The e minal g oups o 5we e p epa ed o cyclisa-
ion and he subsequen cyclisa ion was hen pe o med unde
dilu ion condi ions o supp ess oligome isa ion. Ae ch o-
ma og aphic pu ica ion, 2was ob ained in analy ically pu e
o m.
I should be no ed ha a side p oduc was isola ed du ing
pu ica ion ha did no exhibi he simple
1
H NMR spec um o
he C
4
symme ic 2bu a mo e complex one. This side p oduc
also ep esen s a cyclic e ame acco ding o MS whose educed
symme y is p esumably caused by pa ial epime isa ion. Epi-
me isa ion likely only occu s du ing o ae cyclisa ion since no
e idence o he p esence o s e eoisome s could be ound in
he
1
H NMR spec a o he linea p ecu so s.
1
H NMR spec oscopy indica es ha 2adop s an a e aged
C
4
symme ic con o ma ion in DMSO-d
6
. The NOESY NMR
spec um in he same sol en ea u es c osspeaks be ween he
NH, iazole CH, and he C*H signals, he la e o which
co espond o he p o ons on he s e eogenic cen es. These
c osspeaks accoun o he spa ial p oximi y o he espec i e
se s o p o ons (see ESI‡). Since no c osspeak is isible
be ween he NH signal and he signal o he a oma ic C
3
H, he
p e e ed con o ma ion o 1, cha ac e ised by a con e ging
a angemen o he NH, iazole CH, and C*Hp o ons,seems
o be e ained upon ing enla gemen .
Scheme 1 Syn hesis o cyclic pseudopep ide 2.
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Anion binding s udies
Binding s udies we e es ic ed o 2.5 ol% wa e /DMSO as
sol en and o he oxoanions sul a e, dihyd ogenphospha e
(DHP), and (di)hyd ogenpy ophospha e [(D)HPP] as gues s o
allow compa ison wi h he p e ious wo k on ecep o 1, whose
in e ac ions wi h he same anions was s udied unde analogous
condi ions.
14
Anions such as halides and ni a e we e excluded
because hey did no exhibi de ec able affini y o 1in DMSO.
Sul a e binding. Addi ion o 2 equi . o TBA sul a e o
a solu ion o 2in 2.5 ol% D
2
O/DMSO-d
6
p oduced downeld
shis o he iazole CH signal by 0.35 ppm and o he C*H
signal by 0.30 ppm. The ex en o he shio he iazole CH
signal is signican ly smalle han he one obse ed o he
smalle pseudopep ide 1unde he same condi ions (see ESI‡),
while ha o he C*H signal is la ge .
14
The binding mode o he
wo ecep o s he e o e seems o diffe wi h he ela i ely
mode a e shio he iazole CH signal indica ing ha in e -
ac ions o 2wi h he sul a e anion migh be weake han
hose o 1.
The ESI mass spec um o a solu ion o 2in dichlo ome hane
con aining 1 equi . o TBA sul a e, eco ded in he nega i e
mode, exhibi s wo majo signals (see ESI‡). Besides he signal
o he dep o ona ed ecep o also a s ong signal is isible
whose m/z a io can be assigned o he 1 : 1 complex 2$SO
42
wi h one TBA ca ion pa ially balancing he wo nega i e
cha ges. No e idence o he p esence o highe complexes
could be de ec ed. The p e e en ial o ma ion o a 1 : 1 complex
is also consis en wi h he shape o he ITC iso he m ob ained
by i a ing 2wi h TBA sul a e in 2.5 ol% H
2
O/DMSO. The
esul ing s abili y cons an log K
a
amoun s o 3.1 (DH¼+6.1 kJ
mol
1
,TDS¼+23.6 kJ mol
1
), ende ing he sul a e complex o
2mo e han one o de o magni ude less s able han he co -
esponding 1 : 1 complex o 1.
14
Mo eo e , ing enla gemen
causes sul a e binding o go om exo he mic o 1 o endo-
he mic o 2in 2.5 ol% wa e /DMSO.
The s oichiome y o he sul a e complex sugges s ha 2can
indeed old a ound an anion as p edic ed, bu binding seems o
be no e y efficien . While he exac mode o complex o ma-
ion un o una ely could no be elucida ed, i is e y likely ha i
diffe s p o oundly om he one obse ed o p o ona ed
phospha e-de i ed anions ( ide in a).
Dihyd ogenpy ophospha e binding. C ys als o he complex
be ween 2and DHPP wi h modes quali y o X- ay c ys al-
log aphy we e ob ained om a solu ion o 2in DMSO con-
aining 1 equi . o TBA DHPP. Fig. 1 shows ha anion binding
in he solid-s a e in ol es sandwichingo ahyd ogen-bonded
DHPP dime be ween wo pseudopep ide ings esul ing in an
o e all C
2
symme ic complex. The hyd ogen bonding pa e n
o he DHPP dime commences h ough pai s o oxygen a oms
on each phospho us a om wi h O/O dis ances be ween 2.53 ˚
A
and 2.55 ˚
A. The ou emaining oxygen a oms poin in o he
co ne s o he ec angula complex, in e ac ing wi h he
pseudopep ide ings. I should be no ed ha a simila
hyd ogen-bonded DHPP dime has ecen ly been ound in he
complexes o non-cyclic py ole-de i ed ecep o s de eloped
in he Sessle g oup.
16
The pseudopep ide ings in 2
2
$DHPP
2
adop a sligh ly dis-
o ed con o ma ion wi h a lowe han he ideal C
4
symme y.
Each acan oxygen a om o he anion dime is hyd ogen-
bonded o wo NH g oups o 2, one om he uppe and one
om he lowe ing in he sandwich. The N/O dis ances ange
be ween 2.76 and 2.84 ˚
A. Fou opposing iazole CH bonds ace
he oxygen a oms o he anion dime ha a e in ol ed in he
hyd ogen-bonding in e ac ions. The C/O dis ances o 3.65–
3.85 ˚
A indica e ha his in e ac ion is also weakly s abilising.
The o he ou iazole CH bonds ace he b idging oxygen a om
o he anions a dis ances o 3.65–3.80 ˚
A. Two TBA coun e ions
ll he bowl-shaped ca i ies o he pseudopep ide ings, one on
each side o ming he sandwiched 2 22 complex (see ESI‡).
The emaining wo TBA ca ions could no be loca ed due o he
se e e diso de in he c ys al.
The space lling model shown in Fig. S1a‡illus a es ha he
o e all s uc u e o he complex is e y compac and ha he
DHPP dime pe ec ly lls he space be ween he wo pseudo-
pep ide ings. Bo h ings a e s uc u ally nicely complemen a y,
allowing hem o closely app oach each o he in he sandwich as
isible in he espec i e side iew in Fig. S1b.‡The a angemen
o NH and CH hyd ogen bond dono s om bo h ings abo e one
ano he causes he me hyl g oups in he side chains o one ing
o be a anged abo e he a oma ic ings o he o he pseudo-
pep ide (Fig. 1b), indica ing ha dispe si e in e ac ions be ween
he ings could con ibu e o s abilise he whole agg ega e.
NMR spec oscopy demons a es ha he binding mode
seen in he c ys al s uc u e o he DHPP complex o 2pe sis s
in solu ion. The effec s o TBA DHPP on he
1
H NMR spec um
o 2in 2.5 ol% D
2
O/DMSO-d
6
a e shown in Fig. 2.
Fig. 1 Molecula s uc u e o 2
2
$DHPP
2
showing he 2 : 2 associa ion
o he pseudopep ide and wo DHPP anions wi h he he mal ellipsoids
shown a he 50% p obabili y le el (a). The TBA ca ions and he
hyd ogen a oms excep hose on he NH and iazole CH g oups a e
omi ed o cla i y. (b) shows he same s uc u e as a s ick model om
he op (le ) and he side ( igh ) o u he illus a e he a angemen o
he binding pa ne s.
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Acco ding o hese spec a, he addi ion o TBA DHPP o
a solu ion o 2causes he appea ance o a new se o signals.
This signal se becomes p og essi ely la ge as he amoun o
he sal inc eases while he signals o he ee ecep o simul-
aneously dec ease, showing ha complex o ma ion is slow on
he NMR ime-scale. The complex is p ac ically ully o med
ae addi ion o 1 equi . o he sal .
The obse ed downeld shio mos signals is consis en
wi h anion complexa ion, while he new signal se associa ed
wi h he complex u he mo e illus a es ha complex o ma-
ion in ol es a symme y educ ion om C
4
o he ee ecep o
o C
2
in he complex. This o e all symme y is consis en wi h
he s uc u e o he complex ound in he c ys al s uc u e. NMR
spec oscopy hus indica es ha he DHPP complex o 2
possesses equi alen s uc u es in solu ion and he solid s a e.
To ob ain s uc u al in o ma ion abou his complex in
solu ion, a ROESY NMR spec um o a 1 : 1 mix u e o 2and
TBA DHPP in 2.5 ol% D
2
O/DMSO-d
6
was eco ded. NOE
c osspeaks a e isible in his spec um be ween indi idual pai s
o iazole CH and C*H signals, indica ing he spa ial p oximi y
o he co esponding p o ons. These c osspeaks also show ha
wo ypes o symme y equi alen pai s o iazole CH and C*H
p o ons exis in he complex, which is consis en wi h he
c ys al s uc u e. Addi ional exchange peaks appea be ween he
wo iazole CH and be ween he wo C*H signals, accoun ing
o he dynamics o he complex in solu ion. These exchange
signals can ei he be caused by he exchange o indi idual
pseudopep ide ings o he con e sion o hei mu ual
a angemen in he complex. Un o una ely, no in e molecula
c osspeaks a e isible be ween, o example, me hyl p o ons o 2
and a oma ic p o ons ha would con m he sandwich- ype
a angemen o he wo ings. Ne e heless, he ROESY NMR
spec um p o ides e idence o a symme y ela ionship o
p o ons o 2 ha mi o s he one in he c ys al s uc u e. The
ROESY NMR spec um hus suppo he conclusion de i ed
om he 1D NMR spec a.
The ac ha he addi ion o he exac amoun o TBA DHPP
equi ed o he o ma ion o he 2 : 2 complex (1 equi .) is
sufficien o con e 2in o he espec i e complex sugges s ha
i is he modynamically e y s able. S abili y is in ac so high
ha 2
2
$DHPP
2
can also be ans e ed in o he gas phase
wi hou decomposi ion as demons a ed by ESI mass spec-
ome y. In he mass spec um eco ded in he nega i e mode
o an equimola solu ion o 2and TBA DHPP in dichlo o-
me hane only wo majo signals a e isible a 771.89 and
1279.02 (Fig. 3). The peak wi h he lowe m/z a io can be
assigned o he ianion [(2$DHPP)
2
$TBA]
3
while he o he
co esponds o he same ion wi h an addi ional TBA ca ion. The
iso ope pa e ns o he wo peaks con m hei espec i e
cha ge s a es. The mu ual s abilisa ion o he DHPP dime and
wo ings o pseudopep ide 2 he e o e seem o su i e ans e
o he complex om solu ion o he gas phase.
We also in es iga ed he complex be ween 2and DHPP by
iso he mal i a ion calo ime y (ITC). This i a ion showed
ha complex o ma ion is s ongly exo he mic in 2.5 ol%
wa e /DMSO. The ob ained binding iso he m ea u es a single
sha p ansi ion a a 1 : 1 mola a io o he binding pa ne s
(Fig. 4), which is consis en wi h he s oichiome y de i ed om
he c ys al s uc u e and om MS. The s eep s ep mo eo e
sugges s coope a i i y because e en small amoun s o he sal
lead o he nal 2 : 2 complex. The p esence o o he po en ial
complex species, also absen in he NMR spec oscopic binding
s udy (Fig. 2), is no e iden .
In spi e o i s highe s oichiome y, o ma ion o he DHPP
complex o 2 hus seems o p oceed in a ela i ely simple
ashion, which allowed us o he ITC da a o a simplied
binding model by neglec ing he dime isa ion equilib ium o
he anion and assuming ha he DHPP dime binds as a single
en i y o wo molecules o 2in a s epwise ashion. We hus
ob ained wo binding cons an s, he s one desc ibing
binding o he DHPP dime o one pseudopep ide ing and he
Fig. 2
1
H NMR spec um o 2(0.5 mM) in 2.5 ol% D
2
O/DMSO-d
6
in
he absence (a) and he p esence o 0.25 equi . (b), 0.5 equi . (c), 0.75
equi . (d), 1.0 equi . (e), and 2.0 equi . ( ) o TBA DHPP. The signals o
he iazole and C*H p o ons a e ma ked in g een and blue,
espec i ely.
Fig. 3 ESI mass spec um (nega i e mode) o a solu ion o 2(0.5 mM)
in dichlo ome hane con aining 1 equi . o TBA DHPP. The do ed ed
lines in he inse s show he calcula ed iso opic pa e n o he
espec i e peak.
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second one he subsequen o ma ion o he nal complex ( o
de ails, see ESI‡). Wi h a log K
11
o 6.3 and a log K
21
o 6.4 bo h
binding cons an s a e p ac ically equal in size, leading o a log b
o 12.7 o he o e all s abili y o he complex. This log b,
al hough no ep esen ing he ac ual s abili y cons an as he
dime isa ion equilib ium o he anion is missing, clea ly shows
ha DHPP binding p oceeds e y efficien ly. The ac ha he
second s abili y cons an is la ge han log(K
11
/4) is consis en
wi h coope a i e binding,
17
and he he modynamic pa ame e s
associa ed wi h he indi idual s abili y cons an s indica e ha
DHPP binding is no only en halpically (nega i e DH) bu also
en opically a ou able (posi i e TDS).
ITC did no allow us, un o una ely, o es ima e he dime -
isa ion cons an o he DHPP dime di ec ly because i a ing
a solu ion o TBA DHPP in o 2.5 ol% H
2
O/DMSO p oduced
only small exo he mic hea effec s. As he associa ion cons an
o he DHP dime was p e iously de e mined o amoun o
a log K
a
o 1.71 in DMSO,
11g
i is likely ha also he DHPP dime
(o e en he cyclic DHP e ame , ide in a) is no p esen in 2.5
ol% H
2
O/DMSO o a signican ex en a he concen a ions
used o he binding s udies. I s s abilisa ion by 2can he e o e
be a ibu ed o he p esence o he pseudopep ide ings ha
hold he anions oge he .
Hyd ogenpy ophospha e binding. To in es iga e he effec o
he p o ona ion s a e o he anion on complex o ma ion, also
hyd ogenpy ophospha e (HPP) anions we e conside ed in he
binding s udies. In e es ingly, no majo diffe ences a e isible in
he
1
H NMR spec a o solu ions o 2in 2.5 ol% D
2
O/DMSO-d
6
con aining ei he TBA HPP o TBA DHPP (see ESI‡). Also, he ESI
mass spec um o a mix u e o 2and TBA HPP exhibi s he same
peaks as he spec um in Fig. 3, showing ha he DHPP dime is
bound by he ecep o and no HPP anions. High affini y o 2 o
he DHPP dime hus seems o cause he p o ona ion s a e o he
py ophospha e anion o shiin solu ion o he dip o ona ed
o m, which is hen bound in he o m o he co esponding
dime . The p o ons equi ed o his p ocess likely de i e om
he wa e p esen in he mix u e. Indi ec e idence o he
p o ona ion equilib ium came om he ollowing esul s.
X- ay c ys allog aphy showed ha c ys als o 2g own om
ace one in he p esence o TBA HPP con ain analogous 2 2
2 sandwich- ype a angemen s o wo pseudopep ide ings and
DHPP dime s as in he s uc u e 2
2
$DHPP
2
shown in Fig. 1. The
c ys als ob ained we e, howe e , cen osymme ic (space g oup
P
1) and hus con ain bo h enan iome s o 2(see Fig. S2‡). The
pseudopep ide ings in 2( ac)
2
$DHPP
2
adop simila con o -
ma ions, again wi h a lowe han he ideal C
4
symme y, inde-
penden o whe he he DHPP dime is complexed by he all-Ro
he all-S-enan iome o 2. The binding modes de ec ed in he
s uc u e in Fig. 1 a e e ained in 2( ac)
2
$DHPP
2
. Specically,
he acan oxygen a oms o he DHPP dime hyd ogen-bond o
NH g oups o 2wi h N/O dis ances anging be ween 2.74 and
2.84 ˚
A o all-R-2and 2.71 and 2.86 ˚
A o all-S-2. Mo eo e , pai s
o opposing iazole CH bonds in he pseudopep ide sand-
wiches a e o ien ed owa ds he oxygen a oms o he anion
dime ha a e in ol ed in he hyd ogen-bonding in e ac ions
(C/O dis ances o all-R-2: 3.62–4.09 ˚
A and all-S-2: 3.61–4.36 ˚
A),
while he o he ou iazole CH bonds ace he b idging oxygen
a om o he anions (C/O dis ances o all-R-2: 3.65–3.72 ˚
A and
all-S-2: 3.71–3.80 ˚
A). The O/O dis ances in he DHPP dime s
amoun o 2.51–2.53 ˚
A o he complex wi h all-R-2and 2.49–
2.54 ˚
A o he one wi h all-S-2. O e all, 2( ac)
2
$DHPP
2
is hus
s uc u ally closely ela ed o he complex shown in Fig. 1 wi h
only small diffe ences in he dis ances, con o ma ions o he
pseudopep ide ings, and a angemen o he binding pa ne s.
We a ibu e he p esence o bo h enan iome s o 2in
2( ac)
2
$DHPP
2
o he basic condi ions a ising upon p o ona ion
o he HPP anion. The ac ha he c ys als con ain only he wo
homochi al o ms o 2can ei he be explained by assuming
a dynamic shio he acemisa ion equilib ium o he s e eo-
isome s in e ac ing bes wi h he anion and/o by c ys al
packing effec s. An addi ional low esolu ion acemic c ys al
s uc u e (2( ac)
2
$DHPP
2
-2) was ob ained om c ys als g own in
DMSO/DCM and using HPP TBA as gues (see ESI and Fig. S3‡).
Fu he e idence o he basic condi ions o he c ys al-
lisa ion condi ions came om he p esence o se e al 4-
hyd oxy-4-me hylpen an-2-one molecules, he aldol adduc o
ace one, in he c ys als g own om his sol en . NMR spec-
oscopy showed ha o ma ion o his aldol adduc is induced
by TBA HPP alone and does no equi e he p esence o 2(see
ESI‡). HPP hus seems o be sufficien ly basic in ace one o
media e he aldol eac ion and po en ially also he acemisa ion
o 2. In wa e a pH 7, HPP domina es in he HPP/DHPP
p o ona ion equilib ium by a ac o o ca. 2,
18
bu his si ua-
ion may diffe in o ganic sol en s and he ex en o HPP
p o ona ion can be u he shied by 2. No aldol adduc o ms
in ace one when adding TBA DHPP (see ESI‡), explaining why 2
does no acemise in he p esence o his anion.
These esul s hus demons a e ha 2 e y efficien ly in e -
ac s wi h DHPP in 2.5 ol% wa e /DMSO. The ca i y be ween
wo app op ia ely a anged pseudopep ide ings is ob iously
pe ec ly sui ed o hos he dime o he anion. The espec i e
2
2
$DHPP
2
complex is s abilised by mul iple hyd ogen bonding
in e ac ions be ween he subs a e and iazole CH and NH
hyd ogen bond dono s o 2, which likely cause a mu ual ein-
o cemen o he anion dime and he pseudopep ide sandwich.
Addi ional dispe si e in e ac ions be ween he closely a anged
pseudopep ide ings po en ially u he s abilise he complex.
Fig. 4 ITC binding iso he m ob ained by i a ing a solu ion o TBA
DHPP (6.1 mM) in o a solu ion o 2(0.4 mM) in 2.5 ol% H
2
O/DMSO.
The inse shows he hea pulses o he measu emen ha we e used o
ob ain he iso he m.
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High o e all s abili y is hus achie ed, in spi e o he en opic
disad an age associa ed wi h he 2 : 2 s oichiome y. Indica-
ions o s abili y a e he slow complexa ion equilib ium on he
NMR ime-scale, he nea comple e complex o ma ion when all
componen s a e p esen in he equi ed 1 : 1 a io, and he
su i al o he complex e en upon ans e in o he gas phase.
While py ophospha e binding has also been obse ed o 1,
he in o ma ion ha could be de i ed abou he complex o he
smalle pseudopep ide was less clea .
14
ITC indica ed ha 1
binds one HPP anion wi h a s abili y cons an s log K
a
o 6.6.
Highe complexes in ol ing, o example, wo pseudopep ides
and one anion we e also de ec ed, howe e , whose composi ion
and s abili ies could no be ully cha ac e ised. In con as ,
DHPP binding by 2leads o a s uc u ally well-dened and
s able complex, demons a ing ha ing enla gemen signi-
can ly imp o es he s uc u al complemen a i y be ween
ecep o and he DHPP anion in i s dime ic o m.
Dihyd ogenphospha e binding. Cha ac e isa ion o he
in e ac ion o DHP anions wi h 2showed ha he unde lying
binding mode is closely ela ed o he one o DHPP anions.
S uc u al e idence was de i ed om he X- ay c ys allog aphic
analysis o c ys als o he complex g own om DMSO (Fig. 5).
Fig. 5 shows ha he complex be ween 2and DHP also ea u es
wo closely a anged pseudopep ide molecules ha , in his case,
sandwich a cyclic e ame o DHP anions ins ead o a DHPP
dime . While DHP e ame s ha e been obse ed in o he
s uc u es be o e, his cyclic a angemen is, o he bes o ou
knowledge new. In a p e iously desc ibed DHP complex o
a bis(u ea) ype anion ecep o , ou DHP anions we e ound o
be a anged in a e ahed al ashion.
10b
The ou phospho us a oms a e a anged in he DHP
e ame o 2
2
$DHP
4
a p ac ically equal dis ances wi h wo
opposing phospho us a oms loca ed abo e and wo below he
plane o a squa e, ende ing he whole a angemen o e all C
2
symme ic (see Fig. S4‡). Each DHP anion in e ac s wi h wo
neighbou ing ones ia hyd ogen-bonding in e ac ions be ween
h ee o he ou oxygen a oms. One o hese oxygen a oms bind
o oxygen a oms o bo h neighbou s while each o he o he wo
oxygen a oms binds o only one o he wo neighbou ing DHP
anions. The co esponding O/O dis ances ange be ween 2.57
and 2.61 ˚
A. As a esul o he a angemen o he ou anions,
he oxygen a oms no in ol ed in he s abilisa ion o he
agg ega e di e ge and a e a ailable o he in e ac ions wi h he
pseudopep ide.
Because o he squa e-like s uc u e o he DHP e ame , he
con o ma ions o he wo pseudopep ide ings in 2
2
$DHP
4
a e
less dis o ed han in 2
2
$DHPP
2
albei no ully C
4
symme ic. As
in 2
2
$DHPP
2
, each o he ou di e ging hyd ogen bond accep o s
o he DHP e ame binds o wo NH g oups o 2, one om each
ing o he sandwich (N/O dis ances: 2.70–2.92 ˚
A). Each o he
iazole CH p o ons u he engages in hyd ogen-bonding in e -
ac ions wi h an oxygen a om o he DHP e ame ha is in ol ed
in s abilisa ion o he anion agg ega e (C/O dis ances: 3.18–3.38
˚
A). These a ac i e in e ac ions p esumably con ibu e o he
s abili y o he o e all complex. The a angemen o he wo
pseudopep ide ings esembles ha in 2
2
$DHPP
2
in ha he side
chain me hyl g oups o one ing a e a anged close o he
a oma ic planes o he o he one (see Fig. S5‡). The TBA ca ions
ha could be loca ed in he s uc u e occupy space be ween he
2
2
$DHP
4
complexes a he han he bowl-shaped ca i ies o he
pseudopep ides as in 2
2
$DHPP
2
. O e all, he c ys al s uc u e
solu ion con ains 4 2
2
$DHP
4
complexes, 11 TBA ca ions and one
DMSO molecule. Due o high diso de he loca ions o he 5
emaining TBA ca ions emain unknown.
1
H NMR spec oscopy and mass spec ome y demons a ed
ha he 2 : 4 s oichiome y ound in he solid-s a e s uc u e o
2
2
$DHP
4
is also p esen in solu ion and can u he mo e be
ans e ed o he gas phase. In Fig. 6,
1
H NMR spec a o 2in
he p esence o a ious amoun s o TBA DHP in 2.5 ol% D
2
O/
DMSO-d
6
a e shown.
These spec a illus a e ha o ma ion o he DHP complex
o 2is again slow on he NMR ime-scale and associa ed wi h
a symme y educ ion, consis en wi h he C
2
symme y o he
bound DHP e ame seen in he c ys al s uc u e o 2
2
$DHP
4
.In
con as o DHPP binding, whe e one iazole CH signal mo es
upeld, all ou iazole CH and C*H signals a e shied
downeld upon DHP binding. Mo eo e , he spli ing o he
C*H signals is smalle han in he case o he DHPP complex
and one signal in he pai s o iazole CH and C*H signals is
consis en ly b oade han he co esponding o he one. While
all o hese ea u es accoun o sligh s uc u al diffe ences
be ween he DHPP and he DHP complexes o 2,
1
H NMR
spec oscopy suppo s he assump ion ha he binding modes
ound in he c ys al s uc u es o he espec i e complexes a e
p ese ed in solu ion. DHP binding o 2seems o be somewha
Fig. 5 Molecula s uc u e o 2
2
$DHP
4
showing he 2 : 4 associa ion
o he pseudopep ide and ou cyclically a anged DHP anions wi h he
he mal ellipsoids shown a he 50% p obabili y le el (a). The TBA
ca ions and he hyd ogen a oms excep hose on he NH and iazole
CH g oups a e omi ed o cla i y. (b) Shows he same s uc u e as
a s ick model om he op (le ) and he side ( igh ) o u he illus a e
he a angemen o he binding pa ne s.
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less efficien because 5 equi . o TBA DHP a e equi ed o he
almos comple e disappea ance o he signals o he ee
ecep o in he
1
H NMR spec um.
The signals obse ed in he ESI mass spec um o a solu ion
o 2(0.5 mM) con aining 2 equi . o TBA DHP con m he 2 : 4
composi ion o he complex and hus suppo he complex
s oichiome y assigned c ys allog aphically. The majo signals
in his spec um a 783.89 and a 1297.00 can be assigned o
a iply nega i ely cha ged ion [(2$DHP
2
)
2
$TBA]
3
and o
a doubly nega i ely cha ged anion [(2$DHP
2
)
2
$TBA
2
]
2
,
espec i ely (see ESI‡). A mino hi d signal is isible ha
co esponds o he 1 : 1 complex be ween 2and a DHP anion.
Mass spec ome y hus again p o ides e idence ha he
complex, which in his case comp ises an agg ega e o ou
nega i ely cha ged ions hold oge he by hyd ogen-bonding
and u he s abilised by wo pseudopep ide ings, is a he
s able.
Complex o ma ion is exo he mic acco ding o ITC and he
obse ed binding iso he m suppo s o ma ion o a complex
wi h a highe s oichiome y (see ESI‡). Pa o his iso he m
could be ed by using he model also employed o he DHPP
complex and he esul s sugges ed ha he DHP complex is
indeed less s able han he DHPP complex. Un o una ely, he
complexi y o he equilib ia unde lying o ma ion o he 2 : 4
DHP complex o 2did no allow de i ing mo e de ailed quan-
i a i e in o ma ion om his i a ion.
The binding s udies wi h DHP hus show ha efficien
anion ecogni ion by 2is no es ic ed o DHPP bu ex ends
o DHP. Bo h anions a e able o o m agg ega es wi h he
DHPP dime and he cyclic e ame o DHP being s uc u -
ally closely ela ed in e ms o size and a angemen o
hyd ogen bond accep o s. Bo h anion agg ega es he e o e
pe ec ly in o he space be ween wo sui ably a anged
pseudopep ide ings. Indi idual anions a e connec ed by
hyd ogen bonds, while he whole agg ega es a e u he s a-
bilised by in e ac ions wi h hyd ogen bond dono s o he wo
pseudopep ide ings ha p o ude in o he ca i y be ween
hem. The DHP complex o 2comp ises six indi idual
componen s, which should ende i s o ma ion en opically
un a ou able. The binding s udies ne e heless indica e ha
he modynamic s abili y is subs an ial. The compa ison o
DHP binding o 2wi h ha o 1, which binds wo DHP anions
in solu ion while a linea DHP ime is bound o wo
pseudopep ide ings in he solid s a e,
14
again shows ha he
la ge pseudopep ide o ms he s uc u ally be e dened
complex.
Conclusions
Ring enla gemen o he cyclic pseudopep ide 1,affo ding he
co esponding cyclic pseudooc apep ide 2, u ned ou o ha e
p o ound consequences on oxoanion binding in 2.5 ol% wa e /
DMSO. In spi e o he highe numbe o hyd ogen bond dono s
along he ing, he la ge ecep o 2binds ully dep o ona ed
sul a e anions wi h a lowe affini y han 1. P o ona ed anions,
on he o he hand, which ha e he in insic abili y o o e come
cha ge epulsion by in e -anion hyd ogen bond o ma ion, can
o m agg ega es ha a e s ongly bound o 2. The p e e ed
subs a es a e he s uc u ally closely ela ed DHPP dime and
he cyclic DHP e ame . Thei inco po a ion in o he space
be ween wo pseudopep ide ings causes he mu ual ein-
o cemen o he in e ac ions be ween he indi idual complex
componen s. As a consequence, he complexes pe sis in solu-
ion and can be ans e ed in o he gas phase wi hou
decomposi ion in spi e o he ac ha a e made up o up o six
componen s.
In e es ingly, he sandwich- ype binding mode obse ed o
he DHPP and DHP complexes o 2is somewha eminiscen o
he binding mode we p e iously obse ed o an anion-binding
cyclopep ide.
19
In his case, shielding o he bound anion om
he su ounding sol en combined wi h hyd ophobic in e ac-
ions be ween he cyclopep ide ings in he sandwich complex
cause anion binding o e en occu in compe i i e aqueous
media. Should simila p inciples go e n s abili y o he phos-
pha e complexes o 2, wa e -soluble analogues o he pseudo-
pep ide migh be able o o m such complexes e en unde
aqueous condi ions. Ano he a ac i e ea u e o 2is he
possibili y o a ge la ge anionic agg ega es ha can only be
o med by ce ain anions. Anion ecogni ion is hus associa ed
wi h cha ac e is ic p ope ies o he anions, which could
ende he selec i i y po en ially la ge han i he ypically
ela i ely small diffe ences in shape and coo dina ion s eng h
o indi idual anions a e a ge ed. Bo h aspec s ende 2
a highly in e es ing lead s uc u e o he de elopmen o
phospha e selec i e ecep o s ac ing in wa e . Wo k in his
con ex is cu en ly unde way.
Conflic o in e es
The e a e no conic s o in e es o decla e.
Fig. 6
1
H NMR spec um o 2(0.5 mM) in 2.5 ol% D
2
O/DMSO-d
6
in
he absence (a) and he p esence o 0.5 equi . (b), 1.0 equi . (c), 2.0
equi . (d), 3.0 equi . (e), and 5.0 equi . ( ) o TBA DHP. The signals o he
iazole and C*H p o ons a e ma ked in g een and blue, espec i ely.
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Acknowledgemen s
We hank Johannes Lang and Sebas ian K uppa, Physical
Chemis y a he Depa men o Chemis y in Kaise slau e n,
o help wi h he ESI MS measu emen s, he Academy o Fin-
land (KR g an s no. 263256, 265328 and 292746), and he
Uni e si ies o Kaise slau e n and Jy askyla o nancial
suppo .
No es and e e ences
1 C. A. Coulomb, M´
emoi es de l'Acad´
emie Royale des Sciences,
1788, pp. 569–577.
2(a) M. Me ce and M. R. T u e , J. Chem. Soc., Dal on T ans.,
1973, 2469–2473; (b) J. D. Owen and M. R. T u e , J. Chem.
Soc., Dal on T ans., 1979, 1831–1835; (c) J. W. S eed, Coo d.
Chem. Re ., 2001, 215, 171–221.
3(a) A. P. Bisson, V. M. Lynch, M.-K. C. Monahan and
E. V. Anslyn, Angew. Chem., In . Ed. Engl., 1997, 36, 2340–
2342; (b) K. Chellappan, J. Singh, I.-C. Hwang, J. W. Lee
and K. S. Kim, Angew. Chem., In . Ed., 2005, 44, 2899–2903;
(c) D. Meshche yako , V. B¨
ohme , M. Bol e, V. Hubsche -
B ude , F. A naud-Neu, H. He schbach, A. Van Do sselae ,
I. Thondo and W. M¨
ogelin, Angew. Chem., In . Ed., 2006,
45, 1648–1652; (d) O. B. Be yman, C. A. Johnson II,
L. N. Zakha o , M. M. Haley and D. W. Johnson, Angew.
Chem., In . Ed., 2008, 47, 117–120; (e) C. A. Johnson II,
O. B. Be yman, A. C. Sa he , L. N. Zakha o , M. M. Haley
and D. W. Johnson, C ys . G ow h Des., 2009, 9, 4247–4249.
4(a) J. L. Sessle , P. A. Gale and W.-S. Cho, Anion Recep o
Chemis y, RSC, Camb idge, 2006; (b) K. Bowman-James,
A. Bianchi and E. Ga c´
ıa-Espa˜
na, Anion Coo dina ion
Chemis y, Wiley-VCH, Weinheim, 2011; (c) P. A. Gale,
E. N. W. Howe and X. Wu, Chem, 2016, 1, 351–422; (d) o
an excellen e iew abou ecep o s o phospha e-de i ed
anions, see: A. E. Ha g o e, S. Nie o, T. Zhang, J. L. Sessle
and E. V. Anslyn, Chem. Re ., 2011, 111, 6603–6782.
5(a) F. Weinhold and R. A. Klein, Angew. Chem., In . Ed., 2014,
53, 11214–11217; (b) G. F enking and G. F. Ca amo i, Angew.
Chem., In . Ed., 2015, 54, 2596–2599; (c) F. Weinhold and
R. A. Klein, Angew. Chem., In . Ed., 2015, 54, 2600–2602.
6(a) I. Ma a, I. Alko a, E. Molins and E. Espinosa,
ChemPhysChem, 2012, 13, 1421–1424; (b) I. Ma a, I. Alko a,
E. Molins and E. Espinosa, Chem. Phys. Le ., 2013, 555,
106–109; (c) I. Ma a, E. Molins, I. Alko a and E. Espinosa,
J. Phys. Chem. A, 2015, 119, 183–194.
7(a) P. Colomban, M. Pham-Thi and A. No ak, Solid S a e
Ionics, 1987, 24, 193–203; (b) M. Malchus and M. Jansen,
Ac a C ys allog ., Sec . B: S uc . Sci., 1988, 54, 494–502; (c)
P. H. Toma, M. P. Kelley, T. B. Bo cha d , S. R. By n and
B. Kah , Chem. Ma e ., 1994, 6, 1317–1324; (d) M. E. Ligh ,
P. A. Gale and M. B. Hu s house, Ac a C ys allog ., Sec . E:
S uc . Rep. Online, 2001, 57, o705–o706; (e) R. Cus elcean,
N. J. Williams and C. A. Seipp, Angew. Chem., In . Ed., 2015,
54, 10525–10529; ( ) M. N. Hoque, U. Manna and G. Das,
Sup amol. Chem., 2016, 28, 284–292; (g) K. Pandu angan,
J. A. Ki chen, S. Blasco, E. M. Boyle, B. Fi zpa ick,
M. Feeney, P. E. K uge and T. Gunnlaugsson, Angew.
Chem., In . Ed., 2015, 54, 4566–4570; (h) D. A. Jose,
K. Kuma , B. Ganguly and A. Das, Ino g. Chem., 2007, 46,
5817–5819.
8(a) D. M. Rudke ich, W. Ve boom, Z. B zozka, M. J. Palys,
W. P. R. V. S au hame , G. J. an Hummel, S. M. F anken,
S. Ha kema, J. F. J. Engbe sen and D. N. Reinhoud , J. Am.
Chem. Soc., 1994, 116, 4341–4351; (b)
P. S. Lakshmina ayanan, I. Ra ikuma , E. Su esh and
P. Ghosh, Chem. Commun., 2007, 5214–5216; (c) J. Ju,
M. Pa k, J. m. Suk, M. S. Lah and K.-S. Jeong, Chem.
Commun., 2008, 3546–3548; (d) P. Dydio, T. Zieli´
nski and
J. Ju czak, O g. Le ., 2010, 12, 1076–1078.
9(a) F. A. Co on, B. A. F enz and D. L. Hun e , Ac a
C ys allog ., Sec . B: S uc . C ys allog . C ys . Chem., 1975,
31, 302–304; (b) N. Ohama, M. Machida, T. Nakamu a and
Y. Kuni uji, Ac a C ys allog ., Sec . C: C ys . S uc .
Commun., 1987, 43, 962–964; (c) J. M. Ka le and I. L. Ka le,
Ac a C ys allog ., Sec . C: C ys . S uc . Commun., 1988, 44,
1605–1608; (d) M. E. Ligh , S. Camiolo, P. A. Gale and
M. B. Hu s house, Ac a C ys allog ., Sec . E: S uc . Rep.
Online, 2001, 57, o727–o729; (e) V. Amendola, M. Boiocchi,
D. Es eban-G´
omez, L. Fabb izzi and E. Monzani, O g.
Biomol. Chem., 2005, 3, 2632–2639; ( ) B. Lou, X. Guo and
Q. Lin, J. Chem. C ys allog ., 2009, 39, 469–473; (g)
A. Rajbanshi, S. Wan and R. Cus elcean, C ys . G ow h Des.,
2013, 13, 2233–2237; (h) B. Wu, C. Huo, S. Li, Y. Zhao and
X.-J. Yang, Z. Ano g. Allg. Chem., 2015, 641, 1786–1791.
10 (a) M. A. Hossain, M. Is
¸ıklan, A. P amanik, M. A. Saeed and
F. R. F onczek, C ys . G ow h Des., 2012, 12, 567–571; (b)
V. Blaˇ
zek, K. Molˇ
cano , K. Mlina i´
c-Maje ski, B. Koji´
c-
P odi´
c and N. Basa i´
c, Te ahed on, 2013, 69, 517–526.
11 (a) R. H. Wood and D. F. Pla o d, J. Solu ion Chem., 1975, 4,
977–982; (b) F. Rull, A. D. Vallel, F. Sob on and
S. Vein emillas, J. Raman Spec osc., 1989, 20, 625–631; (c)
S. Valiya ee il, J. F. J. Engbe sen, W. Ve boom and
D. N. Reinhoud , Angew. Chem., In . Ed. Engl., 1993, 32,
900–901; (d) E. A. Ka aye , J. L. Sessle , V. N. Kh us ale
and Y. A. Us ynyuk, J. O g. Chem., 2007, 72, 7244–7252; (e)
V. Blaˇ
zek, N. B ego i´
c, K. Mlina i´
c-Maje ski and N. Basa i´
c,
Te ahed on, 2011, 67, 3846–3857; ( ) G. Baggi, M. Boiocchi,
L. Fabb izzi and L. Mosca, Chem.–Eu . J., 2011, 17, 9423–
9439; (g) N. B ego i´
c, N. Cind o, L. F kanec, K. Uˇ
za e i´
c
and V. Tomiˇ
si´
c, Chem.–Eu . J., 2014, 20, 15863–15871.
12 E. M. Fa ila, E. B. Twum, A. Sengup a, M. Pink, J. A. Ka y,
K. Ragha acha i and A. H. Flood, Angew. Chem., In . Ed.,
2016, 55, 14057–14062.
13 Q. He, M. Kellihe , S. B¨
ah ing, V. M. Lynch and J. L. Sessle , J.
Am. Chem. Soc., 2017, 139, 7140–7143.
14 D. Mungalpa a, H. Kelm, A. Valkonen, K. Rissanen, S. Kelle
and S. Kubik, O g. Biomol. Chem., 2017, 15, 102–113.
15 (a) E. A. Ka aye , G. D. Pan os, M. D. Reshe o a,
V. N. Kh us ale , V. M. Lynch, Y. A. Us ynyuk and
J. L. Sessle , Angew. Chem., In . Ed., 2005, 44, 7386–7390;
(b) J. L. Sessle , E. Ka aye , G. D. Pan os, P. Sche bako ,
M. D. Reshe o a, V. N. Kh us ale , V. M. Lynch and
Y. A. Us ynyuk, J. Am. Chem. Soc., 2005, 127, 11442–11446;
6012 |Chem. Sci.,2017,8, 6005–6013 This jou nal is © The Royal Socie y o Chemis y 2017
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