Cage Compounds Ho Pape
Dynamic Nucleophilic A oma ic Subs i u ion o Te azines
TanausfflSan os,Da id S. Ri e o,Yaiza P8 ez-P8 ez, Endika Ma &n-Encinas,Jo ge Pas#n,
An onio He n#ndez Da anas,and Romen Ca illo*
Abs ac : Adynamic nucleophilic a oma ic subs i u ion o
e azines (SNTz) is p esen ed he ein. I combines all he
ad an ages o dynamic co alen chemis y wi h he e sa ili y
o he e azine moie y.Indeed, lib a ies o compounds o
sophis ica ed molecula s uc u es can be easily ob ained,
which a e suscep ible o pos - unc ionaliza ion by in e se
elec on demand Diels–Alde (IEDDA) eac ion, which also
locks he exchange.Addi ionally, he s uc u es ob ained can be
disassembled upon he applica ion o he igh s imulus,ei he
UV i adia ion o asui able chemical eagen . Mo eo e ,S
NTz
is compa ible wi h he imine chemis y o anilines.The high
po en ial o his me hodology has been p o ed by building wo
esponsi e sup amolecula sys ems:Amac ocycle ha dis-
playsaligh -induced elease o ace ylcholine;and a unca ed
[4++6] e ahed al shape-pe sis en luo escen cage,whichis
disassembled by hiols unless i is pos -s abilized by IEDDA.
In oduc ion
Dynamic co alen chemis y (DCC) has become apowe -
ul ool in sup amolecula chemis y and ma e ials science.
This is p obably due o he abili y o DCC o “e o -checking”
and “p oo - eading”, as i is based on e e sible co alen
eac ions unde he modynamic con ol. This allows o
co ec syn he ic dead-ends as i happens in non-co alen
chemis y,al hough wi h much mo e obus molecula
sys ems.[1–4] The ele ance o DCC on cu en chemis y is
clea ly e lec ed by he numbe o epo ed applica ion in he
syn hesis o sophis ica ed molecula a chi ec u es,[5–9] in
polyme chemis y,[10,11] in inding no el po ous ma e ials,[12]
o bioac i e compounds,[13–17] and in sys ems chemis y.[18–20]
E en when he e a e well-es ablished e e sible eac ions
such as imine chemis y,[21,22] disul ide exchange,[23,24] bo onic
linkages,[25,26] ole in me a hesis,[27,28] and some o he in e es -
ing examples,[29–35] he e is s ill alimi ed se o eac ions
amenable o dynamic co alen chemis y.The e o e,scope
and unc ionali y o he molecula s uc u es syn hesized
could be imp o ed by new addi ions o he oolki o DCC.
Pa icula ly in e es ing would be o en ision ano el dynamic
p ocess which inhe en ly displays ele an physico-chemical
p ope ies and which allows o u he unc ionaliza ion.
In his ega d, we hough ha agood choice o a obus
and e sa ile DCC eac ion could be he nucleophilic
a oma ic subs i u ions (SNA ) o e azines.In ac , SNA is
known o be e e sible in some cases,[36] ye i s dynamic
na u e has been o e looked almos comple ely.[37,38] Ob i-
ously,S
NA equi es an elec on-poo a oma ic ing o be
in ol ed. Bu his equi emen o e s he chance o explo e
e azines as apo en ially op imal moie y o an ex emely
e sa ile dynamic p ocess.Indeed, e azines a e no only
elec on-poo a oma ic ings amenable o SNA ,bu hey a e
also a e y use ul moie y.[39] Thus, hey ha e been p o usely
used as away o a ach di e en compounds and moie ies by
in e se elec on demand Diels–Alde (IEDDA) eac ion,[40]
which has ound many applica ions in biology,[41–46] and
ma e ials science.[47–51] Te azine is a aluable sca old o
build s imula ing a chi ec u es such as co ona[n]a enes.[52–57]
They also show an in e es ing edox pe o mance,[58–60] and
some o hem display luo escence.[61–64] E en when i is
known ha some e azines,such as 3,6-dichlo o-1,2,4,5-
e azine (Cl-Tz-Cl)can unde go SNA ,[65,66] he e e sibili y
Figu e 1. a) Te azine is a e y e sa ile moie y wi h in e es ing p ope -
ies. b) This wo k combines he in insic ad an ages o dynamic
co alen eac ions wi h he chemical e sa ili y o he e azine ing.
[*] T. San os, D. S. Ri e o, Y. P8 ez-P8 ez, D .E.Ma &n-Encinas,
D .A.H.Da anas, D .R.Ca illo
Func ional Molecula Sys ems G oup, Ins i u o de P oduc os
Na u alesyAg obiolog&a(IPNA-CSIC)
A da. As o &sico Fco. S#nchez 3, 38206 La Laguna(Spain)
E-mail: [email p o ec ed]
D .J.Pas#n
Labo a o iodeMa e iales pa a An#lisis Qu&micos (MAT4LL),
Depa amen o de F&sica, Uni e sidaddeLaLaguna (ULL)
38206 La Laguna, Tene i e (Spain)
Suppo ingin o ma ion and he ORCID iden i ica ion numbe (s) o
he au ho (s) o his a icle can be ound unde :
h ps://doi.o g/10.1002/anie.202106230.
T2021 The Au ho s. Angewand e Chemie In e na ional Edi ion
published by Wiley-VCH GmbH. This is an open access a icle unde
he e ms o he C ea i e Commons A ibu ion License, which
pe mi suse, dis ibu ion and ep oduc ion in any medium, p o ided
he o iginal wo k is p ope ly ci ed.
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o he subs i u ion is comple ely unexplo ed. In his ega d,
phenols o hiols may ac bo h as good nucleophiles and as
e icien lea ing g oups,and he e o e i seems easonable o
ocus on hem as op imal candida es as subs i uen s o
e azine o achie e a e e sible SNA .
Ha ing all ha in mind, ano el ool o DCC is he ein
in oduced:The nucleophilic a oma ic subs i u ion o e a-
zines (SNTz) wi h phenols and alkyl hiols (Figu e 1). This as
exchange eac ion combines he in insic ad an ages o
dynamic co alen chemis y wi h he chemical e sa ili y o
he e azine moie y.In ac , i allows no only o ob ain
dynamic lib a ies o compounds,o complex molecula
s uc u es in an easie way,bu i also akes ad an age o
he e azine moie y i sel ,and i s in e es ing physico-
chemical p ope ies.
Thedynamic na u e o SNTz has been success ully
con i med by ob aining he same dis ibu ion o compounds
in ase ies o eac ions conduc ed in bo h o wa d and e e se
di ec ions.Ac i a ion and deac i a ion o he exchange was
obse ed by he p esence o absence o abase, espec i ely.
Addi ionally,o he exci ing ea u es o his dynamic eac ion
we e also p o ed:Pos - unc ionaliza ion by IEDDA, which
also inhibi s he exchange p ocess;pho olysis by UV i adi-
a ion;and inally his exchange eac ion success ully p o ed
i s po en ial in some sup amolecula sys ems.Indeed, ligh
induced gues - elease and esponsi e co alen cages we e
also achie ed by SNTz.
Resul s and Discussion
3,6-di-subs i u ed e azines we e p epa ed s a ing om
he co esponding nucleophile and 3,6-dichlo o-1,2,4,5- e a-
zine (Cl-Tz-Cl)(Figu e 2a), which can be syn hesized in i e
s eps in g am scale.[67] Amines and alipha ic alcohols we e
disca ded om his wo k because p e ious s udies,[39,66,68] and
se e al expe imen s in ou lab showed ha di-subs i u ed
e azines a e equen ly ha d o ob ain wi h ha kind o
nucleophiles:Ha sh condi ions a e equi ed and usually only
low yields a e ob ained. On he o he hand bo h phenols and
hiols gi e good yields o di-subs i u ed e azines a oom
empe a u e and hus we ocused on hem o his wo k.[67]
We ook he eac ion be ween c esol (1)and he
disubs i u ed e azine wi h 4-me hoxyphenol (2-Tz-2)as
he e e ence p ocess,which was compa ed wi h he e e se
eac ion, be ween 4-me hoxyphenol (2)and he c esol
disubs i u ed e azine (1-Tz-1), o es e e sibili y and
exchange abili y in SNTz (Figu e 2b). One equi alen o he
disubs i u ed e azine and wo equi alen s o he co e-
sponding phenol we e sol ed in di e en deu e a ed sol en s,
and inally 3equi alen s o ie hylamine we e added. Fo -
una ely, he expe imen ally indis inguishable NMR spec a
ob ained o eac ions conduc ed in bo h o wa d and e e se
di ec ions demons a e ha equilib ium was achie ed (Fig-
u e 2cand d). In e es ingly,when eac ion was se up di ec ly
om Cl-Tz-Cl and wo equi alen s o phenols 1and 2and
Figu e 2. a) Syn hesis o he disubs i u ed e azines was ca ied ou om Cl-Tz-Cl and he co esponding hiol o phenol. b) Reac ions pe o med
on bo h di ec ions ( o wa d and e e se) and also s a ing di ec ly om Cl-Tz-Cl (neu al), led o iden ical p oduc dis ibu ion. c) 1HNMR o he
o wa d and e e se eac ions in CD3CN. Un o una ely he peaks o 1-Tz-2 and hose o he homodime so e lap, so no quan i ica ion o all he
compounds o he eac ion mix u e can be pe o med by 1HNMR. d) The 13CNMR shows sligh di e ences be ween homo and he e o dime s o
e azine, and he e o e aquan i a i e expe imen can be ca ied ou o ob ain he a ios o all he compounds in equilib ium.
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ie hylamine in ace oni ile (neu al in Figu e 2b), exac ly
he same dis ibu ion o p oduc s han he o wa d and
e e se eac ion was ound.[67]
As expec ed, pola ap o ic sol en s accele a e he eac ion
(Table 1). Indeed, in CDCl3 eac ion was e y slow a oom
empe a u e,al hough p og ession was e iden a 5088C, and
a e 15 hou s a ha empe a u e,equilib ium was eached.
On he o he hand, in deu e a ed DMSO a oom empe -
a u e, eac ion equilib a ed so as ha i was impossible o be
ollowed by NMR, while in ace oni ile i was comple e in less
han wo hou s a oom empe a u e o in 30 minu es hea ing
a 5088C. Thechoice o he base also a ec s he kine ics o he
exchange.T ie hylamine (TEA) and di-isop opyle hylamine
(DIPEA) yield he as es exchange,while less basic com-
pounds such as N-me hylmo pholine(NMM) ake longe
imes o comple ion, and py idine was no e en able o induce
he exchange.Ino ganic bases such as Cs2CO3in DMSO we e
de imen al o he eac ion.[69]
I was also shown ha abase is equi ed o asuccess ul
exchange o phenols.In ac , when i luo oace ic acid was
added a e 10 minu es o he eac ion in ace oni ile, he
p og ess o he eac ion was s opped. A e addi ional
10 minu es,anew addi ion o ie hylamine allows o
eini ia e he exchange o inally each equilib ium. The e-
o e,S
NTz can be s opped and ac i a ed by he p ope
addi ion o an acid o abase, espec i ely,and eminds in his
sense o he imine exchange,bu wi h he opposi e Scheme o
ac i a ion/deac i a ion.[67]
Ob iously,animpo an pa o his wo k was o quan i y
all he species coexis ing in he equilib ium. Howe e ,in he
1HNMR spec a, he peaks co esponding o he he e odime
1-Tz-2 o e lap wi h hose o he homodime s 1-Tz-1 and 2-Tz-
2,and he e o e i is no possible o dis inguish each
compound in he mix u e and as aconsequence, he a io o
all he species o he eac ion canno be calcula ed by
1HNMR (Figu e 2b). Con e sely,some o he peaks in he
13CNMR spec um can be unambiguously assigned o he
he e odime ,and he e o e aquan i a i e 13CNMR could be
used o quan i y each and e e y chemical species in he
eac ion mix u e.(Figu e 2d and Table 2, en y 1).
I is clea om Table 2(en y 1) ha he equilib ium is
shi ed owa ds he elease o c esol 1while phenol 2 ends o
bind he e azine.This esul is easonable conside ing he
espec i e Hamme sigma o bo h subs i uen s on he phenol,
being 1 he bes lea ing g oup ([email protected] o me hoxy, sp=
@0.170 o me hyl g oup). Re e sibili y o his p ocess was
u he p o ed by shi ing he equilib ium backwa ds,i.e.
owa ds he un a o able di ec ion by inc easing he concen-
a ion o one o he chemical species in solu ion.[70] Speci -
ically,once he equilib ium was eached in he eac ion
be ween 2and 1-Tz-1,which implies ha mos o 2is a ached
o he e azine ing, we added 10 mo e equi alen s o c esol
1,ino de o o ce he elease o phenol 2.I isclea ly seen by
NMR ha 2is almos comple ely de ached om he e azine
ing.[67]
Table 1: Equilib a ion ime obse ed o he e e se e e ence eac ion.
Sol en Base [min]
CDCl3TEA 1000[a]
CD3CN TEA 90 (30)[a]
[D6]DMSO TEA <5[b]
[D6]DMSO DIPEA <5
[D6]DMSO NMM 600
[D6]DMSO Py idine n. .[c]
[D6]DMSO Cs2CO3–[d]
[a] Hea ing a 5088C. [b] Equilib ium eached al eady in he i s NMR
spec um acqui ed. [c] No p og ess o he eac ion was obse ed a e
5days. [d] Decomposi ion o he eagen s.
Table 2: Quan i ica ion o di e en equilib ia and hei co esponding
cons an s.
[a] Nucleophiles employed.[b] Schema ic equilib ia and hei co e-
sponding cons an s. [c] All eac ions we e ca ied ou in 0.5 mL o he
speci ied sol en (chosen owing o solubili y and kine ic easons),and
0.02 mmol o he co esponding phenol o hiol, which we e adjus ed o
he co ec s oichiome y,p io o he addi ion o 5 mLo ie hylamine.
Reac ionswe e ollowed by 1HNMR un il no u he changes we e
obse ed.Equilib a ion imes ange om less han 5minu es o
24 hou s. [d] Only he peaks co esponding o he compounds displayed
a one o he ends o he equilib ia can be seen by 1HNMR, and we
assumed ha less han 1% o he es o he compounds is p esen in
he mix u e, so we could es ima e acons an .n.d.: no de e mined.
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To examine he scope o his dynamic p ocess and he
e ec o he na u e o he nucleophile in he ou come o he
equilib ium, ase ies o di e en eac ions we e se up in
deu e a ed sol en s a oom empe a u e (Table 2). Bo h he
o wa d and he e e se eac ions we e ollowed un il no
u he changes we e obse ed. Then, quan i ica ion o all he
compound in he eac ion mix u e was pe o med by quan i-
a i e 13CNMR,[67] excep o he eac ion wi h 4-b omophe-
nol 3(en y 2), ha could be quan i ied by 1HNMR. Mo e-
o e , as in mos o he cases acomple e quan i ica ion o he
species in equilib ium could be achie ed, hen calcula ion o
he co esponding equilib ium cons an s was i ial (Table 2).
Cu iously, he e a e sca ce pape s abou dynamic co alen
eac ions whe e he equilib ium cons an s o he exchanges
a e calcula ed,[71,72] e en when i is akey physico-chemical
p ope y o a e e sible p ocess and i p o ides ag ea deal
o in o ma ion.
F om Table 2, i is clea ha elec on ich phenols end o
emain a ached o he e azine ing (smalle cons an s)
while elec on poo ones a e mo e p one o be eleased
(la ge cons an s) (en ies 1–4). Ac ually,4-b omophenol 3
(en y 2) is mos ly ound ee in he equilib ium, and when he
ex emely elec on poo pen a luo ophenol 4is compa ed o
c esol 1(en y 3), he equilib ium is comple ely shi ed
owa ds he elease o 4.
I is wo h men ioning ha phenols wi h subs i uen s in
o ho posi ion also eached he equilib ium, al hough much
mo e slowly.Indeed, 5and 6only equilib a ed a e 24 hou s
in ace oni ile (en y 5). Thiols on he o he hand migh be
p oblema ic in his eac ion. Many o hem, such as N-ace yl-
L-cys eine,2-me cap oe hanol o all he hiophenols es ed
led o acompe i i e edox p ocess:Reduc ion o he e azine
ing o 1,4-dihyd o-s- e azine,wi h he concomi an oxida-
ion o he hiol o he co esponding disul ide.[67,73] Only
some alipha ic hiols such as dodecane hiol and benzylme -
cap an display an e icien exchange eaching equilib ium so
as ha i canno be ollowed by NMR (en y 7). In e es -
ingly,alkyl hiols end o displace phenols om he e azine
e y e icien ly.Indeed dodecane hiol 7comple ely displaces
c esol om he e azine in 5hou s (en y 6),[67] while in he
o he di ec ion o he eac ion, c esol 1is no able o
subs i u e he hiol a ached o he e azine co e.
Dynamic co alen chemis y in aqueous en i onmen s is
challenging o some eac ions such as imines and bo onic
es e s exchanges due o hei labile na u e.[74–76] Howe e he
bonds in ol ed in SNTz a e mo e obus . Thus we es ed one
exchange be ween 1-Tz-1 and sodium 2-me cap oe hane-
sul ona e 9in amix u e o deu e a ed wa e and ace oni ile
(8:2). We ound ha 0.1 Msodium ca bona e is enough o
p omo e asuccess ul exchange (Figu e 3).
Theini ial suspension o 1-Tz-1 slowly eac s,and while
he mix u e homogenizes, he solu ion p og essi ely ge s
colo ed. The inal esul is amix u e o wa e -soluble
compounds:c esol 1,9-Tz-9 and 1-Tz-9,which a e s able
o days in hose condi ions.
Conside ing he basic condi ions equi ed o SNTz, we
hough ha i migh be possible o combine i wi h imine
chemis y ha i is usually pe o med unde acidic condi ions.
Combina ion o wo o mo e dynamic co alen eac ions in an
o hogonal way is inc easingly in e es ing because i eases he
syn hesis o mul i unc ional molecula a chi ec u es.[77–82]
Consequen ly,dialdehyde 10-Tz-10 was syn hesized and
exposed o oluidine in ace oni ile (Figu e 4). Theco e-
sponding imine p ecipi a ed om he eac ion mix u e,i was
il a ed and sol ed in deu e a ed DMSO.The 1HNMR
clea ly shows he o ma ion o 11-Tz-11 and he e o e
con i ms ha SNTz is compa ible wi h he imine chemis y
o anilines.
Ob iously,one o he s eng hs o his no el dynamic
eac ion is he abili y o pos - unc ionaliza ion by in e se
elec on demand Diels—Alde (IEDDA). Addi ionally,i is
in e es ing o check i ,once he Diels–Alde eac ion ans-
o ms he e azine in o an elec on- iche 1,2-diazine, he
exchange is in e up ed. Thus, he IEDDA eac ion be ween
2-Tz-2 and asligh excess o bicyclic compound 12 was
examined (Figu e 5a). We hough ha 12 was an op imal
dienophile o ollow he eac ion by NMR, because i displays
only h ee single peaks,and once he ini ial cycloaddi ion
inishes and one molecule o N2is eleased, hen a e o
Diels–Alde is expec ed o occu , gi ing he diazine 2-Dz-2
and he u an 13 which displays jus wo single s in he
1HNMR. Fo una ely,IEDDA eac ion was ca ied ou in
high yield as i can be old by he s acked NMR spec a
displayed in Figu e 5b.
A e 48 hou s hea ing a 5088CinCDCl3 he 1HNMR
only showed peaks co esponding o he expec ed inal
p oduc s and he emaining 12.The isola ed yield o such
pos - unc ionaliza ion was 94%. In e es ingly he exchange
eac ion was inhibi ed a e he unc ionaliza ion (Figu e 5c).
Indeed, hea ing 2-Dz-2,and ie hylamine in he p esence o
c esol 1o dodecane hiol 7led o no eac ion a all, e en a e
5days,nei he in DMSO a oom empe a u e,no hea ing a
5088CinCDCl3.The e o e,pos - unc ionaliza ion by IEDDA
is no only an e icien way o a ach di e en molecules o he
dynamic lib a ies o compounds ob ained, bu i is also
acomplemen a y way o cancel he exchange.In e es ingly,
when an in amolecula IEDDA eac ion is possible,such as
in compound 6-Tz-6, hen hea ing he mix u e gi es he
Figu e 3. SNTz in aqueous en i onmen s.
Figu e 4. Combina ion o SNTz and imine chemis y.
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co esponding diazine (6-Dz)in96% yield, which concom-
i an ly implies ha an i e e sible sel -inhibi ion o he
exchange can be igge ed by high empe a u es.This
p ope y migh be used o he kine ic con ol o he dynamic
lib a ies o compounds ob ained.[83–88]
The e a e al e na i e ways o manipula e some o he
e azine compounds ob ained by SNTz. Inspi ed by he wo k
by A. B. Smi h III and R. M. Hochs asse ,[89,90] i is possible
o b eak down he S,S- e azine de i a i es by pho olysis
which gi es wo molecules o he co esponding hiocyana e
and one molecule o ni ogen. Indeed, by UV i adia ion wi h
amedium p essu e Hg lamp (450W), comple e ans o ma-
ion o 7-Tz-7 in o n-dodecyl hiocyana e 14 was achie ed in
wo hou s (Figu e 6a). I is wo h men ioning, ha an O,O-
e azine such as 1-Tz-1 o an O,S- e azines such as 1-Tz-7
a e no deg aded by UV ligh . The e o e,all he S,S- e azine
de i a i es ob ained by SNTz a e po en ially pho o-clea able.
Con olling he beha io o molecula s uc u es is
essen ial o de elop unc ional sys ems.Asi has been
p o ed, SNTz allows o ap ecise chemical con ol o he
compounds ob ained, ei he by pho odeg ada ion unde UV
ligh o by he comple e subs i u ion o phenols by hiols.
Those p ope ies oge he wi h i s dynamic na u e make SNTz
apo en ially aluable ool o he syn hesis o unc ional
sys ems.Wi h all his in mind, we decided o es some o i s
possible applica ions h ough wo examples.Onone hand, we
decided o p o e ha SNTz allows o he easy syn hesis o
pho o clea able ecep o s.Con olled elease o gues by ligh
is e y a ac i e because i is aclean and swi chable p ocess
which has been epo ed in se e al sup amolecula sys-
ems.[91–95]
Owing o he abo emen ioned in insical p ope ies o
S,S- e azines, hey could be employed o c ea e ecep o s
wi h he abili y o elease hei gues a e disassembly
igge ed by ligh . Ac ually, e azine-bea ing c own e he 15
was syn hesized in wo s eps in 44%yield, and i displays an
associa ion cons an o 1.1X102M@1wi h neu o ansmi e
ace ylcholine hexa luo ophospha e (ACh PF6)inace oni ile
(Figu e 6b).[96–99] Howe e ,UVi adia ion causes he mac o-
cycle o b eak down in o wo molecules o di hiocyana e
podand 16,which shows no binding wi h ace ylcholine.
The e o e,S
NTz is no only an e icien way o click molecula
agmen s in o a unc ional s uc u e,bu i con e s mac o-
cycle 15 he abili y o elease ace ylcholine igge ed by UV
i adia ion, al hough i seems di icul o apply his esul s o
biological sys ems o he ime being, conside ing he po en
i adia ion equi ed o hou s o asuccess ul elease.
On he o he hand, SNTz allows clicking phenols oge he
and declicking hem wi h hiols.[100] Such abili y could be used
o syn hesize esponsi e molecula a chi ec u es, ha would
be disassembled upon he p esence o he igh chemical
en i onmen . We decided o es i on ashape pe sis en cage,
as i is one o he adi ional uses o dynamic me hod-
ologies.[27,101–110] We easoned ha phlo oglucinol and Cl-Tz-
Cl should lead o a unca ed [4++6] e ahed al cage,whe e
each o he ou aces is ac ually an i-co ona[6]a ene (Fig-
u e 7a).[111] As expec ed, cage 17 was success ully syn hesized
in one s ep in 43%yield.
This co alen molecula capsule displays an o ange
luo escence wi h amaximum emission wa eleng h in ace-
one o 532 nm (Figu e 7b). Asui able single c ys al was
ob ained by slow di usion o hexane in o ace one/dichlo o-
me hane (1:1). Thecompound 17 c ys allized in he non-
cen osymme ic Pna21space g oup and asingle cage and wo
ace one sol en molecules o m i s asymme ic uni .[67] Each
e ahed al cage is o med by ou phlo oglucinol g oups
Figu e 5. a) In e se elec on demand Diels–Alde (IEDDA) eac ion on
2-Tz-2 wi h bicyclic dienophile 12.b)1HNMR o he eac ion mix u e
be o e and a e hea ing o 24 hand 48 h. c) Diazines do no unde go
SNTz.d)Hea ing con e s he exchangeable 6-Tz-6 in o un eac i e 6-Dz
by an in amolecula IEDDA eac ion.
Figu e 6. a) Pho olysis o 7-Tz-7 by UV i adia ion.b)Release o
ace ylcholine a e mac ocycle 15 is pho o-clea ed.
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loca ed in he e ices and six e azine g oups on he edges.
They o m an almos pe ec e ahed on able o accommo-
da e asphe e o 7 co diame e inside.[67]
In spi e o he epo ed good anion binding abili ies o i-
co ona[6]a enes,[111] cage 17 shows no ema kable associa ion
cons an wi h any anion es ed. This ac is p obably due o
igidi y o he cage compa ed wi h i-co ona[6]a enes:In he
mac ocycle he a oma ic p o on can be accommoda ed
owa ds he ca i y and plays akey ole on he binding e en ,
which is ob iously no possible wi h he cage.
In e es ingly, 17 is able o espond o achemical s imulus
such as he p esence o a hiol. Indeed dodecane hiol 7in he
p esence o ie hylamine is able o apidly disassemble he
cage in o phlo oglucinol and 7-Tz-7 (Figu e 7d). Such eac-
ion can be ollowed by 1HNMR whe e he single peak o
cage 17 disappea s comple ely in less han 30 minu es,and an
up ield single co esponding o phlo oglucinol shows up
(Figu e 7e). No ably, he luo escence o he eac ion mix u e
is los as none o he inal p oduc s is luo escen . As
expec ed, once cage 17 is con enien ly unc ionalized by
IEDDA, he esul ing diazine cage 18 becomes un esponsi e
o he e ec o hiols.To he bes o ou knowledge, he e a e
only acouple o p eceden s o such pos -s abiliza ion by
Diels–Alde eac ion and in bo h cases,only o DCC
p oduc s based on imines.[112,113]
Conclusion
We ha e shown ha nucleophilic subs i u ion o e azines
(SNTz) wi h phenols and alkyl hiols is a uly dynamic
co alen eac ion. Theexamples epo ed he ein may se e as
glimpse o he nume ous applica ions ha SNTz can ind. All
hose possibili ies a e ela ed no only o he dynamic na u e
o he p ocess i sel ,bu also o he inhe en chemical
p ope ies o he e azine.Indeed, i has been shown ha
pos - unc ionaliza ion by IEDDAo he compounds ob ained
allows o he a achmen o molecula agmen s while a he
same ime i inhibi s he exchange.Mo eo e he hiol
de i a i es can be pho olized by UVi adia ion as an e icien
and clean way o b eak down i e e sibly hose compounds.
Func ional sup amolecula sys ems such as a e ahed al
esponsi e luo escen cage and amac ocycle ha eleases
ace ylcholine upon i adia ion we e also s udied.
SNTz is a obus and e sa ile dynamic co alen eac ion
an he e o e i unleashes ahuge po en ial o applica ions in
he syn hesis o po ous o ganic cages,in e locked s uc u es,
co alen adap able ne wo ks and COFs,all o which could be
pos - unc ionalized, and, in some cases hey could also
espond o he igh s imulus,ei he UV i adia ion o
aspeci ic chemical eagen . Mo eo e ,modula ion o he
compounds ob ained h ough IEDDAo many o he chem-
ical eac ions,[114–117] will ease he access o nume ous unc-
ional sys ems.O he well-known p ope ies o e azines
such as luo escence o an in e es ing edox beha io , o esee
also ab igh u u e o SNTz in he ields o molecula senso s
and elec onics.The e a e undoub edly plen y o possibili ies
o his no el dynamic co alen eac ion awai ing o be
explo ed.
Acknowledgemen s
This wo k was inancially suppo ed by Minis e io de Ciencia
eInno aciln(PGC2018-094503-B-C21 and MAT2017-90207-
R) and by Agencia Cana ia de In es igaciln, Inno aciln
ySociedad de la In o maciln(ACIISI) (P oID2020010089).
J.P. hanks Cabildo de Tene i e o he Agus &ndeBe ancou
esea ch posi ion a he Uni e si y o La Laguna and also
Nano ec,INTech, Cabildo de Tene i e and ULL o labo-
a o y acili ies.D.S.R. hanks Minis e io de Ciencia, Inno-
acilnyUni e sidades o his FPU ellowship.E.M.-E.
acknowledges his cu en con ac inanced by Cabildo de
Tene i e,P og am TF INNOVA 2016-21 (wi h MEDI &
FDCANFunds). All he au ho s hank SEGAI-ULL, and
SDS-IPNA, and hey a e pa icula ly g a e ul wi h Nie es M.
Rod &guez and Manuel Cab e a o hei echnical suppo in
his esea ch.
Figu e 7. a) Syn hesis o cage 17.b)Yellow–o ange luo escence o
cage 17 unde UV ligh . c) Single-c ys alX- ay molecula s uc u e o
17.[118] One molecule o ace one lies inside he ca i y while o he is
ou side. d) Cage 17 is disassembledby hiol 7in he p esence o
ie hylamine, howe e pos -s abiliza ion can be achie ed by IEDDA.
e) S acked plo o he 1HNMR o pu e 17, he c ude o he disassem-
bling eac ion mix u e a e 30 minu es and phlo oglucinol all in
CD3CN.
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18788 www.angewand e.o g T2021 TheAu ho s.Angewand eChemieIn e na ional Edi ion publishedbyWiley-VCH GmbH Angew.Chem. In .Ed. 2021,60,18783–18791
15213773, 2021, 34, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/anie.202106230 by Biblio eca Uni e si a ia Up /Ehu, Wiley Online Lib a y on [24/01/2024]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
Con lic o In e es
Theau ho s decla e no con lic o in e es .
Keywo ds: cage compounds ·Diels–Alde eac ion ·
dynamic co alen chemis y ·pho olysis · e azine
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[118] Deposi ion Numbe 2067785 con ains he supplemen a y
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