Doubly bridged calix[8]crowns

Article abstract of DOI:10.1135/cccc20041345

Biscrowned calix[8]arenes were obtained by alkylation of p-tert-butylcalix[8]arene or calix[8]monocrowns with triethylene glycol ditosylate, in the presence of various bases. Of the 22 possible isomers, 1,4:2,5-, 1,3:2,5-, 1,4:2,3-, 1,4:5,8-, and 1,2:3,4-calix[8]biscrown-4 (3-7) were isolated in 7-30% yields. The presence of two crown bridges in 1,3:2,5- and 1,4:2,5-biscrown-4 (4, 5) leads to a significant rigidness of the calix[8]arene macrocycle and implies inherent chirality. The increased preorganization of calix[8]biscrowns, with respect to monocrowns, leads to significant complexing abilities for alkali cations with a marked preference for Cs⁺ over Na⁺.

Full text of DOI:10.1135/cccc20041345

Doubly Bridged Calix[8]crowns
1345
DOUBLY BRIDGED CALIX[8]CROWNS
a
Corrada GERACIa1,*, Grazia M. L. CONSOLIa2, Mario PIATTELLI and
b,
Placido NERI *
a
Istituto di Chimica Biomolecolare, Sezione di Catania, C.N.R., Via del Santuario 110,
1
2
I-95028 Valverde (CT), Italy; e-mail: corrada.geraci@icb.cnr.it, grazia.consoli@icb.cnr.it
Dipartimento di Chimica, Università di Salerno, Via S. Allende, I-84081 Baronissi (SA), Italy;
e-mail: neri@unisa.it
b
Received Decem ber 15, 2003
Accepted May 6, 2004
Dedicated to Professor Ivan Stibor on the occasion of his 60th birthday.
Biscrown ed calix[8]aren es were obtain ed by alkylation of p-tert-butylcalix[8]aren e or calix-
[8]m on ocrown s with trieth ylen e glycol ditosylate, in th e presen ce of various bases. Of th e
22 possible isom ers, 1,4:2,5-, 1,3:2,5-, 1,4:2,3-, 1,4:5,8-, an d 1,2:3,4-calix[8]biscrown -4 (3–7)
were isolated in 7–30% yields. Th e presen ce of two crown bridges in 1,3:2,5- an d 1,4:2,5-
biscrown -4 (4, 5) leads to a sign ifican t rigidn ess of th e calix[8]aren e m acrocycle an d im plies
in h eren t ch irality. Th e in creased preorgan ization of calix[8]biscrown s, with respect to
m on ocrown s, leads to sign ifican t com plexin g abilities for alkali cation s with a m arked pref-
eren ce for Cs+ over Na+.
Keyw ord s: Calixaren es; Calix[8]aren es; Con form ation an alysis; Com plexation ; Crown
eth ers; Host–guest ch em istry; In h eren t ch irality; In tram olecular bridgin g.
Calixcrown s1, a class of h ybrid com poun ds derived from com bin ation of
th e calixaren e2 skeleton with crown -eth er3 ch ain s, h ave attracted in creas-
in g research in terests because of th eir rem arkably selective com plexin g abil-
ities4. Majority of work h as been focused on th e calix[4]aren e fram ework,
both sin gly an d doubly bridged with crown ch ain s of various len gth 4,5
,
wh ile a m ore lim ited n um ber of calix[5]crown s6, calix[6]crown s7, an d
calix[8]crown s8–10 h ave been prepared. With respect to th e last m en tion ed,
we observed in our previous work11 th at in troduction of a sin gle polyeth er
ch ain does n ot sign ifican tly affect th e in trin sic m obility of th e calix[8]aren e
m acrocycle. Th e m ain effect is reduction of th e available space for th e pas-
sage th rough th e calixaren e h ole. Sin ce in troduction of two or m ore bridges
was expected to lead to m ore preorgan ized calix[8]crown derivatives, possi-
bly able to h ost suitable guests, we were in duced to exam in e th e possibility
Collect. Czech. Chem. Commun. (Vol. 69) (2004)
doi:10.1135/cccc20041345

1346
Geraci, Consoli, Piattelli, Neri:
of double bridgin g of th e paren t m acrocycle. In prelim in ary com m un ica-
tion s10,12 we h ave reported several exam ples of doubly bridged calix[8]aren e
(calix[8]biscrown s) an d n ow, followin g our previous paper on sin gly
bridged derivatives11, we give h ere full experim en tal data on syn th esis an d
ch aracterization of th ese com poun ds.
RESULTS AND DISCUSSION
Synthesis
Th e in troduction of two crown -eth er bridges in desired position s of th e
calix[8]aren e skeleton is un doubtedly a h ard task to perform , sin ce in prin -
ciple 22 calix[8]biscrown regioisom ers (see below) can form with each spe-
cific bridgin g elem en t. However, con siderin g th e quite surprisin g results in
term s of yields an d selectivity, obtain ed in th e syn th esis of calix[8]m on o-
crown s by direct alkylation of th e paren t p-tert-butylcalix[8]aren e (1)11, we
were in duced to exam in e a sim ilar route for th e preparation of calix[8]bis-
crown s. In deed, by forcin g th e con dition s un der wh ich th e m on ocrown s h ad
been obtain ed, it was possible to prepare biscrown s in workable am oun ts.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1347
Th us, alkylation of p-tert-butylcalix[8]aren e (1) with 3 equivalen ts of tri-
eth ylen e glycol ditosylate in th e presen ce of Cs2CO3 (8 equivalen ts) in
refluxin g aceton e afforded, besides sm all am oun ts (14–15% total yield) of
kn own calix[8]m on ocrown derivatives (1,2- (2a), 1,4- (2c), an d 1,5-isom er
(2d ))11, th ree n ew com poun ds (Table I, en try 1). Th ese last were isolated by
colum n ch rom atograph y an d iden tified as 1,4:2,5-calix[8]biscrown -4 3
(13%), 1,3:2,5-calix[8]biscrown -4 4 (25%), an d 1,4:2,3-calix[8]biscrown -4 5
(2%)12.
A sim ilar alkylation of 1 in th e presen ce of 8 equivalen ts of NaH in
refluxin g THF/DMF (10:1) followed by ch rom atograph ic separation led to
1,4:2,3-biscrown -4 5 (12%) an d 1,4:2,5-biscrown -4 3 (1%), besides a sign ifi-
can t am oun t (13%) of th e kn own 1,4-m on ocrown 2c (Table I, en try 2)11,12
.
From th ese results it is eviden t th at direct double-crown in g of 1 proceeds
with fair regioselectivity m ain ly govern ed by th e n ature of th e base.
Alkylation of preform ed an d well ch aracterized m on ocrown derivatives is
an obvious altern ative for th e syn th esis of calix[8]biscrown s. Th is route
m ay lead to com poun ds with differen t bridgin g pattern s n ot easily attain ed
by direct alkylation or it m ay serve as access to biscrown s with two differen t
ch ain s. In addition , as will be sh own in th e n ext section , it also represen ts
an in dispen sable tool in structure assign m en t. Th us, th e easily available
1,4-crown -4 2c 11 was reacted with 1 equivalen t of trieth ylen e glycol di-
tosylate in th e presen ce of Cs2CO3 (8 equivalen ts) in refluxin g aceton e
(Table I, en try 3). Colum n ch rom atograph y of th e crude m ixture gave
1,4:2,5-biscrown -4 3, 1,3:2,5-biscrown -4 4, an d 1,4:2,3-biscrown -4 5 with
TABLE I
Yield of calix[8]biscrown -4 in th e alkylation of given substrates with TsO(CH2CH2O)3Ts in
th e presen ce of various bases (8 equivalen ts) un der reflux
Equiv. of
alk. agen t
Tim e
h
Com poun d
(%)
En try Substrate
Base
Solven t
1
1
3
Cs2CO3 Me2CO
25
2a,2c,2d (14–15),
3 (13), 4 (25), 5 (2)
2
3
4
5
6
1
3
1
1
1
1
NaH
THF/DMF (10:1)
67
5
2c (13), 3 (1), 5 (12)
3 (30), 4 (18), 5 (12)
6 (7)
2c
2c
2b
2a
Cs2CO3 Me2CO
KH
THF/DMF (10:1)
24
6
Cs2CO3 Me2CO
4 (7)
a
K2CO3
Me2CO
53
5 (3), 7 (7)
a
12 equivalen ts of base were used.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1348
Geraci, Consoli, Piattelli, Neri:
im proved yields (30, 18, an d 12%, respectively)12. KH-prom oted alkylation
of th e sam e startin g com poun d in THF/DMF un der oth erwise iden tical con -
dition s led to th e previously un reported, h igh ly sym m etrical 1,4:5,8-calix-
[8]biscrown -4 6 (7%) (Table I, en try 4)12.
An alogous reaction perform ed on 1,3-crown -4 2b11 usin g Cs2CO3 as th e
base afforded 1,3:2,5-biscrown -4 4 (7%) (Table I, en try 5), wh ile K2CO3-
prom oted alkylation of 1,2-crown -4 2a gave an addition al n ew com poun d,
1,2:3,4-calix[8]biscrown -4 7 (7%), besides th e kn own 1,4:2,3-biscrown 5
(3%) (Table I, en try 6)12.
Structure Assignment
Th e presen ce of two bridges in com poun ds 3–7 was proved by FAB(+) MS
m easurem en ts, wh ich often con tain ed an in ten se (M + Na)+ ion peak, wh ile
satisfactory elem en tary an alyses were usually obtain ed. Con cern in g th e as-
sign m en t of th e bridgin g pattern , as an ticipated in previous section , it re-
quires discrim in ation am on g a total of 22 possible biscrown regioisom ers
(Fig. 1). Th is was based on th e followin g data: (i) th e n um ber of NMR sig-
FIG. 1
Sch em atic represen tation of 22 possible calix[8]biscrown regioisom ers grouped accordin g to
th e n um ber an d type of sym m etry elem en ts. For each group, th e n um ber of expected NMR res-
on an ces for t-Bu an d ArCH2Ar groups is reported. Sym m etry elem en ts bisectin g two opposite
arom atic rin gs (Ar–Ar sym m etry) or two opposite ArCH2Ar groups (CH2–CH2 sym m etry) are in -
dicated
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1349
n als an d th eir in tegrals; (ii) 2D NMR spectra; (iii) th e n um ber of free versus
h ydrogen -bon ded OH groups13,14; (iv) in depen den t syn th esis of th e doubly
bridged com poun ds from a well ch aracterized sin gly bridged calix[8]aren e.
Conformational Features
In a previous work we observed th at calix[8]m on ocrown s are con form -
ation ally m obile an d th at th e m ain effect of th e presen ce of a sin gle
tran san n ular ch ain is th e reduction of available space for th e rin g in version
process, wh ich m ay occur by eith er th e oxygen or th e tert-butyl th rough th e
an n ulus path way11. Th is effect is stron gly depen den t on th e bridgin g posi-
tion s of th e crown ch ain . On th ese prem ises, it was expected th at in troduc-
tion of two polyeth er bridges sh ould cause a stron ger reduction in th e
con form ation al freedom of th e calix[8]aren e m acrocycle. In addition , it
could be argued th at th e bridgin g position s of th e two ch ain s sh ould h ave
an even m ore relevan t effect on it.
1
In accordan ce with th ese argum en ts, th e 1D H an d 2D COSY NMR spec-
tra of 1,4:2,5-biscrown -4 3 sh ow on e AB an d th ree AX system s for th e
ArCH2Ar groups (Fig. 2), in dicatin g a som ewh at rigid structure. Obviously,
th is rigidn ess is a result of th e steric requirem en t of th e two crossin g
polyeth er ch ain s wh ich , in prin ciple, could on ly in terch an ge via th eir pas-
FIG. 2
Com parison of th e m eth ylen e region of 1H NMR spectra (CDCl3, 295 K) of calix[8]biscrown -4
derivatives 3–7
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1350
Geraci, Consoli, Piattelli, Neri:
sage over th e t-Bu groups. However, com puter m olecular m odelin g in di-
cated th e im practicability of th is route, suggestin g th at th e topology of th e
two crown bridges in 3 is perm an en tly blocked15. In deed, th is con clusion
foun d an experim en tal con firm ation in th e VT 1H NMR spectra of 3 in
DMSO-d6, wh ich sh owed n o h in t of coalescen ce up to 385 K for AB an d AX
system s of ArCH2Ar groups.
On th e oth er h an d, by an alogy to sm aller calixaren e h om ologues16, th e
residual OH groups of 3 are still freely swin gin g th rough th e m acrocycle as
in dicated by th e presen ce of a sin gle C2-sym m etry axis bisectin g opposite
arom atic rin gs. In fact, th eir blockage would lead to an asym m etric com -
poun d. Th ese con sideration s can also be exten ded to th e correspon din g
tetram eth oxy derivative 3a, obtain ed in 60% yield from 3 usin g a large ex-
cess of MeI in th e presen ce of NaH in THF/DMF 17. Th e presen ce of th ree
m eth oxy an d five tert-butyl sign als in th e 1H NMR spectrum of 3a proves
th at a C2-sym m etry axis is still presen t. Hen ce, th e passage of th e OMe
groups th rough th e an n ulus is fast on th e NMR tim e scale.
In terestin gly, a differen t situation is observed for 1,4:5,8-biscrown -4 6,
wh ich is con form ation ally m obile as dem on strated by th e presen ce of
broad reson an ces for ArCH2Ar groups in its room tem perature 1H NMR
spectrum (Fig. 2), wh ich becam e th ree clear sin glets (δ 4.14, 3.99 an d 3.96,
1:2:1) at 330 K. Th is suggests th at th e two polyeth er ch ain s m ust in tercross
to in h ibit th e flippin g m otion of arom atic rin gs an d proves th e relevan t
role of th e bridgin g position s.
Accordin gly, 1,3:2,5-biscrown -4 4, possessin g two crossin g ch ain s, is
con form ation ally blocked, as is proved by th e presen ce of several AX sys-
1
tem s in th e crowded m eth ylen e region of its H NMR spectrum (Fig. 2). On
th e oth er h an d, 1,2:3,4-biscrown -4 7, lackin g in tercrossin g ch ain s, is
con form ation ally m obile, as in dicated by broad sign als in th e m eth ylen e
region (Fig. 2).
A borderlin e situation is observed for 1,4:2,3-biscrown -4 5, wh ich sh ould
be con form ation ally m obile sin ce th e two ch ain s do n ot cross. However, its
1H NMR spectrum clearly sh ows AX system s for ArCH2Ar groups, in dicatin g
con form ation al blockage (Fig. 2). Th is apparen t con tradiction can be ex-
plain ed con siderin g th at th e 1,4-bridge, as dem on strated previously11, in -
h ibits th e passage of tert-butyl groups th rough th e an n ulus an d, very likely,
also th e passage of th e 2,3-ch ain is in h ibited because of its bulkin ess. Obvi-
ously, sim ilar con sideration s can also apply to tetram eth oxy derivative 5a,
1
wh ose H NMR spectrum sh ows AX system s for ArCH2Ar groups.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1351
Stereochemical Features
Th e presen ce of a sole C2-sym m etry axis in 1,4:2,5-biscrown -4 structure
m akes 3 in h eren tly ch iral17. As dem on strated in th e previous section , th e
actual geom etrical relation sh ip of its crown bridges is perm an en t, th us
m akin g 3 n ot racem izable. In addition , it is worth n otin g th at th e residual
m obility of OH-bearin g rin gs h as n o in fluen ce in th is respect sin ce th eir
m otion can n ot allow in tercon version of en an tiom ers. First eviden ce of th is
in h eren t ch irality was obtain ed by addition of excess Pirkle’s reagen t
((+)-(S)-1-(+)-(9-an th ryl)-2,2,2-trifluoroeth an ol) to a CDCl3 solution of 3
wh ich , upon coolin g to 4 °C for 72 h , caused doublin g of tert-butyl an d
oth er reson an ces in th e 1H NMR spectrum 17. A defin itive proof was ob-
tain ed by direct resolution of th e racem ate ach ieved by HPLC usin g
Ch iralpak AD or Ch iralcel OD ch iral station ary ph ases17. Th e latter gave in -
ferior separation an d resolution factors. Un der optim ized con dition s, suffi-
cien t am oun ts of en an tiom ers of 3 were separated to allow th e m easure-
m en t of ch iroptical properties. In particular, opposite specific optical rota-
tion s ( [α ]2D5 30°) an d specular quan titative CD spectra were obtain ed, in di-
catin g th eir en an tiom eric n ature.
Sim ilarly, HPLC en an tioresolution of tetram eth oxy-1,4:2,5-biscrown -4 3a
was ach ieved, h owever with in ferior efficien cy with respect to th e paren t
FIG. 3
tert-Butyl region of 1H NMR spectra (CDCl3, 295 K) of 1,4:2,3-calix[8]biscrown -4 5 in th e ab-
sen ce (bottom ) an d in th e presen ce of 1 or 10 equivalen ts (m iddle an d top, respectively) of
(–)-(S)-α-m eth ylben zylam in e
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1352
Geraci, Consoli, Piattelli, Neri:
tetrah ydroxy com poun d 3. Th is suggested th at h ydrogen bon din g am on g
h ydroxy groups of 3 an d th e station ary ph ase could play an im portan t role
in en an tiodifferen tiation 17. In order to furth er clarify th is aspect we pre-
pared partially m eth ylated derivatives of 3, n am ely 3b an d 3c. Th eir struc-
ture assign m en t an d th eir HPLC en an tiodifferen tiation were previously re-
ported17
.
An in terestin g stereoch em ical feature of 1,4:2,3-biscrown -4 5 is a direct
con sequen ce of in h ibited passage of th e 2,3-ch ain th rough th e an n ulus. In
fact, th is bridge m ust be situated above or below th e m ean plan e con tain -
in g th e 1,4-crown , givin g rise to two equivalen ts structures. Of course, th is
structure is ach iral owin g to th e presen ce of a CH2–CH2 sym m etry plan e;
1
h owever, splittin g of H NMR sign als was observed upon addition of som e
ch iral reagen ts ((S)-α-m eth ylben zylam in e (Fig. 3), Pirkle’s reagen t, h ydro-
quin idin e, Eu(h fc)3). Th is result is n ot surprisin g in th e ligh t of an alogous
splittin g observed for sym m etrical ach iral calixaren es after addition of
ch iral reagen ts18a,19, in th e presen ce of wh ich th e en an tiotropic groups in 5
becam e diastereotopic an d an isoch ron ous.
Complexation Tests
As dem on strated in a previous section , th e presen ce of two polyeth er
ch ain s in calix[8]biscrown s causes a stron g reduction in th e con form ation al
freedom of th e calix[8]aren e skeleton leadin g to som ewh at rigid com -
poun ds wh en th e bridges in tercross each oth er. Th is suggests th at calix-
[8]biscrown s could possess a m ore preorgan ized com plexin g site with re-
spect to calix[8]m on ocrown s, wh ich are in efficien t ion oph ores because of
th eir pron oun ced residual m obility11. Th is com plexin g poten tial was in ves-
1
tigated for alkali cation s by two-ph ase picrate extraction 20 an d H NMR ex-
perim en ts.
Th e result of alkali picrate extraction experim en ts (Table II) clearly in di-
cates th at th e above con sideration s are correct. For exam ple, 1,4:2,5-bis-
crown -4 3 an d 1,3:2,5-biscrown -4 4 exh ibited sign ifican t extraction ability
toward alkali m etal cation s, th us con firm in g a good preorgan ization of th e
ion oph oric cavity. Th is becom es m ore sign ifican t if com pared to th e un de-
tectable com plexin g ability of th e correspon din g 1,4-calix[8]m on ocrown -4
(Table II). Im proved efficien cy was observed for m eth oxy derivatives 3a an d
4a with respect to th e paren t h ydroxy com poun ds, in accordan ce with a
sim ilar observation on calix[4]aren e derivatives. In all in stan ces a m arked
preferen ce for Cs+ was n oted, wh ereas Na+ was extracted with lower effi-
cien cy. Th is im plies a good Cs+/Na+ selectivity factor in accordan ce with
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1353
TABLE II
Extraction percen tage of alkali picrates by calix[8]biscrown -4 from water to dich lorom eth an e
at 20 °C
Ligan ds
Li+
Na+
K+
Rb+
Cs+
3
≤1
≤1
≤1
≤1
≤1
≤1
1.7
3.8
21.9
5.8
6.8
3.8
5.6
≤1
6.8
3a
≤1
18.0
2.0
5.5
2.6
4.8
≤1
37.5
7.0
7.8
4.3
7.8
5.8
≤1
3b
≤1
3c
3.4
0.9
1.4
≤1
4
4a
1.2
5
≤1
≤1
≤1
≤1
<1
5a
≤1
4.5
≤1
≤1
6
≤1
≤1
≤1
7
≤1
≤1
≤1
≤1
18-Crown -6a
4.2
2.6
55.5
13.8
30.7
41.7
20.0
63.5
1,3-alternate-25,27-Dipropoxycalix[4]aren e
2.5
crown -6b
a,b
Taken from ref. 21 an d ref. 22, respectively.
FIG. 4
Meth ylen e an d tert-butyl region s of 1H NMR spectra (CDCl3, 295 K) of free ligan d 3a (bottom )
an d 24 h after th e addition of solid cesium picrate (m iddle). Th e correspon din g region s of th e
1H NMR spectrum of Cs+ 3a com plex at 275 K is also reported (top)
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1354
Geraci, Consoli, Piattelli, Neri:
oth er calix[8]biscrown -3 derivatives10b. Th e Cs+/Na+ selectivity peak of th e
best-perform in g biscrown derivative 3a appears to be h igh er th an th at of
th e classic 18-crown -6 (Table II), wh ich is n otorious for its h igh K+/Na+
preferen ce21. However, th e 3a results are sign ifican tly less selective in com -
parison to 1,3-altern ate calix[4]crown -6 (Table II)22, wh ich belon gs to th e
m ost Cs+/Na+ selective ion oph ores curren tly kn own 23
.
Com plexation of cesium cation by 3a an d 4a was also followed by
1H NMR experim en ts. Addition of solid cesium picrate to a CDCl3 solution
1
of 3a led to profoun d spectral ch an ges in th e tert-butyl region of its H NMR
spectrum (Fig. 4), wh ile less pron oun ced sh ifts were observed for 4a. In ad-
dition to ch em ical sh ift ch an ges, th e Cs+–3a com plex form ation causes a
broaden in g of NMR reson an ces due to th e slowin g down of a dyn am ic pro-
cess. Th e process is blocked, on th e NMR tim e scale, at tem peratures below
280 K wh ere a sh arp spectrum con tain in g six tert-butyl reson an ces is ob-
tain ed in dicatin g an asym m etric con form ation . Th is ph en om en on is proba-
bly attributable to h in dran ce of th e swin gin g m otion of m eth oxylated rin gs
(see above), wh ich could be also in volved, in addition to th e crown ch ain s,
in th e com plexation of th e Cs+ cation .
CONCLUSIONS
Th e in trin sic m obility of th e calix[8]aren e m acrocycle requires th e in tro-
duction of bridgin g scaffoldin g elem en ts for th e preparation of preorga-
n ized calix[8]aren e h osts. Because previous work dem on strated th at a sin gle
polyeth er ch ain is in effective in th is regard, in troduction of two crown
bridges was in vestigated as a m ore efficien t sh apin g of th e calix[8]aren e ske-
leton . Th e results reported in th is paper dem on strate th at doubly crown ed
calix[8]aren es can be obtain ed by direct alkylation of p-tert-butylcalix-
[8]aren e with trieth ylen e glycol ditosylate in th e presen ce of various bases.
Altern atively, th ey can be syn th esized by an alogous alkylation of kn own
calix[8]m on ocrown derivatives.
Th is last approach is also an in dispen sable tool in bridgin g-pattern as-
sign m en t for th e 22 possible isom ers, sin ce th e preexisten ce of a bridge
with kn own pattern stron gly reduces th e n um ber of structures com patible
with spectroscopic data.
From th e con form ation al viewpoin t, th e in troduction of two polyeth er
ch ain s can lead to in h ibition of th e flippin g m otion of arom atic rin gs
th rough th e calix[8]aren e m acrocycle, in particular wh en th e two crown s
cross each oth er or wh en th ey are close en ough to m utually exert steric
h in dran ce. As an addition al con sequen ce, th e crossin g of crown bridges
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1355
leads to in h eren t ch irality in th e case of 1,3:2,5- or 1,4:2,5-biscrown deriva-
tives, in som e cases con firm ed by en an tioselective HPLC resolution an d
ch iroptical properties.
Th e in creased rigidity of calix[8]biscrown derivatives leads to a better
preorgan ization with respect to calix[8]m on ocrown s. Con sequen tly, sign ifi-
can t com plexin g abilities toward alkali cation s are observed with a m arked
preferen ce for Cs+ over Na+.
EXPERIMENTAL
Gen eral
Meltin g poin ts were m easured on a Mel Tem p II Laboratory Devices an d are un corrected. 1H
an d 13C NMR spectra were acquired on a Bruker ARX 250 spectrom eter (1H at 250.13 MHz
an d 13C at 62.9 MHz). Ch em ical sh ifts (δ) are expressed in ppm down field from in tern al
TMS, couplin g con stan ts (J) are given in Hz. FAB MS m easurem en ts were perform ed on a
VG-ZAB 2-SE in strum en t, usin g 3-n itroben zyl alcoh ol as m atrix. Elem en tal an alyses were
obtain ed from th e Departm en t of Ph arm aceutical Scien ces, Un iversity of Catan ia. Colum n
ch rom atograph y was carried out on SiO2 (Kieselgel 60, 63–200 µm , Merck). All ch em icals
were reagen t grade an d were used with out furth er purification . An h ydrous THF an d DMF
were purch ased from Aldrich . p-tert-Butylcalix[8]aren e (1)24 an d calix[8]m on ocrown -4
11
2a–2c
were prepared as reported.
Syn th esis of Calix[8]biscrown s by Cs2CO3-Prom oted Alkylation of
p-tert-Butylcalix[8]aren e
A suspen sion of 1 (0.50 g, 0.38 m m ol) in Me2CO (36 m l) was stirred in th e presen ce of
Cs2CO3 (1.00 g, 3.08 m m ol) at reflux for 30 m in . Trieth ylen e glycol ditosylate (0.530 g,
1.15 m m ol) dissolved in Me2CO (4 m l) was th en slowly added an d th e m ixture refluxed un -
der stirrin g for 25 h . After evaporation un der vacuum th e residue was triturated with 0.1
M
HCl (50 m l), collected by filtration , wash ed with MeOH an d dried. Th e crude product was
subjected to colum n ch rom atograph y (SiO2, gradien t AcOEt/cycloh exan e) to afford 1,4:2,5-
calix[8]biscrown -4 3 an d 1,3:2,5-calix[8]biscrown -4 4, in addition to sm all am oun ts of
1,4:2,3-calix[8]biscrown -4 5 (2%) an d kn own m on ocrown derivatives (14–15% of a m ixture
of 1,2-m on ocrown -4 2a, 1,4-m on ocrown -4 2c, an d 1,5-m on ocrown -4 2d ).
1,4:2,5-Calix[8]biscrown-4 3: Wh ite powder (75.4 m g, 13%). M.p. 207–210 °C. RF 0.38
(AcOEt/cycloh exan e, 1:4 v/v). For C100H132O12 calculated: 78.70% C, 8.72% H; foun d:
78.40% C, 8.70% H. 1H NMR (CDCl3, 295 K): 1.19, 1.21, 1.25, 1.28, 1.35 s- 18 H, 18 H, 9 H,
18 H, 9 H, respectively (C(CH3)3); 3.39 an d 4.55 AX system , 4 H, J = 14.1 (ArCH2Ar); 3.53
an d 4.32 AX system , 4 H, J = 13.9 (ArCH2Ar); 3.56 an d 4.25 AX system , 4 H, J = 13.8
(ArCH2Ar); 3.60–4.05 overlapped, 24 H (OCH2CH2); 4.06 an d 4.17 AB system , 4 H, J = 15.5
(ArCH2Ar); 6.95–7.25 overlapped, 16 H (ArH); 7.59, 8.51, 8.92 s- 1 H, 2 H, 1 H, respectively
(ArOH). 13C NMR (CDCl3, 295 K): 31.07, 32.0 (t, ArCH2Ar); 31.3, 31.5 (q, CH3); 33.9, 34.2 (s,
(C(CH3)3); 70.0, 70.8, 71.5, 74.3 (t, OCH2CH2); 125.0, 125.2, 125.6, 125.7, 126.0, 126.4 (d,
ArCH); 126.6, 126.8, 127.6, 133.0, 133.3, 133.4, 133.5 (s, ArCCH2); 141.4, 142.8, 143.1,
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1356
Geraci, Consoli, Piattelli, Neri:
146.5, 147.0 (s, ArCt-Bu); 148.3, 148.7, 150.6, 151.1, 151.6 (s, ArCO). FAB(+) MS, m/z: 1547
(M + Na)+.
1,3:2,5-Calix[8]biscrown-4 4: Wh ite powder (145 m g, 25%). M.p. 170 °C (dec). RF 0.47
(Me2CO/cycloh exan e, 1:4 v/v). For C100H132O12 calculated: 78.70% C, 8.72% H; foun d:
78.97% C, 8.75% H. 1H NMR (CDCl3, 340 K): 1.22, 1.24, 1.25, 1.26, 1.29, 1.30 s- 9 H, 18 H,
9 H, 9 H, 9 H, 18 H, respectively (C(CH3)3); 2.70, 2.87, 3.11 m - 1 H each ; 3.30–4.27 over-
lapped, 34 H (ArCH2Ar an d OCH2CH2); 4.28, 4.34, 4.48 d- 1 H each , J = 12.2, 15.0, 14.9, re-
spectively (ArCH2Ar); 7.03–7.22 overlapped, 16 H (ArH); 7.39, 8.47, 8.64, 8.95 s- 1 H each
(ArOH). 13C NMR (CDCl3, 295 K): 31.4, 31.6 (q, CH3); 30.0, 30.2, 31.9, 32.5 (t, ArCH2Ar);
33.9, 34.2 (s, C(CH3)3); 69.4, 70.6, 71.1, 71.4, 71.9, 73.1, 74.3, 74.7 (t, OCH2CH2); 124.9,
125.1, 125.2, 125.3, 125.4, 125.6, 125.7, 125.8, 126.0, 126.4, 126.8, 126.9, 127.1 (d, ArCH);
126.8, 126.9, 127.5, 127.1, 127.6, 127.9, 132.9, 133.3, 133.8, 133.9, 134.2, 134.4 (s,
ArCCH2)); 141.8, 143.0, 143.2, 143.5, 146.1, 146.7, 147.1, 147.2 (s, ArCt-Bu); 148.1, 148.5,
149.7, 150.5, 151.4, 151.5, 153.5 (s, ArCO). FAB(+) MS, m/z: 1547 (M + Na)+.
Syn th esis of Calix[8]biscrown s by NaH-Prom oted Alkylation of
p-tert-Butylcalix[8]aren e
To a suspen sion of 1 (1.00 g, 0.77 m m ol) in THF/DMF (63/7 m l) was added NaH (148 m g,
6.17 m m ol) un der stirrin g. Th e m ixture was refluxed for 30 m in an d trieth ylen e glycol
ditosylate (1.06 g, 2.31 m m ol) in THF (10 m l) was th en added dropwise. Th e reaction m ix-
ture was refluxed un der stirrin g for 67 h . After coolin g th e solven t was rem oved un der
vacuum to leave a residue wh ich was suspen ded in 0.1 M HCl (100 m l). Workup of th e m ix-
ture followed th e previous procedure to give 1,4:2,3-calix[8]biscrown -4 5, besides m on o-
crown derivative 2c (13%) an d a sm all am oun t 1,3:2,5-biscrown 4 (1%).
1,4:2,3-Calix[8]biscrown-4 5: Wh ite powder (141 m g, 12%). M.p. 148–150 °C. RF 0.16
(AcOEt/cycloh exan e, 1:4 v/v). For C100H132O12 calculated: 78.70% C, 8.72% H; foun d:
78.92% C, 8.74% H. 1H NMR (CDCl3, 295 K): 1.14, 1.24, 1.26, 1.28 s- 18 H each (C(CH3)3);
3.38 d, 1 H, J = 14.0 (ArCH2Ar); 3.39–4.24 overlapped, 36 H (ArCH2Ar an d OCH2CH2);
4.29 d, 2 H, J = 15.0 (ArCH2Ar); 5.09 d, 1 H, J = 15.5 (ArCH2Ar); 6.95 br s, 4 H (ArH);
7.03–7.20 overlapped, 12 H (ArH); 8.60, 8.80 br s- 2 H each (ArOH). 13C NMR (CDCl3,
295 K): 29.3, 30.7, 31.2, 31.8, 32.2 (t, ArCH2Ar); 31.4, 31.5, 31.6 (q, CH3); 33.9, 34.2, 34.3 (s,
C(CH3)3); 70.3, 70.8, 71.4, 73.0, 73.7 (t, OCH2CH2); 124.9, 125.6, 126.0, 127.2 (d, ArCH);
126.8, 127.6, 127.7, 127.9, 132.6, 132.7, 133.3, 133.5 (s, ArCCH2); 143.1, 143.5, 145.5, 147.2
(s, ArCt-Bu); 147.8, 148.3, 151.3, 152.6 (s, ArCO). FAB(+) MS, m/z: 1547 (M + Na)+.
Syn th esis of Calix[8]biscrown s by Cs2CO3-Prom oted Alkylation of
1,4-Calix[8]m on ocrown -4 2c
Cs2CO3 (193 m g, 0.590 m m ol) was added un der stirrin g to solution of 1,4-calix[8]crown -4
2c (104 m g, 0.0740 m m ol) in Me2CO (15 m l). Th e m ixture was kept un der reflux for 30 m in ,
th en a solution of trieth ylen e glycol ditosylate (34 m g, 0.074 m m ol) in Me2CO (5 m l) was
added dropwise. Th e reaction was refluxed for 5 h . Usual workup of th e crude product fol-
lowed by colum n ch rom atograph y (SiO2, gradien t Et2O/CH2Cl2) afforded 1,4:2,5-calix[8]-
biscrown -4 3, 1,4:3,5-calix[8]biscrown -4 4, an d 1,4:2,3-calix[8]biscrown -4 5 in 30, 18, an d
12% yield, respectively.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1357
Syn th esis of 1,4:5,8-Calix[8]biscrown -4 6 by KH-Prom oted Alkylation of
1,4-Calix[8]m on ocrown -4 2c
KH (18 m g, 0.45 m m ol) was added un der stirrin g to a solution of 1,4-calix[8]crown -4 2c
(80 m g, 0.056 m m ol) in THF/DMF (7/0.7 m l). Th e m ixture was refluxed for 30 m in an d th en
a solution of trieth ylen e glycol ditosylate (26 m g, 0.057 m m ol) in THF (1 m l) was added
dropwise. Th e reaction m ixture was refluxed un der stirrin g for 24 h . Usual workup of th e
reaction m ixture followed by colum n ch rom atograph y (SiO2, gradien t AcOEt/cycloh exan e)
afforded 1,4:5,8-calix[8]biscrown -4 6 in 7% (6 m g) yield, wh ite powder. M.p. 240 °C dec.
RF 0.30 (AcOEt/cycloh exan e, 1:4 v/v). For C100H132O12 calculated: 78.70% C, 8.72% H;
foun d: 78.45% C, 8.75% H. 1H NMR (CDCl3, 330 K): 1.23, 1.30 s- 36 H each (C(CH3)3); 3.78,
3.83, 3.87 m - 8 H each (OCH2CH2); 3.96, 3.99, 4.14 br s- 4 H, 8 H, 4 H (ArCH2Ar); 7.09 an d
7.17 AB system , 8 H, J = 3.2 (ArH); 7.13 br s, 8 H (ArH); 7.93 s, 4 H (ArOH). 13C NMR
(CDCl3, 295 K): 29.7, 30.1 (t, ArCH2Ar); 31.3, 31.6 (q, CH3); 33.9, 34.2 (s, C(CH3)3); 69.9,
70.4, 74.6 (t, OCH2CH2); 125.5, 125.7, 126.2 (d, ArCH); 126.9, 127.4, 133.0, 133.2 (s,
ArCCH2); 142.0, 146.9 (s ArCt-Bu); 149.5, 151.0 (s, ArCO). FAB(+) MS, m/z: 1547 (M + Na)+.
Syn th esis of 1,3:2,5-Calix[8]biscrown -4 4 by Cs2CO3-Prom oted Alkylation of
1,3-Calix[8]m on ocrown -4 2b
To a solution of 1,3-calix[8]crown -4 2b (76 m g, 0.054 m m ol) in Me2CO (15 m l) was added
Cs2CO3 (141 m g, 0.43 m m ol) un der stirrin g. Th e m ixture was kept un der reflux for 30 m in ,
th en a solution of trieth ylen e glycol ditosylate (25 m g, 0.054 m m ol) in Me2CO (1 m l) was
added dropwise. Th e reaction was refluxed un der stirrin g for 6 h . Followin g usual workup,
th e crude product was subjected to preparative TLC (SiO2, AcOEt/cycloh exan e, 1:4 v/v), to
afford 1,3:2,5-calix[8]biscrown -4 4 in 7% (6 m g) yield.
Syn th esis of Calix[8]biscrown s by K2CO3-Prom oted Alkylation of
1,2-Calix[8]m on ocrown -4 2a
K2CO3 (55 m g, 0.40 m m ol) was added un der stirrin g to a solution of 1,2-calix[8]crown -4
2a (70 m g, 0.049 m m ol) in Me2CO (5 m l). Th e suspen sion was refluxed for 30 m in an d
th en trieth ylen e glycol ditosylate (23 m g, 0.05 m m ol) in Me2CO (1 m l) was added dropwise.
Th e reaction m ixture was refluxed un der stirrin g for 30 h an d an addition al am oun t of
K2CO3 (27 m g, 0.195 m m ol) was added. Th e reaction was stirred un der reflux for addition al
24 h . Usual workup of th e reaction m ixture followed by preparative TLC (SiO2, AcOEt/cyclo-
h exan e, 1:4 v/v) afforded 1,4:2,3-calix[8]biscrown -4 5 (3%) an d 1,2:3,4-calix[8]biscrown -4 7.
1,2:3,4-Calix[8]biscrown-4 7: Wh ite powder (5 m g, 7%). M.p. 184–187 °C. RF 0.21 (Me2CO/
cycloh exan e, 1:4 v/v). For C100H132O12 calculated: 78.70% C, 8.72% H; foun d: 78.60% C,
8.73% H. 1H NMR (CDCl3, 295 K): 1.10, 1.23, 1.24, 1.26 s- 18 H each (C(CH3)3); 3.43, 3.58,
3.70, 3.87, 4.03, 4.12 br m - 4 H, 4 H, 4 H, 16 H, 4 H, 8 H, respectively (OCH2CH2 an d
ArCH2Ar); 6.93 s, 4 H (ArH); 7.02 d, 2 H, J = 2.3 (ArH); 7.11–7.14 overlapped, 10 H (ArH);
8.57, 9.15 br s- 2 H each (ArOH). 13C NMR (CDCl3, 295 K): 28.8, 29.7, 32.2 (t, ArCH2Ar);
31.3, 31.5 (q, CH3); 33.9, 34.2 (s, C(CH3)3); 70.1, 70.2, 71.0, 73.3, 73.4 (t, OCH2CH2); 124.8,
125.4, 125.6, 125.8, 126.1, 126.6 (d, ArCH); 127.5, 132.3, 133.9, 133.2 133.3 (s, ArCCH2);
143.1, 143.7, 145.4, 146.6 (s, ArCt-Bu); 147.5, 149.0, 151.1, 152.8 (s, ArCO). FAB(+) MS, m/z:
1547 (M + Na)+.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1358
Geraci, Consoli, Piattelli, Neri:
Exh austive Meth ylation of 1,4:2,5-Calix[8]biscrown -4 3
A solution of 3 (52 m g, 0.034 m m ol) in an h ydrous THF/DMF (5/0.5 m l) an d NaH (26 m g,
1.1 m m ol) was stirred at reflux for 30 m in . Two aliquots of CH3I (68 µl each , 1.1 m m ol)
were th en added over a 30 m in in terval an d th e reaction stirred un der reflux for addition al
30 m in . Evaporation un der vacuum left a residue wh ich was suspen ded in 1 M HCl, collected
by filtration , dried an d purified by colum n ch rom atograph y (SiO2, gradien t AcOEt/cyclo-
h exan e) to give tetram eth oxy-1,4:2,5-calix[8]biscrown -4 3a (32 m g, 60%). Wh ite powder.
M.p. 130–133 °C. RF 0.58 (AcOEt/cycloh exan e, 1:4 v/v). For C104H140O12 calculated: 78.95% C,
8.92% H; foun d: 79.10% C, 8.90% H. 1H NMR (CDCl3, 295 K): 1.10, 1.15, 1.21, 1.22, 1.25 s-
18 H, 9 H, 18 H, 9 H, 18 H, respectively (C(CH3)3); 2.90–3.36 overlapped 24 H (OCH2CH2);
3.38, 3,54, 3.63 s- 3 H, 3 H, 6 H (OCH3); 3.64 d, 2 H, J = 15.3 (ArCH2Ar); 3.70 d, 2 H, J =
14.9 (ArCH2Ar); 3.93 d, 4 H, J = 15.2 (ArCH2Ar); 4.08 d, 2 H, J = 12.4 (ArCH2Ar); 4.14 d, 2 H,
J = 11.2 (ArCH2Ar); 4.23 d, 2 H, J = 14.8 (ArCH2Ar); 4.37 d, 2 H, J = 15.3 (ArCH2Ar); 6.87 d,
2 H, J = 2.3 (ArH); 6.88 br s, 4 H (ArH); 6.91 s, 2 H (ArH); 6.99 d, 2 H, J = 2.2 (ArH); 7.12 s,
2 H (ArH); 7.14 d, 2 H, J = 2.3 (ArH); 7.18 d, 2 H, J = 2.3 (ArH). 13C NMR (CDCl3, 295 K):
29.2, 30.6, 31.6, 34.18 (t, ArCH2Ar); 31.4, 31.5 (q, CH3); 33.7, 34.2 (s, C(CH3)3); 59.8, 60.3,
60.8 (q, OCH3); 69.9, 70.1, 71.1, 72.2 (t, OCH2CH2); 124.8, 125.5, 125.9, 126.3, 126.4, 126.5
(d, ArCH); 132.3, 133.1, 133.2, 133.4, 133.6, 133.7, 134.2 (s, ArCCH2); 145.4, 145.7, 145.9 (s,
ArCt-Bu); 153.3, 153.6, 153.9, 154.4 (s, ArCO). FAB(+) MS, m/z: 1581 (M + H)+.
Mon om eth ylation of 1,4:2,5-Calix[8]biscrown -4 3
A solution of 3 (78 m g, 0.051 m m ol) in an h ydrous THF/DMF (5/0.5 m l) was refluxed un der
stirrin g for 30 m in in th e presen ce of CsF (10 m g, 0.066 m m ol). CH3I (26 µl, 0.41 m m ol)
was th en added an d th e reaction m ixture refluxed for 24 h . After a secon d addition of CsF
(10 m g, 0.066 m m ol) an d CH3I (26 µl, 0.41 m m ol) th e reaction was kept un der reflux for
20 h . Followin g usual workup, th e crude product was subjected to preparative TLC (SiO2,
Et2O/CH2Cl2, 1:33 v/v) to afford 7-m eth oxy-1,4:2,5-calix[8]biscrown -4 3b an d 6-m eth oxy-
1,4:2,5-calix[8]biscrown -4 3c.
7-Methoxy-1,4:2,5-calix[8]biscrown-4 3b: Wh ite powder (57 m g, 80%). M.p. 174–178 °C.
RF 0.20 (Et2O/CH2Cl2, 5:95 v/v). For C101H134O12 calculated: 78.76% C, 8.77% H; foun d:
78.53% C; 8.75% H. 1H NMR (CDCl3, 295 K): 1.16, 1.17, 1.21, 1.27, 1.35 s- 9 H, 18 H, 18 H,
18 H, 9 H, respectively (C(CH3)3); 3.37 an d 4.38 AX system , 4 H, J = 14.2 (ArCH2Ar);
3.42–3.89 overlapped, 24 H (OCH2CH2); 3.64 an d 4.27 AX system , 4 H, J = 14.4 (ArCH2Ar);
3.94 s, 3 H (OCH3); 3.96 an d 4.05 AB system , 4 H, J = 15.6 (ArCH2Ar); 4.00 an d 4.16 AB sys-
tem , 4 H, J = 15.4 (ArCH2Ar); 6.96 d, 2 H, J = 2.0 (ArH); 7.00–7.05 overlapped, 6 H (ArH);
7.12 an d 7.24 AX system , 4 H, J = 2.3; 7.15 s, 2 H (ArH); 7.26 s, 2 H (ArH); 7.68, 7.82 s- 1 H,
2 H, respectively (ArOH). 13C NMR (CDCl3, 295 K): 30.4 30.9 (t, ArCH2Ar); 31.3, 31.4, 31.7
(q, CH3); 33.9, 34.18, 34.2 (s, C(CH3)3); 62.1 (q, OCH3); 69.4, 69.8, 70.7, 71.1, 73.7, 74.2 (t,
OCH2CH2); 124.8, 125.0, 125.2, 125.6, 125.7, 126.4 (d, ArCH); 126.9, 127.1, 133.0, 133.1,
133.2, 133.4 (s, ArCCH2); 141.3, 142.2 (s, ArCt-Bu); 146.4, 146.9, 147.3, 149.8, 151.6 (s,
ArCO). FAB(+) MS, m/z: 1539 (M + H)+.
6-Methoxy-1,4:2,5-calix[8]biscrown-4 3c: Wh ite powder (9 m g, 12%). M.p. 189–192 °C.
RF 0.24 (Et2O/CH2Cl2, 5:95 v/v). For C101H134O12 calculated: 78.76% C, 8.77% H; foun d:
79.00% C, 8.79% H. 1H NMR (CDCl3, 295 K): 1.11, 1.14, 1.19, 1.21, 1.22, 1.27, 1.31, 1.33 s-
9 H each (C(CH3)3); 3.32 an d 4.44 AX system , 2 H, J = 14.7 (ArCH2Ar); 3.38 an d 4.30 AX
system , 2 H, J = 14.5 (ArCH2Ar); 3.45–3.90 overlapped, 24 H (OCH2CH2); 3.53 an d 4.22 AX
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1359
system , 2 H, J = 15.0 (ArCH2Ar); 3.63 an d 4.51 AX system , 2 H, J = 15.0 (ArCH2Ar); 3.81 an d
4.11 AB system , 4 H, J = 15.5 (ArCH2Ar); 3.94 an d 4.12 AB system , 2 H, J = 16.0 (ArCH2Ar);
3.95 s, 3 H (OCH3); 3.96 an d 4.16 AB system , 2 H, J = 11.3 (ArCH2Ar); 6.79 an d 7.11 AX sys-
tem , 2 H, J = 2.0 (ArH); 6.88 d, 1 H, J = 2.0; 6.90 an d 7.09 AB system , 2 H, J = 2.0 (ArH);
6.91–7.26 overlapped, 9 H (ArH); 7.10 an d 7.21 AX system , 2 H, J = 2.1 (ArH); 7.57, 8.01 s,
1 H, 2 H, respectively (ArOH). 13C NMR (CDCl3, 295 K): 29.7, 30.4, 30.7, 32.0, 31.1 (t,
ArCH2Ar); 31.3, 31.5, 31.7 (q, CH3); 34.0, 34.2, (s, C(CH3)3); 61.7 (q, OCH3); 69.4, 69.8,
70.0, 70.7, 70.8, 71.3, 73.1, 73.4, 74.7, 75.1 (t, OCH2CH2); 124.4, 124.9, 125.1, 125.3, 125.5,
125.6, 125.8, 126.3, 126.6, 126.9 (d, ArCH); 127.0, 127.8, 132.5, 132.9, 133.3, 133.4 (s,
ArCCH2); 141.2, 141.9, 142.5, 145.9, 146.0, 146.8, 146.9, 147.6 (s, ArCt-Bu); 149.7, 150.1,
150.6, 151.0, 151.6, 152.1, 152.4, 153.2 (s, ArCO). FAB(+) MS, m/z: 1539 (M + H)+.
Exh austive Meth ylation of 1,3:2,5-Calix[8]biscrown -4 4
NaH (54.0 m g, 2.25 m m ol) was added to a solution of 4 (107 m g, 0.070 m m ol) in an h y-
drous THF (5 m l) an d th e suspen sion was stirred at reflux for 30 m in . CH3I (140 µl,
2.25 m m ol) was added an d th e resultin g m ixture was refluxed overn igh t. Evaporation un der
vacuum left a residue wh ich was suspen ded in 1 M HCl, collected by filtration , wash ed with
MeOH, an d dried to give tetram eth oxy-1,3:2,5-calix[8]biscrown -4 4a (104 m g, 95%). Wh ite
powder. M.p. 150–153°C. RF 0.28 (AcOEt/cycloh exan e, 1:4 v/v). For C104H140O12 calculated:
78.95% C, 8.92% H; foun d: 78.72% C, 8.80% H. 1H NMR (CDCl3, 295 K): 1.02, 1.04, 1.14,
1.19, 1.23, 1.33, 1.34 s- 9 H, 9 H, 9 H, 18 H, 9 H, 9 H, 9 H, respectively (C(CH3)3); 2.10–4.40
overlapped, 40 H (ArCH2Ar an d OCH2CH2); 3.36, 3.54, 3.59, 3.78 s- 3 H each (OCH3);
6.78 br s, 3 H (ArH); 6.95 d, 1 H, J = 2.2; 6.98 br, 1 H (ArH); 7.02 br s, 5 H; 7.05 d, 1 H,
J = 2.5 (ArH); 7.16 d, 1 H, J = 2.2 (ArH); 7.18 d, 1 H, J = 2.5 (ArH); 7.20 br s, 1 H (ArH);
7.26 br s, 2 H (ArH). 13C NMR (CDCl3, 295 K): 29.7, 30.2, 30.4, 30.9 (t, ArCH2Ar); 31.3, 31.4,
31.6 (q, CH3); 34.2 (s, C(CH3)3); 60.0, 60.4, 61.0 (q, OCH3); 69.2, 69.6, 69.7, 69.9, 70.6,
70.7, 70.9, 71.0, 71.8, 72.6, 72.8 (t, OCH2CH2); 124.3, 124.7, 125.0, 125.1, 125.6, 125.9,
126.3, 126.5, 127.1, 127.4, 127.6 (d, ArH); 132.0, 132.4, 132.6, 132.9, 133.1, 133.3, 133.4,
133.6, 133.7, 134.2, 134.5 (s, ArCCH2); 145.2, 145.6, 145.8 (ArCt-Bu); 152.7, 152.8, 153.4,
153.9, 154.1, 154.3, 154.6 (s, ArCO). FAB(+) MS, m/z: 1581 (M + H)+.
Exh austive Meth ylation of 1,4:2,3-Calix[8]biscrown -4 5
To a solution of 5 (53 m g, 0.035 m m ol) in an h ydrous THF (5 m l) was added NaH (27.0 m g,
1.12 m m ol) un der stirrin g. Th e m ixture was refluxed for 30 m in an d th en CH3I (70 µl,
1.12 m m ol) was added. Th e reaction was refluxed for 20 h un der stirrin g. Evaporation un der
vacuum left a residue wh ich was suspen ded in 1 M HCl, collected by filtration , dried, an d
purified by preparative TLC (SiO2, AcOEt/cycloh exan e, 1:4 v/v) to give tetram eth oxy-1,4:2,3-
calix[8]biscrown -4 5a. Wh ite powder (30 m g, 58%). M.p. 160–163 °C. RF 0.19 (AcOEt/cyclo-
h exan e, 1:4 v/v). For C104H140O12 calculated: 78.95% C, 8.92% H; foun d: 78.66% C, 8.94% H.
1H NMR (CDCl3, 295 K): 0.97, 1.06, 1.13, 1.31 s, 18 H each (C(CH3)3); 2.73–4.30 overlapped,
34 H (ArCH2Ar an d OCH2CH2); 3.33, 3.58 s, 6 H each (OCH3); 3.40 an d 4.99 AX system ,
2 H, J = 14.8 (ArCH2Ar); 3.66 an d 4.38 AX system , 4 H, J = 15.8 (ArCH2Ar); 6.69 d, 2 H, J =
2.2 (ArH); 6.81 d, 2 H, J = 2.2 (ArH); 6.93 d, 2 H, J = 2.4 (ArH); 6.96 d, 2 H, J = 2.4 (ArH);
7.02 d, 2 H, J = 2.3 (ArH); 7.17 br s, 6 H (ArH). FAB(+) MS, m/z: 1581 (M + H)+.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

1360
Geraci, Consoli, Piattelli, Neri:
Picrate Extraction Experim en ts
Th ese m easurem en ts (Table II) were perform ed followin g Pedersen ’s procedure20a: equal
volum es (5 m l) of solution at equal con cen tration (2.5 × 10–4 m ol/l) of calix[8]biscrown -4
derivative (in CH2Cl2) an d alkali m etal picrate (in H2O) were m agn etically stirred for 8 days
at 20 °C in a th erm ostatted stoppered vial. Th e two ph ases were separated an d th e extrac-
tion percen tage (A0 – A/A0 × 100) was determ in ed by m easurin g th e absorban ce (A) of aque-
ous ph ase at 356 n m an d th e correspon din g absorban ce (A0) of a blan k experim en t.
Financial support from the Italian MIUR (COFIN-2003, Supramolecular Devices Project) is grate-
fully acknowledged. Thanks are due to Mr R. Rapisardi (I.C.T.P.-Sez. di Catania, C.N.R.) for FAB MS
measurements, to Mrs C. Rocco (I.C.B.-Sez. di Catania, C.N.R.) for NMR spectra acquisition.
REFERENCES AND NOTES
1. a) Alfieri C., Dradi E., Pochini A., Ungaro R., Andreetti G. D.: J. Chem. Soc., Chem.
Commun. 1983, 1075; b) Asfari Z., Wenger S., Vicens J.: J. Inclusion Phenom. Mol. Recogn.
Chem. 1994, 19, 137, and references therein; c) Casnati A., Ungaro R., Asfari Z., Vicens J.
in: Calixarenes 2001 (Z. Asfari, V. Böhmer, J. Harrowfield and J. Vicens, Eds), p. 365.
Kluwer, Dordrecht 2001.
2. For comprehensive reviews on calixarenes, see: a) Vicens J., Böhmer V. (Eds): Calixarenes,
a Versatile Class of Macrocyclic Compounds. Kluwer, Dordrecht 1991; b) Böhmer V.: Angew.
Chem., Int. Ed. Engl. 1995, 34, 713; c) Ikeda A., Shinkai S.: Chem. Rev. 1997, 97, 1713;
d) Gutsche C. D.: Calixarenes Revisited. The Royal Society of Chemistry, Cambridge 1998;
e) Asfari Z., Böhmer V., Harrowfield J., Vicens J. (Eds): Calixarenes 2001. Kluwer,
Dordrecht 2001.
3. a) Pedersen C. J.: Angew. Chem., Int. Ed. Engl. 1988, 27, 1021; b) Gokel G.: Crown Ethers
and Cryptands. Royal Society of Chemistry, Cambridge 1991; c) Dietrich B., Viout P.,
Lehn J.-M.: Macrocyclic Chemistry, Aspects of Organic and Inorganic Supramolecular
Chemistry. VCH, Weinheim 1993.
4. a) Ungaro R., Casnati A., Ugozzoli F., Pochini A., Dozol J.-F., Hill C., Rouquette H.:
Angew. Chem., Int. Ed. Engl. 1994, 33, 1506; b) Asfari Z., Harrowfield J. M., Sobolev A. N.,
Vicens J.: Aust. J. Chem. 1994, 47, 757; c) Yamamoto H., Shinkai S.: Chem. Lett. 1994,
1115; d) Casnati A., Pochini A., Ungaro R., Bocchi C., Ugozzoli F., Egberink R. J. M.,
Struijk H., Lugtenberg R., de Jong F., Reinhoudt D. N.: Chem. Eur. J. 1996, 2, 436;
e) Sachleben R. A., Urvoas A., Bryan J. C., Haverlock T. J., Hay B. P., Moyer B. A.: Chem.
Commun. 1999, 1751; f) Lamare V., Dozol J. F., Fuangswasdi S., Arnaud-Neu F., Thuery P.,
Nierlich M., Asfari Z., Vicens J.: J. Chem. Soc., Perkin Trans. 2 1999, 271; g) Asfari Z.,
Thuery P., Nierlich M., Vicens J.: Tetrahedron Lett. 1999, 40, 499; h) Asfari Z., Thuery P.,
Nierlich M., Vicens J.: Aust. J. Chem. 1999, 52, 343.
5. For more recent examples, see: a) Arduini A., Pochini A., Secchi A.: Eur. J. Org. Chem.
2000, 2325; b) Ji H. F., Dabestani R., Brown G. M., Sachleben R. A.: Chem. Commun.
2000, 833; c) Stephan H., Gloe K., Paulus E. F., Saadioui M., Böhmer V.: Org. Lett. 2000,
2, 839; d) Marchand A. P., Chong H.-S., Pavan K. T., Huang Z., Alihodzic S., Watson W. H.,
Ejsmont K.: Tetrahedron 2002, 58, 10205; e) Kim S. K., Sim W., Vicens J., Kim J. S.:
Tetrahedron Lett. 2003, 44, 805; f) Kim S. K., Vicens J., Park K.-M., Lee S. S., Kim J. S.:
Tetrahedron Lett. 2003, 44, 993; g) Csokai V., Grün A., Bitter I.: Tetrahedron Lett. 2003,
44, 4681.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Doubly Bridged Calix[8]crowns
1361
6. a) Kraft D., Arnecke R., Böhmer V., Vogt W.: Tetrahedron 1993, 49, 6019; b) Gordon J. L. M.,
Böhmer V., Vogt W.: Tetrahedron Lett. 1995, 36, 2445; c) Cacciapaglia R., Mandolini L.,
Arnecke R., Böhmer V., Vogt W.: J. Chem. Soc., Perkin Trans. 2 1998, 419; d) Caccamese S.,
Notti A., Pappalardo S., Parisi M. F., Principato G.: Tetrahedron 1999, 55, 5505;
e) Caccamese S., Notti A., Pappalardo S., Parisi M. F., Principato G.: J. Inclusion Phenom.
Mol. Recogn. Chem. 2000, 36, 67.
7. a) Casnati A., Jacopozzi P., Pochini A., Ugozzoli F., Cacciapaglia R., Mandolini L., Ungaro R.:
Tetrahedron 1995, 51, 591; b) Li J. S., Chen Y. Y., Lu X. R.: Tetrahedron 1999, 55, 10365;
c) Chen Y. Y., Li J. S., Xin J., Zhong Z. L., Gong S. L., Lu X. R.: Synth. Commun. 1999, 29,
705; d) Chen Y. Y., Yang F. F., Lu X. R.: Tetrahedron Lett. 2000, 41, 1571; e) Chen Y. Y.,
Yang F. F., Gong S. L.: Tetrahedron Lett. 2000, 41, 4815; f) Chen Y. Y., Yang F. F.: Chem.
Lett. 2000, 484; g) Blanda M. T., Farmer D. B., Brodbelt J. S., Goolsby B. J.: J. Am. Chem.
Soc. 2000, 122, 1486; h) Chen Y., Yang F., Thuery P., Nierlich M., Vicens J.: J. Inclusion
Phenom. Mol. Recogn. Chem. 2002, 42, 261.
8. Neri P., Geraci C., Piattelli M. in: Recent Research Developments in Organic Chemistry (S. G.
Pandalai, Ed.), Vol. 1, p. 285. Transworld Research Network, Trivandrum 1997.
9. a) Geraci C., Piattelli M., Neri P.: Tetrahedron Lett. 1996, 37, 3899; b) Yang F., Chen Y.:
Eur. J. Org. Chem. 2001, 365.
10. a) Geraci C., Piattelli M., Neri P.: Tetrahedron Lett. 1995, 36, 5429; b) Geraci C., Chessari G.,
Piattelli M., Neri P.: Chem. Commun. 1997, 921.
11. Geraci C., Piattelli M., Chessari G., Neri P.: J. Org. Chem. 2000, 65, 5143.
12. Geraci C., Piattelli M., Neri P.: Tetrahedron Lett. 1996, 37, 7627.
13. For a discussion on chemical shift of OH groups in partially alkylated calix[8]arenes, see
ref. 11 and Cunsolo F., Consoli G. M. L., Piattelli M., Neri P.: J. Org. Chem. 1998, 63, 6852.
14. For examples of the use of OH chemical shift as a structural probe, see refs 6a, 13 and
Neri P., Battocolo E., Cunsolo F., Geraci C., Piattelli M.: J. Org. Chem. 1994, 59, 3880.
15. Molecular modeling was performed with MacroModel V4.5 computer program:
Mohamadi F., Richards N. G. J., Guida W. C., Liskamp R., Lipton M., Caufield C.,
Chang G., Hendrickson T., Still W. C.: J. Comput. Chem. 1990, 11, 440.
16. a) Magrans J. O., de Mendoza J., Pons M.: J. Org. Chem. 1997, 62, 4518; b) Caccamese S.,
Bottino A., Cunsolo F., Parlato S., Neri P.: Tetrahedron: Asymmetry 2000, 11, 3103.
17. Caccamese S., Principato G., Geraci C., Neri P.: Tetrahedron: Asymmetry 1997, 8, 1169.
18. For other examples of inherently chiral calix[8]arenes, see: a) Ikeda A., Suzuki Y., Shinkai S.:
Tetrahedron: Asymmetry 1998, 9, 97; b) Geraci C., Bottino A., Piattelli M., Gavuzzo E.,
Neri P.: J. Chem. Soc., Perkin Trans. 2 2000, 185.
19. See K. A., Fronczek F. R., Watson W. H., Kashyap R. P., Gutsche C. D.: J. Org. Chem.
1991, 56, 7256.
20. a) Pedersen C.: J. Fed. Proc. Fed. Am. Soc. Expl. Biol. 1968, 27, 1305; b) Arduini A.,
Pochini A., Reverberi S., Ungaro R., Andreetti G. D., Ugozzoli F.: Tetrahedron 1986, 42,
2089.
21. Kopolow S., Hogen Esch T. E., Smid J.: Macromolecules 1973, 6, 133.
22. Casnati A., Pochini A., Ungaro R., Ugozzoli F., Arnaud F., Fanni S., Schwing M.-J.,
Egberink R. J. M., de Jong F., Reinhoudt D. N.: J. Am. Chem. Soc. 1995, 117, 2767.
23. For other examples of calix[4]crown-based Cs+/Na+ selective ionophores, see:
a) Arnaud-Neu F., Asfari Z., Souley B., Vicens J.: New J. Chem. 1996, 20, 453; b) Asfari Z.,
Lamare V., Dozol J. F., Vicens J.: Tetrahedron Lett. 1999, 40, 691.
24. Munch J. H., Gutsche C. D.: Org. Synth. 1990, 68, 243.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)