Rapid evaluation of suitable substrates with high affinity to artificial caffeine receptors by MS based techniques

Article abstract of DOI:10.1515/znb-2005-1010

A modification of our triphenylene ketal based receptor facilitates electrospray tandem mass spectrometry investigations. Binding affinities of eleven potential substrates, e.g. caffeine and other xanthine alkaloids, are probed in the gas phase with colli

Full text of DOI:10.1515/znb-2005-1010

Rapid Evaluation of Suitable Substrates with High Affinity to
Artificial Caffeine Receptors by MS Based Techniques
Daniela Mirka,b, Heinrich Luftmannb, and Siegfried R. Waldvogela,b
a Kekule´-Institut fu¨r Organische Chemie und Biochemie, Rheinische Friedrich Wilhelms-Universita¨t
Bonn, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany
b Westfa¨lische Wilhelms-Universita¨t Mu¨nster, Organisch-Chemisches Institut, Corrensstr. 40,
D-48149 Mu¨nster, Germany
Reprint requests to Prof. Dr. S. R. Waldvogel. Fax: +49(0) 228-73 9608.
E-mail: waldvogel@uni-bonn.de
Z. Naturforsch. 60b, 1077 – 1082 (2005); received July 29, 2005
A modification of our triphenylene ketal based receptor facilitates electrospray tandem mass spec-
trometry investigations. Binding affinities of eleven potential substrates, e.g. caffeine and other xan-
thine alkaloids, are probed in the gas phase with collision induced dissociation. The relative stabilities
of the substrate-receptor complexes are rapidly determined and the findings are correlated with the
corresponding results in solution.
Key words: Supramolecular Chemistry, Mass Spectrometry, Host-Guest Complexes, Receptors
Introduction
ticular electrospray ionization (ESI) [13 – 15], the del-
icate transfer of large molecules from solution to the
gas phase including the mass spectrometric investiga-
tion of their non-covalent interactions with appropri-
ate binding partners became feasible. Mass spectrome-
try offers a rapid screening process wherein only very
small samples are required. Thus, the presented fast
evaluation method will open up for further applica-
tions, e.g. for doping control analysis [16].
The detection of small, biologically relevant
molecules is of particular interest due to their om-
nipresence in everyday life. Alkylated oxopurines, e.g.
caffeine (13), belong to the most frequently consumed
alkaloids [1, 2]. Many of those target molecules ex-
hibit a C3 or pseudo-C3 symmetry, therefore receptors
with a complementary scaffold are popular [3]. Based
on functionalized triphenylene ketals [4], the first ar-
tificial caffeine receptors were established by us, re-
cently [5]. These contain an unusual large and rigid
backbone providing concave and convergent preorga-
Results and Discussion
For a mass spectrometric investigation the construc-
nized functional groups for the supramolecular inter- tion of the modified receptor 1 (Fig. 1) was required.
action. A chiral modification of the receptors allowed 1 exhibits a N,N-dibenzylamino substituent on one of
the first enantiofacial discrimination on single hetero- the three receptor arms, which is easily protonated and
cyclic guest molecules [6]. The binding modes for such facilitates the detection by ESI-MS. The tertiary amino
highly dynamic supramolecular aggregates were stud- group or the corresponding ammonium moiety should
ied by different spectroscopic means creating a highly not influence the host-guest interaction. The three urea
consistent picture in solution and for the solid state [7]. moieties are capable of hydrogen bonding with the
A detailed protocol for the synthesis of the scaffold and considered substrates and exhibit the same binding site
the corresponding receptors was recently reported [8].
Herein, we present a novel approach for the detec-
tion of caffeine and other xanthine alkaloids by tan-
dem mass spectrometry. Exciting advances in mass
as our first artificial caffeine receptor [5]. Therefore,
the results should be comparable with earlier findings
[5, 7].
For the synthesis of 1 trisamine 2 was treated
spectrometry have made gas phase studies of organic with a 5:1 mixture of hexyl isocyanate and 3-(N,N-
supramolecular aggregates possible [9, 10], e.g. the dibenzylamino)propyl isocyanate (8) yielding sym-
enantiomer discrimination of peptides [11, 12]. With metric receptor 3 as major product and the desired
the development of soft ionization techniques, in par- receptor 1 (Scheme 1). Separation was achieved via
c
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D. Mirk et al. · MS Screening with Artificial Caffeine Receptors
a) Hexyl isocyanate and R-NCO 8 (5:1), NEt , CH2Cl2, 16 h, 0 ◦C to r. t.
3
Scheme 1. Synthesis of receptor 1.
a) Benzyl bromide, K2CO3, NaOH (2 N), CH2Cl2, 16 h, reflux; b) 1. aq. KOH (20%), 16 h, reflux; 2. HCl; c) aq. NaOH
(20%), pH = 7; d) 1. DPPA, NEt3, toluene (anhydr.), 3 d, r. t.; 2. reflux
Scheme 2. Synthesis of amino-substituted isocyanate 8.
detail [8]. Amino-substituted isocyanate 8 was ob-
tained in a multi-step sequence (Scheme 2). Start-
ing from commercially available γ-aminobutyric acid
(4) standard procedures yielded the known 4-(N,N-
dibenzylamino)butyric acid (7). The last step, the
conversion into the carboxylic acid azide interme-
diate followed by Curtius rearrangement leading to
the corresponding isocyanate 8 was performed using
diphenylphosphoryl azide (DPPA) as mild azide trans-
fer reagent. DPPA was introduced in organic synthe-
sis by Shioiri [17] and is easily available in large
scale [18]. However, treatment of 7 with thionyl chlo-
ride led to a five-membered lactam by intramolecu-
lar attack of the free electron pair of the amino group
Fig. 1. Modified receptor 1 for MS investigations.
on the highly reactive carbonyl carbon of the car-
boxylic acid chloride. This was accompanied by the
column chromatography. Choosing the appropriate ra-
tio of isocyanates, the formation of receptors involv-
ing more than one protected amino function was sup-
pressed and therefore mono-amino substituted 1 could
be obtained in reasonable yields. Due to the hydro-
gen bonding capacity of the receptor, the empty re-
ceptor binds also solvent molecules and consequently
the microanalysis was slightly deviated, whereas the
structure was verified by the usual spectroscopic
means.
loss of benzyl chloride. Due to the moisture sensitiv-
ity of 8, a good match of microanalysis or IR spec-
tra could not be obtained, but the nature of isocyanate
8 was proven by treatment with a primary amine
followed by structural confirmation of the resulting
product.
The collision-induced dissociation (CID) behavior
of receptor 1 with different substrates 9 – 19 (Fig. 2)
was studied in the gas phase [19]. Mixtures of 1, a nine-
fold excess of the specific substrate, catalytic amounts
The preparation of all-syn trisamine 2 as well as of fumaric acid, and methanol in THF were analyzed
the following urea formation by treatment with iso- by electrospray ionization tandem mass spectrometry
cyanates is well elaborated and has been reported in (ESI-MS/MS). Surprisingly, not the monocation but
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D. Mirk et al. · MS Screening with Artificial Caffeine Receptors
1079
Fig. 3. Relative intensities of theophylline-1 complex and
free receptor in dependence on acceleration voltage.
Fig. 4. Points
of intersection
for substrates
9 – 19.
quality of different substrates. Increasing the acceler-
ation voltage stepwise led to the dissociation of the
substrate-receptor complex and therefore, the detected
intensity of the complex decreased while the intensity
of the empty receptor increased.
Figure 3 illustrates these findings with theophylline
(9). The relative intensities of the complex and the
empty receptor 1 are depicted in dependence on the
acceleration voltage. The point of intersection (for 9 at
6.8 V), wherein the relative intensities for the free re-
ceptor as well as for the complex are 0.5, is a specific
criterion for the individual substrate and indicates the
stability of the corresponding receptor complex. These
data were determined for each substrate and the indi-
vidual results are summarized in Fig. 4.
The investigations do not allow the quantification
of association constants, but the relative stabilities of
Fig. 2. Investigated substrates.
the doubly charged system consisting of receptor 1, different substrate-receptor complexes can be clearly
the corresponding substrate and two protons was de- assigned. A higher voltage at the point of intersec-
tected. Employing the non-functionalized receptor 3 tion corresponds to a higher acceleration voltage of the
gave no reliable cationic species under the same condi- cations and therefore, a higher stability of the particu-
tions. Cone voltage was kept at a maximum of 14 V to lar substrate-receptor aggregate is revealed.
prevent the dissociation of the complexes before they
First, theophylline (9) and its derivatives 7-
enter the quadrupole analyzer. Separation of a spe- benzyltheophylline (10), 7-tert-butyltheophylline (11),
cific [M2+] cation, acceleration and subsequent colli- and 7-iso-propyltheophylline (12) are compared with
sion with argon enabled us to compare the association each other. Those substrates are able to form hydro-
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D. Mirk et al. · MS Screening with Artificial Caffeine Receptors
gen bonds with receptor 1 using two carbonyl moieties Conclusion
and nitrogen N9. The alkyl substituents on N1 and N3
The synthesis of N,N-dibenzylamino-substituted re-
are pointing between the receptor arms. The intersec-
tion point of theophylline is relative high, indicating
that the affinity of theophylline towards the receptor is
higher than the affinity for most of the other substrates.
That can be explained by comparing the steric demand
of derivatives 9 – 12. The theophylline-receptor com-
plex has the highest stability among these substrates.
Exchanginghydrogen in position 7 to benzyl (10) leads
to a higher steric demand of the substrate and there-
fore the stability of the substrate-receptor complex de-
creases. But the affinity of 10 increases compared to
11 and 12, due to the fact that the benzyl group is able
to turn vertical to the receptor arms, whereas the bulky
iso-propyl and tert-butyl groups require more space,
leading to significant repulsive interactions.
ceptor 1 provided a tool for the fast screening of vari-
ous substrates using mass spectrometric analysis. We
could demonstrate that our investigations furnished
reasonable results, which allowed qualitative conclu-
sions concerning the stability of different substrates in
receptor 1. These results were mostly consistent with
earlier findings and facilitate new insights, whereas
NMR spectroscopy could not be applied. Based on
these findings, we are currently ameliorating the re-
ceptor’s qualities, allowing a competition between sub-
strates and the simultaneous determination of associ-
ation constants. The results will be presented in due
course.
Experimental Section
Similar affinities were found for caffeine (13) and its
methoxy (14) and bromo derivatives (15), respectively.
Their points of intersection are in the same range.
NMR spectroscopic determination of the binding con-
stant to receptor 3 in solution resulted in 35600
2000 M−1 for caffeine and 9240 220 M−1 for 8-
methoxycaffeine (14) [5], seemingly the opposite re-
sult to the MS-MS screening experiments. But since
the acceleration voltage varies in a very small range
(0 – 10 V), the dissociation of the complexes takes
place at very low tension. Keeping in mind that the de-
cay is a gas phase process and a second proton may in-
terfere with the supramolecular interaction, still a good
consistency in the general course for the complex for-
mation to suitable substrates was found. Furthermore,
binding constants of 9240 or 35600 M−1, respec-
tively, are very low compared to the binding constant
of 1,3,7-trimethyluric acid (16) in receptor 3, which
could not be assigned up to now, but was estimated
to be > 200000. Comparing those numbers legiti-
mates qualitative conclusions, since 16 leads clearly
to the highest voltage at the point of intersection,
indicating that the 1,3,7-trimethyluric acid-receptor
complex is the most stable among the investigated
complexes.
All reagents were used in analytical grades. Solvents were
desiccated if necessary by standard protocols. Column chro-
matography was performed on silica gel (particle size 63 –
200 µm, Merck, Darmstadt, Germany) using mixtures of cy-
clohexane with ethyl acetate as eluents. TLC was done on
silica gel 60 F254 on glass (Merck, Darmstadt, Germany).
Melting points were determined on a Melting Point Appa-
ratus SMP3 (Stuart Scientific, Watford Herts, UK) and were
uncorrected. NMR spectra were recorded on a Bruker ARX
300 (Analytische Messtechnik, Karlsruhe, Germany) using
TMS as internal standard or CDCl3 with δ = 7.26 ppm for
1H NMR, and δ = 77.0 ppm for 13C NMR. EI mass spectra
were obtained on a MAT8200 (Finnigan-MAT, Bremen, Ger-
many) and ESI on a QUATTRO LCZ (Waters-Micromass,
Manchester, UK).
General procedure for the MS-screening experiments
Solutions (1 mmol/l each) of receptor 1 and substrates
9 – 19 were prepared by dissolving appropriate amounts in
tetrahydrofuran. Samples were prepared by mixing 100 µl
of receptor solution, 900 µl of the respective substrate so-
lution, 200 µl methanol, and 1 µl fumaric acid. The MS-
screening experiments were acquired on a QUATTRO LCZ
(Waters-Micromass, Manchester, UK). Samples were intro-
duced by using a standard electrospray source with a syringe
pump (flow rate: 1 ml/h). Applied parameters: capillary volt-
age 3.3 kV, cone voltage 27 V, unit resolution, collision gas
1.3×10−3 mbar argon.
6-Phenyl-lumazin (17) forms a stable complex as
well, whereas triallyltrizintrione 18 and oxadiazintri-
one 19 only represent weak binding partners. For the
latter substrate a binding constant in receptor 3 mea-
sured by NMR spectroscopy in dichloromethaneis also
N,N-Dibenzylamino-substituted receptor 1
All-syn trisamine 2 (600 mg, 0.82 mmol) was dissolved in
dichloromethane (20 ml) and chilled to 0 ◦C. Triethylamine
(0.35 ml, 2.50 mmol, 3.0 eq.) was added, followed by the ad-
dition of a mixture of hexyl isocyanate (4.5 ml, 3.09 mmol,
available [5]. This represents with 1240 115 M−1
a
very small value, which clearly correlates with the re-
sults of our MS screening experiments.
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D. Mirk et al. · MS Screening with Artificial Caffeine Receptors
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3.8 eq.) and 3-(N,N-dibenzylamino)propyl isocyanate (8) Subsequently, 6 N hydrochloric acid (100 ml) was added at
(174 mg, 0.62 mmol, 0.76 eq.) in dichloromethane (5 ml). ambient temperature and the solution was concentrated in
The reaction mixture was allowed to warm to ambient tem- vacuo. The remaining residue was crystallized twice from
perature, stirred overnight, and then diluted with ethyl acetate acetic acid (50 ml) and hydrochloride 6 was obtained in col-
(125 ml). The organic phase was subsequently washed with orless crystals (55.72 g, 0.174 mol, 64%).
0.1 M hydrochloric acid (75 ml) at 5 ◦C and brine (3×75 ml),
dried over anhydrous MgSO4 and concentrated in vacuo.
For the separation of the products the crude residue was ad-
sorbed on silica and subjected to column chromatography
(cyclohexane:ethyl acetate = 50:50) yielding receptor 3 [5]
(394 mg, 0.35 mmol, 43%) (RF (CH:EE = 50:50): 0.46) and
1 (115 mg (0.09 mmol, 11%) (RF (CH:EE = 50:50): 0.24) as
an off-white foam.
◦
M. p. 146 – 147 C. – 1H NMR (300 MHz, D2O): δ =
2.10 − 2.18 (m, 2H, 3-H), 2.46 (t,3J = 6.9 Hz, 2H, 2-
H), 3.22 – 3.28 (m, 2H, 4-H), 4.48 (s, 4H, N-benzyl-CH2),
7.53 – 7.63 (m, 10H, arom. CH). – 13C NMR (75 MHz,
D2O): δ = 19.15 (C-3), 31.12 (C-2), 51.88 (C-4), 57.74
(N-benzyl-CH2), 129.45, 129.86, 130.67, 131.50 (arom. C),
177.15 (CO).
1: 1H NMR (300 MHz, CDCl3): δ = 0.66 − 3.20 (m,
75H, bicyclo-H, CH2, CH3), 7.21 – 7.56 (m, 10H, phenyl-
H), 7.57 – 7.94 (m, 6H, triphenylene-H). – 13C NMR
(75 MHz, CDCl3) (selected signals of 77 detected): δ =
13.96 (CH3), 39.88 (NHCH2), 101.18 (spiro-C), 122.08,
124.48 (triphenylene-C), 129.25, 129.31 (phenyl-C), 147.74
(triphenylene-C). – MS (ESI (ES+)): m/z (%) = 1267.8 (10),
1266.9 (33), 1265.9 (84), 1264.9 (87) [M+H+].
4-(N,N-Dibenzylamino)butyric acid (7) [20]
4-(N,N-Dibenzylamino)butyric acid hydrochloride (6)
(11.00 g, 34.4 mmol) was dissolved in water (250 ml) and
neutralized with aqueous sodium hydroxide solution (20%).
After removal of water under reduced pressure, the residue
was dissolved in chloroform (150 ml) at reflux conditions,
filtered hot and washed with chloroform (3×20 ml). Evapo-
ration of the volatiles yielded a colorless, viscous oil (9.78 g,
34.4 mmol, 100%).
Benzyl 4-(N,N-dibenzylamino)butyrate (5)
1H NMR (300 MHz, CDCl3): δ = 1.75 (tt,3J = 6.6 Hz,
6.6 Hz, 2H, 3-H), 2.20 (t, 3J = 6.6 Hz, 2H, 2-H), 2.12 (t, 3J =
6.6 Hz, 2H, 4-H), 3.60 (s, 4H, N-benzyl-CH2), 7.20 – 7.33
(m, 10H, arom. CH), 12.04 (bs, 1H, COOH). – 13C NMR
(75 MHz, CDCl3): δ = 21.82 (C-3), 34.47 (C-2), 53.05 (C-
4), 58.03 (N-benzyl-CH2), 127.49, 128.42, 129.41 (arom.
CH), 136.94 (quat. C), 177.93 (CO). – MS (EI, 70 eV): m/z
(%) = 283.1 (7) [M+], 210.1 (74) [CH2NBn2+], 91.0 (100)
[C7H7+].
4-Aminobutyric acid (39.95 g, 0.387 mol) was dissolved
in dichloromethane (250 ml), potassium carbonate (72 g,
0.514 mol, 1.3 eq.) and 2 N aqueous sodium hydroxide solu-
tion (100 ml) were added. The biphasic mixture was heated
at reflux conditions and benzyl bromide (170 ml, 1.40 mol,
3.6 eq.) was added drop by drop within 15 min. into the hot
mixture. After 16 h, the mixture was brought to ambient tem-
perature and the aqueous phase was extracted with diethyl
ether (150 ml). The combined organic phases were washed
with brine (2 × 150 ml), dried over anhydrous MgSO4 and
concentrated in vacuo. Excess benzyl bromide was removed
by distillation, 5 (115.55 g, 0.309 mol, 80%) remained as
yellow oil and was used without further purification.
3-(N,N-Dibenzylamino)propyl isocyanate (8)
4-(N,N-Dibenzylamino)butyric
acid
(7)
(4.77 g,
16.8 mmol) was dissolved in dry toluene (125 ml),
treated with triethylamine (2.8 ml, 20.2 mmol, 1.2 eq.),
diphenylphosphoryl azide (DPPA) (4.4 ml, 20.2 mmol,
1.2 eq.) and stirred at ambient temperature for 3 d, followed
by refluxing until gas evaporation was no longer observed.
Upon removal of the solvents under reduced pressure the
remaining oil was purified by distillation in high vacuum
yielding 8 as yellow oil (1.78 g, 6.3 mmol, 38%).
B. p. 154 – 156 ◦C/5×10−5 mbar. – 1H NMR (300 MHz,
CDCl3): δ = 1.81 − 1.89 (m, 2H, 3-H), 3.12 – 3.19, 3.23 –
3.29 (m, 4H, 2-H, 4-H), 4.55, 4.61 (s, 4H, N-benzyl-CH2),
7.21 – 7.33 (m, 10H, arom. CH). – 13C NMR (75 MHz,
CDCl3): δ = 21.82 (C-3), 34.47 (C-2), 53.05 (C-4), 58.03
(N-benzyl-CH2), 127.49, 128.42, 129.41 (arom. C), 136.94
1H NMR (300 MHz, CDCl3): δ = 1.86 (tt, 3J = 6.9 Hz,
3
6.9 Hz, 2H, 3-H), 2.37, 2.47 (2 × t, J = 6.9 Hz, 4H, 2-H,
4-H), 3.56 (s, 4H, N-benzyl-CH2), 5.05 (s, 2H, O-benzyl-
CH2), 7.20 – 7.37 (m, 15H, arom. CH). – 13C NMR (75 MHz,
CDCl3): δ = 22.32 (C-3), 31.88 (C-2), 52.42 (C-4), 58.24
(N-benzyl-CH2), 70.74 (O-benzyl-CH2), 126.84, 126.94,
127.57, 127.73, 128.09, 128.13, 128.16, 128.25, 128.35,
128.49, 128.61, 128.65, 128.74, 128.80, 128.98 (arom. CH),
133.29, 136.09 (quat. C), 173.36 (CO). – MS (EI, 70 eV):
m/z (%) = 373.3 (3) [M+], 282.2 (9) [M+ −Bn], 210.1 (85)
[CH2NBn+2 ], 91.0 (100) [C7H7+].
4-(N,N-Dibenzylamino)butyric acid hydrochloride (6) [20]
A solution of benzyl-4-(N,N-dibenzylamino)-butyrate (5) (quat.-C), 177.93 (CO). – MS (EI, 70 eV): m/z (%) = 280.2
(101.76 g, 0.272 mol) in aqueous potassium hydroxide solu- (67) [M+], 251.1 (5) [M+–CO], 189.1 (62) [M+–C7H7],
tion (20%, 80 ml) was heated at reflux conditions over night. 91.0 (100) [C7H7+], 77.0 (13) [C6H5+].
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D. Mirk et al. · MS Screening with Artificial Caffeine Receptors
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft and the State of Northrhine-Westfalia
(Bennigsen-Foerder-Award). D. M. gratefully acknowledges
the Fonds der Chemischen Industrie for a stipend.
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