Facile N-alkylation of acridine esters with 1,3-propane sultone in ionic liquids

Article abstract of DOI:10.1039/c0gc00758g

Hydrophilic chemiluminescent acridinium esters containing N-sulfopropyl groups are extremely useful labels in the clinical diagnostics industry. The synthesis of these labels is normally accomplished by N-alkylation of the acridine ester precursors with the carcinogenic reagent 1,3-propane sultone in neat reactions where the alkylating reagent also serves as the solvent. Product yields are often poor, the reactions are not reproducible and are also difficult to scale-up. In our efforts to develop a greener and a more efficient synthesis of N-sulfopropyl acridinium esters, we have discovered that commonly used room temperature ionic liquids such as [BMIM][BF₄] and [BMIM][PF ₆] are excellent media for the N-alkylation of poorly reactive acridine esters with 1,3-propane sultone. Advantages include a significant reduction in the amount of toxic 1,3-propane sultone needed for good conversion to product, and minimal formation of polysulfonated products. The alkylation reaction in ionic liquids is amenable to scale-up for the synthesis of gram quantities of hydrophilic, chemiluminescent acridinium esters. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00758g

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PAPER
Facile N-alkylation of acridine esters with 1,3-propane sultone in
ionic liquids
Anand Natrajan* and David Wen
Received 1st November 2010, Accepted 23rd December 2010
DOI: 10.1039/c0gc00758g
Hydrophilic chemiluminescent acridinium esters containing N-sulfopropyl groups are extremely
useful labels in the clinical diagnostics industry. The synthesis of these labels is normally
accomplished by N-alkylation of the acridine ester precursors with the carcinogenic reagent
1,3-propane sultone in neat reactions where the alkylating reagent also serves as the solvent.
Product yields are often poor, the reactions are not reproducible and are also difficult to scale-up.
In our efforts to develop a greener and a more efficient synthesis of N-sulfopropyl acridinium
esters, we have discovered that commonly used room temperature ionic liquids such as
[BMIM][BF4] and [BMIM][PF6] are excellent media for the N-alkylation of poorly reactive
acridine esters with 1,3-propane sultone. Advantages include a significant reduction in the amount
of toxic 1,3-propane sultone needed for good conversion to product, and minimal formation of
polysulfonated products. The alkylation reaction in ionic liquids is amenable to scale-up for the
synthesis of gram quantities of hydrophilic, chemiluminescent acridinium esters.
Introduction
Chemiluminescent acridinium esters have detection limits in
the attomole range and are extremely useful labels for both
immunoassays and nucleic acid assays in the clinical diagnostics
industry.1 The hydrophilic acridinium ester NSP-DMAE-NHS2
(Fig. 1, 2b) and its derivatives containing N-sulfopropyl (NSP)
groups are used extensively as chemiluminescent labels in
automated immunoassays such as in Siemens Healthcare Diag-
R
nostics’ ADVIA Centaurꢀ systems. A key step in the synthesis
of various NSP-DMAE derivatives is the difficult N-alkylation
of the acridine N-hydroxysuccinimide (NHS) ester precursor
(Fig. 1, 1b) with 1,3-propane sultone. The N-alkylation of
tertiary amines with 1,3-propane sultone can be carried out in
organic solvents,3 but the poor reactivity of the acridine ester
Fig. 1 N-Alkylation of acridine esters with 1,3-propane sultone.
1b necessitates performing the N-alkylation of this substrate
with a 50-fold excess of 1,3-propane sultone in a sealed tube
where the sultone acts as both alkylating reagent and solvent.2
Decomposition of the alkylating reagent 1,3-propane sultone4c
(both thermal and hydrolytic decomposition of propane sultone
is reported) competes with the N-alkylation of the acridine
nitrogen resulting in a tarry reaction mixture from which the
acridinium ester is isolated by reverse-phase HPLC. Typically,
total yield of product 2b is only 25% after HPLC purification
because of decomposition and, the formation of polysulfonated
material. The reaction is also difficult to scale up and is suscep-
tible to gel formation depending upon the quality of the sultone
reagent, which can further lower yields. Polysulfonation also
makes HPLC purification of the product 2b quite challenging.
Besides suffering from low yields and a difficult purifica-
tion process, another significant drawback is the requirement
for conducting the N-alkylation reaction in neat 1,3-propane
sultone. It has been reported that 1,3-propane sultone is a
potent carcinogen4 that induces cancer in rats even after a
single exposure, and that malignant tumors observed in humans
exposed to this chemical appear to be consistent with the
results seen from these animal studies.4a Unfortunately, there
Siemens Healthcare Diagnostics, Advanced Technology &
Pre-Development, 333 Coney Street, East Walpole, MA, 02032, USA.
E-mail: anand.natrajan@siemens.com; Fax: 1-508-660-4591;
Tel: 1-508-660-4582
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are few published reports that are preparatively useful for the
N-alkylation of poorly reactive acridine esters with 1,3-propane
sultone under milder conditions without the need for using a
large excess of the sultone reagent and extensive chromatogra-
phy. Adamczyk5 et al. have reported that introduction of the
N-sulfopropyl group in acridine N-sulfonylcarboxamides with
poor reactivity can be performed using the reagent neopentyl
3-trifloxypropane sulfonate. However, N-alkylation using this
reagent required 7 days to afford 34% conversion to product, and
moreover the triflate had to be synthesized in three steps from
neopentyl alcohol. In addition, acid hydrolysis of the neopentyl
group was required to unmask the N-sulfopropyl group. In our
experience too, with the exception of methyl triflate, other alkyl
triflates show poor reactivity towards the acridine nitrogen of
acridine esters such as 1a. Therefore, despite its toxicity, 1,3-
propane sultone remains an attractive alkylating reagent for
the introduction of the water-soluble, N-sulfopropyl group of
hydrophilic acridinium esters.
In exploring greener alternatives towards the syntheses of N-
sulfopropyl acridinium esters by N-alkylation of their acridine
ester precursors, one of our primary objectives was to reduce the
usage of the toxic reagent 1,3-propane sultone in the manufac-
turing processes of these chemiluminescent labels. Our goal was
to both minimize the environmental impact of this carcinogen as
well as to alleviate the exposure risk to personnel involved in the
manufacture of these compounds. We also wanted to develop a
robust N-alkylation process that would be reproducible, be of
general synthetic utility for a variety of ring-substituted acridine
ester precursors and that would be amenable to scale-up for
the synthesis of gram quantities of N-sulfopropyl acridinium
esters without the need for extensive chromatography. Finally, in
our attempts to identify a suitable and benign reaction medium
for the N-alkylation reaction, we wanted to ensure that one
carcinogen (1,3-propane sultone) was not merely substituted
with another carcinogenic or toxic solvent.
as reaction media for various synthetic transformations, and
their unique properties can confer reactivity not normally
observed in common organic solvents. An excellent review of the
extensive literature can be found in a two volume book edited by
Wasserscheid and Welton.9 Kamlet–Taft parameters for various
ionic liquids have been reported in the literature.10,17 In general,
the reported Kamlet–Taft parameter p* is high for ionic liquids
(typically > 0.8) indicating that these compounds are quite
polar. On the other hand, a and b values show considerable
variation and depend upon the structure of the cation and
anion. For example, the 1-butyl-3-methylimidazolium cation
[BMIM] has a higher value of a (a = 0.625 for [BMIM][OTf])
than the 1-butyl-1-methylpyrrolidinium cation [BMPY] (a =
0.396 for [BMPY][OTf]) indicating that the former cation is
a stronger hydrogen bond donor.17 For anions, b values, which
are indicative of their basicity, are higher for anions such as
triflate (OTf) and tetrafluoroborate (BF4) when compared to the
bis(trifluoromethylsulfonyl)imide [N(Tf)2] anion,10,17 Another
empirically-derived solvent polarity scale is the Reichardt scale
{ET(30) scale}, and an extensive compilation of ET(30) values
of ionic liquids and other solvents has been published by
Reichardt.11
In our initial experiments, we wanted to test the hypothesis
that increased solvent polarity, as reflected by its p* value,
would facilitate the N-alkylation of acridine esters with 1,3-
propane sultone. We selected the unsubstituted acridine ester
1a (Fig. 1) as the substrate for these experiments. The choice
of organic solvents was fairly straightforward (solvents listed
in Table 1 are commonly used in synthesis) but, the choice of
the ionic liquid(s) was not, given that a significant number of
ionic liquids are commercially available and, many more have
been described in the literature. To guide our selection of ionic
liquids for the N-alkylation reaction and narrow our choices, we
attempted to answer the following questions. Was there relevant
literature precedent to support the use of a specific ionic liquid
as a reaction medium in analogous reactions such as the N-
alkylation of heterocycles? What are the toxicological properties
of the ionic liquid that would replace 1,3-propane sultone as the
solvent in the N-alkylation reaction of acridine esters? Would
the selected ionic liquid withstand the reaction conditions such
as elevated temperature necessary for the N-alkylation reaction?
Although the N-alkylation of acridines in ionic liquids, to
the best of our knowledge, has not been reported in the
Results and discussion
The N-alkylation of acridine esters with 1,3-propane sultone is
representative of a substitution-type reaction where uncharged
reactants yield a zwitterionic product. In the transition state of
the reaction, the acridine nitrogen develops a partial positive
charge which is accompanied by the development of a partial
negative charge on the (incipient) sulfonate moiety. Based
on studies by Hughes, Ingold and co-workers,6 an increase
in polarity of the reaction medium is expected to facilitate
this reaction. For organic solvents, the empirically determined
Kamlet–Taft parameter p*, which is a measure of solvent dipo-
larity/polarizability, is a useful indicator of solvent polarity.7 In
addition, the Kamlet–Taft parameters a and b which denote the
hydrogen bond donating and accepting ability respectively of a
solvent, are also useful descriptors of a solvent’s properties. A
comprehensive list of p*, a and b values of a variety of organic
solvents has been compiled by Kamlet et al.7e For solvents that
are traditionally considered non-polar, p* is low (p* = 0.43 for
p-xylene) and it increases for solvents that are considered polar
such as dimethyl sulfoxide (p* = 1.0) and water (p* = 1.09).
Ionic liquids8,9 constitute a relatively new class of non-
aqueous, polar compounds that are being explored extensively
Table 1 N-Alkylation of acridine ester (1a) with 10 equivalents 1,3-
propane sultone in various solvents
Temperature (◦C),
reaction time (h)
Solvent
HPLC conversion to 2a (%)
p-Xylene
DMSO
DMSO
Diethylene glycol 155, 1
diethyl ether
140, 4
155, 1
155, 16
5
<10
0
0
DMF
155, 6
155, 6
155, 24
210, 2
155, 16
155, 24
35
60
67
55
82
87
Sulfolane
Sulfolane
Sulfolane
[BMIM][BF4]
[BMIM][PF6]
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literature, several preparative N-alkylation reactions of nitrogen-
containing heterocycles in ionic liquids have been reported,
such as the N-alkylation of 2,4-thiazolidinones, phthalim-
ides, pyrroles and other nitrogen heterocycles.12 Specifically,
[BMIM][PF6] was useful for improving yields in the N-alkylation
of 2,4-thiazolidinones;12a both [BMIM][PF6] and [BMIM][BF4]
were useful reaction media for the N-alkylation of phthalimides,
indole and benzimidazole with various electrophiles;12b both
[BMIM][PF6] and [BMIM][BF4] were used as solvents for the N-
alkylation of pyrrole with various electrophiles;12c [BMIM][BF4]
was used a co-solvent for the N-alkylation of indole and
pyrrole12d and, [BMIM]BF4] was used as the solvent for the
N-alkylation of benzotriazole.12e The ionic liquids [BMIM]BF4]
and [BMIM][PF6] are also readily available from various com-
mercial vendors and seemed to be suitable reaction media for
exploring the N-alkylation of acridine esters with 1,3-propane
sultone.
able to withstand these temperatures without decomposition.
It h◦as been shown that [BMIM][PF6] can be distilled at
300 C and high vacuum with minimal decomposition,15a but
lower decomposition temperatures (150 ◦C) were reported for
[BMIM][N(Tf)2]15b measured by gravimetry. Measurement of
free imidazoles by potentiometic titration has been reported
to be a more accurate method for measuring ionic liquid
decomposition,15c and [BMIM][BF4] was observed to be more
stable than [BMIM][PF6], although the total amount of imida-
zoles formed at 140 ◦C was quite small for both ionic liquids
even after heating for several days. Based on these studies, both
[BMIM][PF6]and[BMIM][BF4] appear to be quite stable so as to
withstand the reaction conditions required for the N-alkylation
of acridine esters with 1,3-propane sultone.
To assess the impact of the polarity of the solvent on the
N-alkylation of acridine esters with propane sultone, we inves-
tigated this N-alkylation reaction in various solvents (Table 1)
using 1a as the substrate and measured the formation of the
product NSP-DMAE methyl ester (Fig. 1, 2a), by HPLC anal-
ysis. The solvents that we investigated ranged from non-polar
p-xylene to polar aprotic solvents such as dimethyl formamide
(DMF), dimethyl sulfoxide (DMSO), diethylene glycol diethyl
ether, sulfolane and, the two ionic liquids [BMIM][BF4] and
[BMIM][PF6]. The Kamlet–Taft parameters of these solvents
are listed in Table 3, and although they are from different
studies the same set of dyes (4-nitroaniline and N,N-diethyl-4-
nitroaniline) were used to calculate these parameters.10 Kamlet–
Taft parameters for diethylene glycol diethyl ether was not listed
by Kamlet et al.7e but the structurally similar methyl ether was
reported to have p* = 0.64. We conducted the N-alkylation of
acridine methyl ester 1a (25–50 mg) with ten equivalents of
1,3-propane sultone in these various solvents using the same
concentrations of reagents and measured conversion to the
acridinium ester 2a by HPLC analysis. The results of these
measurements are summarized in Table 1. The concentration of
the acridine ester substrate was kept as high as possible (~0.25 M)
for efficient reaction, and all reactions gave homogeneous solu-
tions at the temperatures indicated in Table 1. The N-alkylation
reaction in the non-polar solvent p-xylene, as expected, led
to very poor conversion. In the polar aprotic solvent DMSO,
product formation was minimal at short reaction times and
extended heating led to substantial decomposition with no trace
of product. The reaction in DMF led to only modest conversion
of 35% after 6 h of heating and, extended reaction times only
led to decomposition. Hardly any reaction was observed at a
short reaction time in diethylene glycol diethyl ether, another
polar aprotic solvent whose Kamlet–Taft parameter p* indicates
that it is less polar than both DMF and DMSO. Among
the polar aprotic solvents that were investigated, the solvent
sulfolane proved to be superior to DMF, and afforded modest
conversion (60%) to product after 6 h at 155 ◦C. A longer
reaction time of 24 h improved conversion somewhat to 67%
without apparent decomposition of product or starting material
by HPLC analysis but produced a foul-smelling reaction mixture
indicating that the solvent may have decomposed. When the
reaction was conducted at a higher temperature of 210 ◦C
for 2 h in sulfolane, further improvement was not observed.
Inclusion of five equivalents of the organic bases 2,6-di-tert-
butylpyridine or 2,6-di-tert-butyl-4-methylpyridine in sulfolane
Until recently, ionic liquids were generally considered to be
benign due to their low vapor pressure, but a large number of
recent studies have shown that they can be quite toxic to aquatic
and other organisms.13 Many ionic liquids have significant solu-
bility in water and can easily be introduced into the environment
by this route. In their screen, Pretti et al.13a observed that
ionic liquids with imidazolium, pyrrolidinium and pyridinium
cations were non-toxic to zebrafish but two ionic liquids with
quaternary alkylammonium cations and long alkyl chains were
more toxic than organic solvents. A comprehensive evaluation
of the toxicological properties of both cations and anions of
alkyl imidazolium ionic liquids using an (eco)toxicological test
battery has also been reported.13d Toxicity was related to the
lipophilicity of the cation but anion effects were less pronounced.
-
Among anions, BF4 or chloride ions were observed to be less
toxic than the bis(trifluoromethylsulfonyl)imide anion.13d Stolte
et al. compared the effect of head groups and side chains
in the cations of structurally diverse ionic liquids and also
related toxicity to the lipophilicity of the cation.13e The general
consensus that emerges from these studies is that (a) within a
class, cations with long alkyl chains should be avoided because
they start resembling cationic surfactants which are known to
be toxic and, (b) the structure of the cation also contributes to
toxicity.13e,13f For anions the picture is not as clear except for
the bis(trifluoromethylsulfonyl)imide anion. A recent review by
Pham et al. summarizes the literature on toxicological studies of
ionic liquids.13h Based on the literature on toxicological studies,
both ionic liquids [BMIM]BF4] and [BMIM][PF6], with their
relatively short alkyl chains do appear to be less toxic than
more hydrophobic ionic liquids. A direct comparison of the
carcinogenicity/cytotoxicity of 1,3-propane sultone and the two
ionic liquids is not available. However, 1,3-propane sultone is a
potent alkylating reagent whereas the two ionic liquids can be
reasonably expected not to react with proteins and nucleic acids.
Ironically, Malhotra and Kumar recently screened a number of
imidazolium ionic liquids against 60 human tumor cell lines
(National Cancer Institute, USA) and observed anti-tumor
activity (unspecified mechanism) only for the more hydrophobic
compounds.14
Finally, N-alkylation of the poorly reactive acridine nitro-
gen with 1,3-propane sultone requires elevated temperature
(~150 ◦C) and ionic liquids selected for this reaction should be
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Table 2 N-Alkylation of acridine ester (1a) with 1,3-propane sultone
its interaction with the more acidic [BMIM] cation. In the
case of primary n-butylamine, faster reaction rate was also
observed with the more basic triflate anion (higher b) than
the bis(trifluoromethylsulfonyl)imide anion when paired with
the [BMPY] cation. In this case the triflate anion was thought
to stabilize the transition state of the reaction more effectively
by being a stronger hydrogen bond acceptor for the incipient
ammonium ion.
in various ionic salts
1,3-Propane sul-
tone (equivalents)
Reaction
time (h)
HPLC conver-
sion to 2a (%)
Ionic liquid
[BMPY][N(Tf)2]
[BMPY][N(Tf)2]
[BMPY][N(Tf)2]
[BMIM][BF4]
[BMPY][BF4]
[BMPY][BF4]
2.5
5.0
5.0
5.0
2.5
5.0
2.5
5.0
4
4
25
35
40
45
39
43
<10
<10
24
24
24
24
24
24
For the N-alkylation of acridine ester 1a with 1,3-
propane sultone, the ionic solvents selected for this sec-
ond study (Table 2) were 1-butyl-1-methylpyrrolidinium
tetrafluoroborate [BMPY][BF4], 1-butyl-1-methylpyrrolidinium
bis(trifluoromethylsulfonyl)imide [BMPY][N(Tf)2] and the
phosphonium ionic liquid trihexyltetradecylphosphonium
bis(trifluoromethylsulfonyl)imide [THTDP] [N(Tf)2]. The
[BMPY] cation has a lower value of a and was not expected
to interact as well as the [BMIM] cation with the acridine
nitrogen. Consequently a faster reaction with 1,3-propane
sultone and better conversion to product was expected in
ionic liquids containing this cation. We also compared the
impact of anion basicity by pairing the [BMPY] cation with
both the more basic tetrafluoroborate anion (higher b) as well
as the less basic bis(trifluoromethylsulfonyl)imide anion. The
phosphonium ionic liquid represented a unique case, and was
selected because while it has the lowest p* among the various
ionic liquids in this study and therefore was expected to be
less effective in transition state stabilization in the N-alkylation
reaction, it also has the lowest value of a and clearly would be
the least effective in deactivating the acridine nitrogen.
[THTDP][N(Tf)2]
[THTDP][N(Tf)2]
Table 3 Kamlet–Taft parametersa of the solvents used in the N-
alkylation of acridine ester (1a) with 1,3-propane sultone
Solvent
p*
a
b
p-Xylene
0.43
0.88
1.00
0.98
0
0
0
0
—
DMF
0.69
0.76
—
DMSO
Sulfolane
[BMPY][N(Tf)2]
[BMIM][PF6]
[BMIM][BF4]
[THTDP][N(Tf)2]
0.954
1.032
1.047
0.83
0.427
0.634
0.627
0.37
0.252
0.207
0.376
0.27
a From refs. 7e and 10.
All the reactions listed in Table 2 were conducted in a similar
manner using the same concentrations of reagents (~0.1 M
acridine ester 1a in the ionic salt limited by solubility) and only
2.5–5 equivalents of distilled 1,3-propane sultone. We reasoned
that by using only a limited quantity of the alkylating reagent,
differences in reactivity in the various ionic salts would be
more easily discerned. The results in Table 2 indicate that both
sets of cations ([BMPY] and [BMIM]) are equally effective
in solvating the transition state of the N-alkylation reaction
when paired with tetrafluoroborate anion. All three ionic salts
[BMPY][BF4], [BMIM][BF4] and [BMPY][N(Tf)2] also afforded
similar conversion of 40–45% to product after 24 h using 5
equivalents of 1,3-propane sultone. Enhanced reactivity and
improved conversion to product was not observed with the
[BMPY] cation even with the more basic tetrafluoroborate
anion. Anion basicity (b) also did not have any impact on
the N-alkylation reaction as indicated by the similar levels of
conversion observed with the [BF4] anion (b = 0.376) and the
[PF6] anion (b = 0.207) when paired with the [BMIM] cation
(Table 1) or, when the [BMPY] cation was paired with [BF4]
anion and less basic [N(Tf)2] anion (Table 2). Our results suggest
that for the N-alkylation of acridine esters, the polarity of the
ionic liquid as reflected by the Kamlet–Taft parameter p* and,
its ability to solvate the transition state of the reaction is the
most important parameter dictating reactivity and conversion.
Consistent with this conclusion are the results observed in
[THTDP][N(Tf)2] which showed the poorest conversion because
it is the least polar ionic liquid investigated in this study (lowest
p*) despite containing a cation which should interact only
weakly (lowest a) with the acridine nitrogen of 1a. The acridine
◦
at 155 C for 16 h also did not improve conversion from 60%.
In contrast to the other solvents, as indicated by the results
in Table 1, both ionic liquids [BMIM][PF6] and [BMIM][BF4]
proved to be excellent media for the N-alkylation reaction,
affording >80% conversion to the N-sulfopropyl acridinium
ester. These alkylation reactions proceeded cleanly with little
evidence of decomposition by HPLC analysis, and were run for
16–24 h for optimal conversion.
The results in Table 1 are consistent with the prediction6 that
an increase in the polarity of the reaction medium will facilitate
the N-alkylation reaction of acridine ester 1a with 1,3-propane
sultone. This reaction has a charged transition state, and the
extent of conversion to product increases with an increase in the
polarity of the solvent as reflected by its Kamlet–Taft parameter
p*. The only exception is DMSO where the alkylating reagent
may have reacted with the solvent.16
In the next set of experiments (Table 2), we attempted
to determine whether the acidity and basicity of the ions
comprising the ionic liquid would also affect the N-alkylation
reaction of the acridine ester substrate 1a with 1,3-propane
sultone. Besides solvating the transition state of the reaction,
the cations and anions of an ionic liquid can also interact
with the two reacting species. For example, Crowhurst et al.17
have reported that in the reaction of tertiary tri-n-butylamine
with methyl-p-nitrobenzenesulfonate, with the same triflate
anion, the less acidic [BMPY] cation (lower a) afforded faster
reaction rates than the [BMIM] cation which was attributed,
in part to reduction in the nucleophilicity of the amine by
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nitrogen of 1a and similar acridine esters is very hindered and
large organic cations may be sterically excluded from interacting
with it.
Having identified suitable ionic liquids and reaction condi-
tions for the N-alkylation reaction of acridine ester 1a with
reduced quantities of 1,3-propane sultone, we next turned our
attention to determine whether the reaction in ionic liquids was
practical i.e. would these reactions be amenable to scale-up for
the synthesis of gram quantities of N-sulfopropyl acridinium
esters and would product isolation be straightforward without
the need for extensive chromatography? While the reactions in
Table 1 were carried out on a small scale (25–50 mg acridine
ester), using distilled 1,3-propane sultone, unsurprisingly, scale-
up of the reaction to 1–2 g of the acridine ester 1a led to
even better conversion to product (>85%). Moreover, the larger
scale reactions did not require distillation of the toxic sultone
reagent and were more tolerant to the quality of the sultone
reagent with no evidence of polymerization or gel formation
in the reactions. For example, the reaction in [BMIM][PF6]
was carried with 2 grams of the acridine methyl ester 1a and
was conveniently worked up by diluting the reaction mixture in
ethyl acetate and collecting the crude product 2a by filtration.
Hydrolysis of the methyl ester with hydrochloric acid followed
by simple precipitation afforded good recovery (1.68 g, 66%)
of the N-sulfopropyl acridinium carboxylic acid 2c in excellent
purity (94%). A similar reaction carried out in [BMIM][BF4]
using 1 g of the acridine ester 1a gave, after hydrolysis of the
methyl ester 2a, 0.79 g (62%) of the N-sulfopropyl acridinium
carboxylic acid 2c. The alkylation reaction in the two ionic
liquids also showed minimal polysulfonation. This is illustrated
in Fig. 2, where HPLC analyses of the N-alkylation reactions
of acridine methyl ester 1a with 1,3-propane sultone in either
neat 1,3-propane sultone or in [BMIM][PF6], are shown. As
is evident from Fig. 2, the reaction in ionic liquid shows
mostly monosulfonated product 2a eluting at 6.7 min, whereas
the reaction conducted in neat 1,3-propane sultone shows a
significant amount of polysulfonation that is manifested as a
series of peaks of diminishing intensity eluting after the main
product peak. In Fig. 2, the starting material 1a elutes at
10.3 min. Polysulfonated acridinium ester byproducts can be
converted to the desired monosulfonate by acid hydrolysis but
clearly, acid-sensitive functional groups in the acridinium ester
are also expected to be cleaved by this procedure.
Fig. 2 HPLC chromatograms of N-alkylation reactions of 1a with 1,3-
propane sultone, (a) neat reaction (upper panel) and, (b) in [BMIM][PF6]
respectively.
The N-alkylation reaction in ionic liquids could be extended
to other acridine ester substrates as well as illustrated in Fig. 3.
Acridinium ester labels with alkoxy groups at C-2 and/or C-7 of
the acridinium ring exhibit enhanced light output and improved
sensitivity in immunoassays when compared to unsubstituted
acridinium esters.19 The synthetic precursors of these acridinium
esters with alkoxy groups in the acridine ring were also N-
alkylated cleanly with 1,3-propane sultone in ionic liquids. The
presence of the alkoxy groups necessitated using a slightly
greater excess of the sultone reagent and inclusion of the
base 2,6-di-tert-butylpyridine to obtain efficient conversion.
Even though these reactions were conducted under anhydrous
conditions, we suspect that acidic impurities in the propane
sultone reagent may protonate the more basic acridine nitrogen
of these alkoxy-substituted substrates thereby requiring base for
neutralization. As illustrated in Fig. 3, N-alkylation reactions of
both monoalkoxy-substituted and dialkoxy-substituted acridine
ester precursors with 15 equivalents of 1,3-propane sultone in
[BMIM][PF6] in the presence of 2,6-di-tert-butylpyridine (7.5
equivalents) afford excellent conversion to the N-sulfopropyl
acridinium esters. These reactions too proceeded very cleanly
with minimal polysulfonation and the products could be
conveniently separated from the base and ionic liquid by
chromatography on silica gel. The compound 6b is a criti-
cal synthetic intermediate in the synthesis of a hydrophilic,
high-light-output, acridinium ester label that is currently
used in Siemens Healthcare Diagnostics’ ADVIA Centaur,
The absence of polysulfonation in ionic liquids allowed for
a significant improvement in product yield of NSP-DMAE-
NHS ester 2b as exemplified by the N-alkylation of acridine
NHS ester precursor 1b with ten equivalents of 1,3-propane
sultone in [BMIM][PF6]. N-Alkylation of 0.5 g of the acridine
ester precursor (Fig. 1, 1b) led to, after HPLC purification,
0.356 g (56%) of the product NSP-DMAE-NHS ester 2b which,
represents a greater than doubling of the yield using five-fold
less toxic 1,3-propane sultone over the procedure described by
Law2 using the same reaction scale. Although feasible, we did
not attempt to recycle the ionic liquid from these N-alkylation
reactions to minimize exposure to the toxic sultone reagent. The
formation of hydrogen fluoride in [BMIM][PF6] in the presence
of traces of water has been reported to be a concern,18 which
we avoided by drying the ionic liquid at high vacuum over
phosphorus pentoxide prior to reaction.
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Fig. 3 N-Alkylation of alkoxy-substituted acridine esters with 1,3-propane sultone.
R
high-sensitivity troponin assay (TnI-Ultraꢀ assay). The presence
of the bulky methoxyhexa(ethylene) glycol moieties in the
acridine ring further reduces the reactivity of the acridine
nitrogen of 6a, requiring a vast excess (typically > 100-fold)
of 1,3-propane sultone to obtain good conversion in the neat
reaction. In [BMIM][PF6], the N-alkylation of 6a with 15
equivalents of 1,3-propane sultone and in the presence of 7.5
equivalents of 2,6-di-tert-butylpyridine led to 90% conversion
to the acridinium ester 6b, thereby greatly curtailing the amount
of the toxic alkylating reagent. Isolation of the acridinium ester
6b was equally straightforward using chromatography on silica
gel.
in the ionic liquids [BMIM][BF4] and [BMIM][PF6] afford excel-
lent conversion to the commercially useful, chemiluminescent,
N-sulfopropyl acridinium esters using only a limited quantity of
the carcinogenic sultone reagent. In contrast to N-alkylation
reactions in neat 1,3-propane sultone, the reactions in ionic
liquids are (a) amenable to scale-up to gram quantities, (b)
are reproducible, (c) proceed cleanly with minimal polysul-
fonation or polymerization and, (d) permit product isolation
in a straightforward manner. Ionic liquids may offer a unique
reaction medium for similar and difficult N-alkylation reactions
of heterocycles.
In light of the encouraging results observed in the N-
alkylation of acridine esters in ionic liquids, we attempted to re-
place the sultone reagent with non-toxic 3-halopropylsulfonate
salts as alkylating reagents. However, these reagents afforded
minimal conversion even after extensive heating in ionic liquids.
The current study also prompts the question whether there
is scope for further improvement in the synthetic process of
N-sulfopropyl acridinium esters. Our results suggest that an
increase in the polarity (p*) of ionic liquids may afford faster
reactions and may permit further reduction of the alkylating
reagent 1,3-propane sultone in these reactions. For example,
ethylammonium nitrate (p* = 1.24) and sec-butylammonium
thiocyanate (p* = 1.28) are more polar20 than [BMIM][BF4]
and [BMIM][PF6] but for obvious reasons cannot be used for
N-alkylation reactions. Several of the quaternary tetraethylam-
monium salts reported in this study are fairly low melting (p*
values were not reported), and similar salts with inert anions
could be useful in the N-alkylation reaction of acridine esters,
and moreover they may also be less toxic than imidazolium-
based ionic liquids.13e,f
Experimental
General
Chemicals and ionic liquids were purchased from Sigma–Fluka–
Aldrich (Milwaukee, WI, USA). The ionic liquids were dried
under high vacuum over phosphorus pentoxide prior to use.
HPLC analyses and purification were performed using either a
Beckman–Coulter HPLC system or a Waters HPLC system. For
HRMS (High Resolution Mass Spectra), samples were dissolved
in HPLC-grade methanol and analyzed by direct-flow injection
(injection volume = 5 mL) ElectroSpray Ionization (ESI) on a
Waters Qtof API US instrument in the positive ion mode. NMR
spectra of the N-sulfopropyl acridinium esters were recorded in
CF3COOD on a Varian 500 MHz spectrometer.
General procedure for the small scale N-alkylation of
2¢,6¢-dimethyl-4¢-methoxycarbonylphenyl acridine-9-carboxylate
(1a) with 1,3-propane sultone.
The following procedure illustrated in DMF solvent was
typical. A mixture of 2¢,6¢-dimethyl-4¢-methoxycarbonylphenyl
acridine-9-carboxylate 1a (50 mg, 0.13 mmol) and distilled 1,3-
propane sultone (160 mg, 10 equivalents) in anhydrous DMF
(0.5 mL) was heated in an oil bath at 155 ◦C. After 6 h, HPLC
analysis was performed using a 3.9 ¥ 300 mm, 10 micron,
Conclusions
In conclusion, we have discovered that the N-alkylation of
poorly reactive acridine phenolic esters with 1,3-propane sultone
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C18 column from Phenomenex and a 30-minute gradient of
10% →100% MeCN/water (each with 0.05% TFA) at a flow
rate of 1 mL min-1 and UV detection at 260 nm. Product 2a
eluted at 17.5 min. Comparison with the amount of unreacted
starting material eluting at 26 min indicated approximately 35%
conversion. When HPLC analysis was performed using a 4.0 ¥
50 mm, YMC, 3 micron C18 column and 10-minute gradient of
10% → 90% MeCN/water (each with 0.05% TFA) at a flow rate
of 1 mL min-1 and UV detection at 260 nm, product eluted at
6.7 min and starting material at 10.3 min as illustrated in Fig. 2.
Small-scale reactions in other solvents were performed sim-
ilarly. Reaction with neat 1,3-propane sultone was carried out
in a sealed tube with 2¢,6¢-dimethyl-4¢-methoxycarbonylphenyl
acridine-9-carboxylate 1a (25 mg, 0.065 mmol) and 1,3-propane
sultone (396 mg, 50 equivalents).
(>85% conversion to product by HPLC). Product isolation and
conversion to the acridinium carboxylic acid 2c was performed
as described previously (0.793 g, 62%).
N-Alkylation on a half-gram scale of 2¢,6-dimethyl-4¢-
N-succinimidyloxycarbonylphenyl acridine-9-carboxylate (1b)
with 1,3-propane sultone in [BMIM][PF6]
To an 8 dram vial was added 0.50 g (1.07 mmol) of 2¢,6-dimethyl-
4¢-N-succinimidyloxycarbonylphenyl acridine-9-carboxylate 1b,
5 g (17.6 mmol) of 1-butyl-3-methylimidazolium hexafluo-
rophosphate [BMIM][PF6] (Fluka) and 1.31 g (10.7 mmol) of
1,3-propane sulton◦e (Aldrich) under nitrogen. This sealed vial
was heated to 155 C for 16 h. Then the reaction mixture was
cooled to ~40 ◦C and added dropwise to 100 mL of ethyl acetate
with stirring which gave a yellow precipitate. The mixture was
stirred at room temperature for 2 h and filtered. The filter cake
was washed with ethyl acetate (30 mL ¥ 2) and dried under high
vacuum which gave 0.753 g of a yellow solid. The crude product
was purified by preparative HPLC on a Waters HPLC system
using an YMC, C18 50 ¥ 500 mm column, with a solvent flow
rate of 60 mL min-1, UV detection at 260 nm, elution being
performed with 35% MeCN/water (with 0.05% TFA). After
lyophilization of the HPLC fractions, the product NSP-DMAE-
NHS ester 2b, (0.356 g, 56%), was obtained as a yellow powder.
dH (500 MHz, CF3COOD) 2.67 (s, 6 H), 3.05 (br s, 2 H), 3.25
(br s, 4 H), 3.94 (t, 2 H, J = 6.11), 5.96 (d, 2 H, J = 8.56), 8.17 (s,
2 H), 8.23 (dd, 2 H, J = 8.56, 6.85), 8.64 (t, 2 H, J = 8.07), 8.86
(d, 2 H, J = 8.31), 9.03 (d, 2 H, J = 9.29); HRMS m/z (M + H)+
591.1432 (591.1437 calculated).
N-Alkylation on a gram scale of 2¢,6¢-dimethyl-4¢-methoxy-
carbonylphenyl acridine-9-carboxylate (1a) with 1,3-propane
sultone in [BMIM][PF6] followed by hydrolysis
To an 8 dram vial was added 2.0 g (5.19 mmol) of the acridine
ester 1a, 15 g (52.8 mmol) of 1-butyl-3-methylimidazolium
hexafluorophosphate [BMIM][PF6] (Fluka) and 6.34 g (51.9
mmol) of 1,3-propane sultone (Aldrich) under nitrogen. This
sealed vial was heated to 155 ◦C for 24 h. Then the reaction
mixture was cooled to ~40 ◦C and added dropwise into 500 mL
of ethyl acetate with stirring which gave a yellow precipitate. The
mixture was stirred at room temperature for 2 h and filtered.
The filter cake was washed with ethyl acetate (3 ¥ 50 mL) to
give 6.19 g of a yellow solid (2a containing ethyl acetate) which
was used directly in the next step as follows. A small portion of
2a was purified by HPLC for spectral analysis. dH (500 MHz,
CF3COOD) 2.64 (s, 6 H), 3.05 (br s, 2 H), 3.94 (br s, 2 H), 4.17
(d, 3 H, J = 1.47), 5.96 (dd, 2 H, J = 17.12, 8.31), 8.10 (s, 2 H),
8.23 (t, 2 H, J = 7.70), 8.65 (t, 2 H, J = 8.07), 8.88 (d, 2 H, J =
8.56), 9.02 (d, 2 H, J = 9.05); HRMS m/z (M + H)+ 508.1438
(508.1430 calculated).
N-Alkylation of 2¢,6¢-dimethyl-4¢-methoxycarbonylphenyl
2-isopropyloxyacridine-9-carboxylate (3a) with 1,3-propane
sultone in [BMIM][PF6]
A mixture of 3a (0.213 g, 0.48 mmol), 1,3-propane sultone
(0.88 g, 7.21 mmol, 15 equivalents) and 2,6-di-tert-butylpyridine
(0.79 mL, 3.6 mmol, 7.5 equivalents) in [BMIM][PF6] (3 mL)
was heated and stirred at 155 ◦C in a tightly capped, round
bottom flask under an inert atmosphere. After 16 h, the reaction
was cooled to room temperature. A small portion (2 uL) was
withdrawn, diluted with MeCN (0.2 mL)and analyzed by HPLC
using a 3.9 ¥ 300 mm, 10 micron, C18 column from Phenomenex
and a 30-minute gradient of 10% →100% MeCN/water (each
with 0.05% TFA) at a flow rate of 1 mL min-1 and UV detection
at 260 nm. Product 3b eluted at 19.5 min. Comparison with
the amount of unreacted starting material 3a eluting at 30 min
indicated 90% conversion. The reaction mixture was diluted with
ethyl acetate (5 mL) and loaded onto a column of silica gel. The
column with eluted with 500 mL each of ethyl acetate to remove
base and starting material followed by 40% methanol/ethyl
acetate to elute product. Product fractions were combined and
concentrated under reduced pressure to give a dark yellow solid
(0.25 g, 93%) which could be used as such further elaboration.
For spectral analysis, a small portion was purified by preparative
HPLC as described previously to remove trace (ionic liquid)
impurities. dH (500 MHz, CF3COOD) 1.50 (d, 6 H, J = 6.11),
2.53 (s, 6 H), 2.91 (m, 2 H), 3.32 (br s, 2 H), 4.06 (s, 3 H), 4.90
(dt, 1 H, J = 12.17, 6.02), 5.80 (m, 2 H), 7.84 (d, 1 H, J = 2.69),
7.98 (s, 2 H), 8.05 (dd, 1 H, J = 8.80, 6.85), 8.18 (dd, J = 10.03,
The above 6.19 g of crude acridinium ester 2a was added to
80 mL of 1 N HCl. The reaction mixture was heated to 110 ◦C for
◦
4 h and then cooled to 2–8 C overnight. A yellow precipitate
was formed which was recovered by filtration. The filter cake
was washed with de-ionized water (40 mL ¥ 3) and diethyl ether
(20 mL ¥ 2) and dried under high vacuum over P2O5 which gave
the acridinium carboxylic acid 2c as a yellow powder (1.68 g, 66%
yield from 1a, 94% purity by HPLC). dH (500 MHz, CF3COOD)
2.65 (s, 6 H), 3.04 (m, 2 H), 3.93 (t, 2 H, J = 6.11), 5.96 (m, 2
H), 8.16 (s, 2 H), 8.23 (dd, 2 H, J = 8.68, 6.97), 8.64 (t, 2 H, J =
8.07), 8.87 (d, 2 H, J = 8.07), 9.02 (d, 2 H, J = 9.54); HRMS m/z
(M + H)+ 494.1273 (494.1273 calculated).
N-Alkylation on a gram scale of 2¢,6-dimethyl-4¢-methoxy-
carbonylphenyl acridine-9-carboxylate (1a) with 1,3-propane
sultone in [BMIM][BF4] followed by hydrolysis
To an 8 dram vial was added 1.0 g (2.6 mmol) of the acridine
ester 1a, 10 g (44.2 mmol) of 1-butyl-3-methylimidazolium
tetrafluoroborate [BMIM][BF4] (Fluka) and 3.18 g (26.0 mmol)
of 1,3-propane sultone◦(Aldrich) under nitrogen. This sealed
vial was heated to 155 C for 24 h. Then the reaction mixture
was cooled to room temperature which gave a clear, red liquid
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2.69), 8.40 (m, 1 H), 8.68 (dd, 1 H, J = 8.68, 0.86), 8.81 (d, 1 H,
J = 3.18), 8.82 (d, 1 H, J = 3.91); HRMS m/z (M + H)+ 588.1678
(588.1668 calculated).
was purified by preparative HPLC as described previously to
remove trace (ionic liquid) impurities. dH (500 MHz, CF3COOD)
2.54 (s, 6 H), 2.92 (m, 2 H), 3.62 (s, 6 H), 3.82 (t, 2 H, J = 6.24),
4.05 (br s, 4 H), 4.08 (s, 3 H), 5.19 (m, 1 H), 5.84 (m, 2 H), 8.00
(s, 2 H), 8.03 (d, 1 H, J = 1.71), 8.11 (t, 1 H, J = 7.83), 8.25, dd,
1 H, J = 9.78, 1.71), 8.46 (t, 1 H, J = 8.07), 8.78 (d, 1 H, J =
8.80), 8.88 (d, 1 H, J = 9.54), 8.91 (d, 1 H, J = 10.03); HRMS
m/z (M + Na)+ 648.1874 (648.1879 calculated).
N-Alkylation of 2¢,6¢-dimethyl-4¢-methoxycarbonylphenyl
2,7-di-isopropyloxyacridine-9-carboxylate (4a) with 1,3-propane
sultone in [BMIM][PF6]
A mixture of 4a (0.220 g, 0.44 mmol), 1,3-propane sultone
(0.80 g, 6.6 mmol, 15 equivalents) and 2,6-di-tert-butylpyridine
(0.724 mL, 3.3 mmol, 7.5 equivalents) in [BMIM][PF6] (3 mL)
was heated and stirred at 155 ◦C in a tightly capped, round
bottom flask under an inert atmosphere. After 16 h, the reaction
was cooled to room temperature. A small portion (2 uL) was
withdrawn, diluted with MeCN (0.2 mL) and analyzed by HPLC
using a 3.9 ¥ 300 mm, 10 micron, C18 column from Phenomenex
and a 30-minute gradient of 10% →100% MeCN/water (each
with 0.05% TFA) at a flow rate of 1 mL min-1 and UV detection
at 260 nm. Product 4b eluted at 22.3 min. Comparison with
the amount of unreacted starting material 4a eluting at 31 min
indicated 93% conversion. The reaction mixture was diluted with
ethyl acetate (5 mL) and loaded onto a column of silica gel. The
column was eluted with 500 mL each of ethyl acetate to remove
base and starting material followed by 40% methanol/ethyl
acetate to elute product. Product fractions were combined and
concentrated under reduced pressure to give a dark yellow solid
(0.286 g, quantitative) which could be used as such further
elaboration. For spectral analysis, a small portion was purified
by preparative HPLC as described previously to remove trace
(ionic liquid) impurities. dH (500 MHz, CF3COOD) 1.59 (d, 12
H, J = 6.11), 2.64 (s, 6 H), 2.98 (br s, 2 H), 3.89 (br s, 2 H), 4.17
(s, 3 H), 4.99 (hep, 2 H, J = 6.08), 5.86 (br s, 2 H), 7.89 (d, 2
H, J = 1.96), 8.09 (s, 2 H), 8.17 (dd, 2 H, J = 9.90, 1.83), 8.83
(d, 2 H, J = 10.03); HRMS m/z (M + H)+ 624.2271 (624.2267
calculated).
N-Alkylation of 2¢,6¢-dimethyl-4¢-methoxycarbonylphenyl-
2,7-bis(3,6,9,12,15,18-hexaoxanonadec-1-yloxy)acridine-9-
carboxylate (6a) with 1,3-propane sultone in [BMIM][PF6]
A mixture of 6a (0.158 g, 0.162 mmol), 1,3-propane sul-
tone (0.297 g, 2.433 mmol 15 equivalents) and 2,6-di-tert-
butylpyridine (0.269 mL, 1.217 mmol, 7.5 equivalents) in
[BMIM][PF6] (0.9 mL) was heated and stirred at 155 ◦C in a
2 dram vial, under an inert atmosphere. After 16 h, the reaction
was cooled to room temperature. A small portion (2 uL) was
withdrawn, diluted with MeCN (0.2 mL) and analyzed by HPLC
using a 4.0 ¥ 50 mm, YMC, 3 micron C18 column and 10-minute
gradient of 10% → 90% MeCN/water (each with 0.05% TFA)
at a flow rate of 1 mL min-1 and UV detection at 260 nm,
Product 6b eluted at 7.0 min. Comparison with the amount
of unreacted starting material 6a eluting at 9.0 min indicated
90% conversion. The reaction mixture was diluted with ethyl
acetate (5 mL) and loaded onto a column of silica gel. The
column was eluted with 500 mL each of ethyl acetate to remove
base and starting material followed by 40% methanol/ethyl
acetate to elute product. Product fractions were combined and
concentrated under reduced pressure to give a dark yellow solid
(0.110 g, 62%, 92% purity by HPLC) which could be used as such
further elaboration. For spectral analysis, a small portion was
purified by preparative HPLC as described previously to remove
trace (ionic liquid) impurities. dH (500 MHz, CF3COOD) 2.65
(s, 6 H), 3.01 (br s, 2 H), 3.68 (s, 6 H), 3.90 (t, 2 H, J = 6.11), 3.97
(m, 4 H), 3.99–4.05 (m, 28 H), 4.09 (m, 4 H), 4.19 (s, 7 H), 4.33
(br s, 4 H), 4.60 (m, 4 H), 5.92 (br s, 2 H), 7.93 (d, 2 H, J = 2.45),
8.11 (s, 2 H), 8.22 (dd, J = 9.78, 2.20), 8.92 (d, 2 H, J = 10.03);
HRMS m/z (M + H)+ 1096.4746 (1096.4787 calculated).
N-Alkylation of 2¢,6¢-dimethyl-4¢-methoxycarbonylphenyl
2-[(1,3-dimethoxypropyl)oxy]acridine-9-carboxylate (5a) with
1,3-propane sultone in [BMIM][PF6]
A mixture of 5a (0.095 g, 0.188 mmol), 1,3-propane sul-
tone (0.345 g, 2.83 mmol, 15 equivalents) and 2,6-di-
tert-butylpyridine (0.310 mL, 1.41 mmol,7.5 equivalents) in
[BMIM][PF6] (1.3 mL) was heated and stirred at 155 ◦C in a
tightly capped, round bottom flask under an inert atmosphere.
After 16 h, the reaction was cooled to room temperature. A small
portion (2 uL) was withdrawn, diluted with MeCN (0.2 mL) and
analyzed by HPLC using a 3.9 ¥ 300 mm, 10 micron, C18 column
from Phenomenex and a 30-minute gradient of 10%→70%
MeCN/water (each with 0.05% TFA) at a flow rate of 1 mL min-1
and UV detection at 260 nm. Product 5b eluted at 23 min.
Comparison with the amount of unreacted starting material
5a eluting at 32 min indicated 81% conversion. The reaction
mixture was diluted with ethyl acetate (5 mL) and loaded onto
a column of silica gel. The column was eluted with 250 mL each
of ethyl acetate to remove base and starting material followed by
40% methanol/ethyl acetate to elute product. Product fractions
were combined and concentrated under reduced pressure to give
a dark yellow oil (0.200 g, quantitative) which could be used as
such further elaboration. For spectral analysis, a small portion
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