Origins of Life and Evolution of Biospheres (2019) 49:199–211

https://doi.org/10.1007/s11084-019-09589-2

PREBIOTIC CHEMISTRY

Imidazolium-Catalyzed Synthesis
of an Imidazolium Catalyst

Arthur L. Weber 1,2 & Andro C. Rios 2,3

Received: 10 September 2019 / Accepted: 14 November 2019 / Published online: 8 December 2019
# Springer Nature B.V. 2019

Abstract
The chemistry of imidazolium-catalyzed imidazolium synthesis was studied as part of an effort
to develop a plausible prebiotic synthesis of a small catalytic molecule capable of catalyzing its
own synthesis. Specifically, we investigated the one-pot 1-ethyl-3-methylimidazolium acetate
(EMIM-Ac) catalyzed synthesis of 1,3-dibutyl-4,5-difuryl-imidazolium acetate (DBDFIM-
Ac) from furfural, n-butylamine, formaldehyde, and acetic acid at 80 °C. Liu et al. (2012) had
previously demonstrated the first reaction of the synthetic process, the EMIM-Ac catalyzed
benzoin condensation of furfural that yields furoin. Our early studies established the second
reaction of the synthetic process, the multicomponent reaction of furoin, n-butylamine,
formaldehyde, and acetic acid that yields the imidazolium salt, DBDFIM-Ac. Studies of the
complete two-reaction process that uses furfural for the synthesis of DBDFIM-Ac showed that
the highest yield of DBDFIM-Ac was obtained when the mole ratio of n-butylamine,
formaldehyde, and acetic acid relative to furfural was respectively (0.5:0.25:0.25:1.0-furfural),
or one-half of the stoichiometric ratio (1.0:0.5:0.5:1.0-furfural). A time course study of the
process showed transient formation of furoin, the obligatory reaction intermediate. DBDFIM-
Ac and the imidazolium side product, 1,3-dibutyl-4,5-trifuryl-imidazolium acetate (DBTFIM-
Ac), were stable under the reaction conditions. Imidazolium products (DBDFIM and
DBTFIM) and the furoin intermediate were not formed in control reactions (80 °C, 24 h) in
which EMIM catalyst was either absent or replaced with an equal volume of acetonitrile or
DMF. The imidazolium product, DBDFIM-Ac, was shown to catalyze the synthesis of
structurally similar 1,3-dipentyl-4,5-difuryl-imidazolium acetate (DPDFIM-Ac) from furfural,
n-pentylamine, formaldehyde, and acetic acid at 80 °C.

Keywords Origins of life . Prebiotic . Imidazolium catalysis . Benzoin condensation . Catalytic

feedback . Reflexive catalysis . Maillard reaction

* Arthur L. Weber
arthur.l.weber@nasa.gov

1
SETI Institute, Ames Research Center, Mail Stop 239-4, Moffett Field, CA 94035, USA
2
Center for the Emergence of Life, NASA Ames Research Center, Moffett Field, CA 94035, USA
3
Blue Marble Space Institute, Ames Research Center, Mail Stop 239-4, Moffett Field, CA 94035, USA
200 Weber A.L., Rios A.C.

Introduction

One of the generally accepted requirements of the emergence of life is that prebiotically
synthesized molecules or molecular systems participating in biogenesis need to feedback and
catalyze the chemical processes needed for their persistence and evolution (Pross 2011; Pascal
et al. 2013). However, most origins studies have focused on the synthesis of biological
monomers and polymers under prebiotic conditions but have not studied or established “catalytic
feedback” by the actual products of their synthetic reactions. To develop a prebiotically plausible
process that produced molecules capable of catalyzing reactions involved in their own synthesis
Clairmont et al. (2015) studied imidazolium-catalyzed imidazolium synthesis. In their model
process imidazolium catalysts synthesized from formaldehyde, aniline and acetic acid were
shown to catalyze the synthesis of additional imidazolium catalyst. This model process used
prebiotically plausible reactants and reactions; however, it was carried out in DMF solvent, and
required two temporally separated reactions to produce imidazolium catalysts. Also, the newly
synthesized imidazolium catalyst required purification by flash chromatography before it was
employed to catalyze the next cycle of imidazolium synthesis.
To better understand and advance the development of a more plausible model of prebiotic
imidazolium-catalyzed imidazolium synthesis, we here describe studies of imidazolium-
catalyzed imidazolium synthesis that used 1-ethyl-3-methylimidazolium acetate (EMIM-Ac)
to catalyze the synthesis of 1,3-dibutyl-4,5-difurylimidazolium acetate (DBDFIM-Ac) from
furfural, n-butylamine (nBA), formaldehyde (HCHO), and acetic acid (AcOH). As shown in
Scheme 1, initially the synthesis of DBDFIM-Ac was conceived as the three-reaction solvent-
free process: 1) EMIM-Ac catalyzed synthesis of furoin from furfural (Liu et al. 2012; Zang
et al. 2018; Wilson and Chen 2016), 2) furoin oxidation to furil (Wang et al. 2012; Wilson et al.
2016), and 3) furil reaction with nBA, HCHO, and AcOH to give the desired imidazolium
(DBDFIM-Ac) (Zimmermann et al. 2010). Alternatively, previous studies showing imidazole
(and possibly imidazolium) synthesis from α-hydroxyketones (dihydroxyacetone and benzoin)
suggested that DBDFIM-Ac synthesis might require only two reactions, reaction-1 followed
by reaction-4 also shown in Scheme 1 (Clairmont et al. 2015; Siddiqui et al. 2005; Khodaei
et al. 2007; Sangshetti et al. 2008; Sivakumar et al. 2010; Mohammadi et al., 2012).
The condensation of furfural to give furoin (reaction-1) is classified as a benzoin condensation
(or benzoin addition) in which two aldehydes react to give an acyloin (α-hydroxyaldehyde). There
have been numerous studies of catalysis of the benzoin condensation by azolium heterocyclic
catalysts, such as imidazolium, thiazolium, and triazolium salts (Enders et al. 2007; Nair et al.
2004). In modern life the thiazolium ring of thiamine is an essential catalytic cofactor for
transketolase involved in the reversible benzoin-like transfer of glycolaldehyde from ketoses to
the aldehyde of aldoses yielding the terminal α-hydroxyketone group of a new ketose (Kluger and
Tittmann 2008). For our studies we selected imidazolium catalysts rather than thiazolium catalysts
(e.g. thiamine), because even though thiazolium salts are more effective catalysts, imidazolium

Scheme 1 Initially proposed pathway of imidazolium-catalyzed imidazolium acetate synthesis

Imidazolium-Catalyzed Synthesis of an Imidazolium Catalyst 201

salts are more stable (Duclos and Haake 1974) and their prebiotic synthesis is less complicated. The
oxidation of furoin to furil (reaction-2) by inorganic oxidants has been examined by Wilson and
Chen (2016) and Wang et al. (2012). Reaction-3, the multicomponent reaction of furil, nBA,
HCHO, AcOH that yields the desired imidazolium salt product was thoroughly studied by
Zimmermann et al. (2010). This reaction is a variant of the Radziszewski reaction for the synthesis
of imidazoles from a diketone, an aldehyde, and ammonia (July et al. 2014; Radziszewski 1882).
The Radziszewski reaction is also considered a source of imidazoles detected in modern atmo-
spheric ambient aerosol particles (Teich et al. 2016), and imidazolium products synthesized in
model studies of simulated evaporating cloud droplets (De Haan et al. 2011).

Experimental

Materials All reagents were purchased from Sigma-Aldrich and used without additional
purification (furfural 99%, furoin 98%, furil 98%, formaldehyde (HCHO 37 wt.% in H2O),
n-butylamine (nBA) 99.5%, n-amylamine (n-pentylamine) 99%, acetic acid (AcOH) ≥99%, 1-
ethyl-3-methylimidazolium acetate (EMIM-Ac) 97%, HPLC grade acetonitrile (ACN) and
methanol, ammonium acetate 99.99 + %, Dimethyl sulfoxide-d6 (DMSO-d6), and 1,3,5-
trimethoxybenzene (TraceCERT®).

HPLC Analysis

HPLC analysis was performed on a Shimadzu Prominence LC-2039C HPLC System

equipped with a Shimadzu PDA detector (4 nm bandwidth) and autosampler (15 °C). Reaction
samples were diluted 1600-fold with 50% aqueous ACN, and 5.0 μl samples injected and
separated on a reverse phase Shimadzu C-18 column (3 μm, 4.6 × 50 mm) at 30 °C at a 1 ml/
min flow rate using eluent-A (10 mM aqueous ammonium acetate) and eluent-B (ACN). The
elution gradient began with 20% B (80% A). After injection the eluent was changed to 80% B
over 15 min, and then decreased to 20% B over 3 min, and maintained at 20% B until the end
of the run at 28 min. HPLC elution times (min): furfural (1.15), furoin (1.95), furil (3.72), U1
(4.02), U2 (4.15). U3 (5.16), U4 (6.25), U5 (8.04), U6 (8.21), DBDFIM (8.40), DBTFIM
(10.35), DPDFIM (10.77), and DPTFIM (12.43).
HPLC analysis at 270 nm of diluted samples of the QNMR-analyzed solution (calc. Conc.
0.113 M) of the purified DBDFIM-Ac preparation provided an estimate of the ratio of HPLC
peak area to solution’s molar concentration that was used to calculate (from reaction HPLC
peaks areas) the percent yields of DBDFIM from furoin and furfural (see Figs. 2a,b and 4a,b).

TLC Analysis

Thin-layer chromatography used Merck HPTLC Silica gel RP-18 WF254S plates that were
eluted with ACN/0.20 M ammonium acetate (55/45 v/v). Reaction solutions were diluted 10-
fold with water before being applied to the TLC plate. After development the TLC plates were
illuminated by a Spectroline UV-312 nm transilluminator to visualize UVabsorbing substances
as dark spots. The plates were photographed using a Sony NEZ-5R camera, and NIH’s ImageJ
image processing program (http://imagej.nih.gov/ij/) was used to split the RGB photographic
images into their red, green, and blue channels. The green channel was used for Fig. 1.
Relative TLC mobility: furoin (1.0) DBDFIM (0.32), unknown-1 (0.66), unknown-2 (0.65),
202 Weber A.L., Rios A.C.

furil (0.84). Unknown-1 and unknown-2 are different substances, since they were separated by
TLC using ACN/0.20 M ammonium acetate (60/40 v/v).

NMR Analysis

1H, 13C,COSY, HMBC and HSQC NMR data (including QNMR data) were obtained using a
Bruker Avance III HD 500 MHz spectrometer equipped with a multinuclear Smart Probe.
These experiments were conducted using the NMR Facility located within the Department of
Chemistry and Biochemistry at the University of California, Santa Cruz. QNMR was per-
formed using 1,3,5-trimethoxybenzene as an internal standard in DMSO-d6 (“Quantitative
NMR Sigma-Aldrich technical document”).

Mass Analysis

Mass spectral data were recorded on a Thermo Finnigan LCQ Deca Max XP (Thermo-Fisher
San Jose), equipped with an electrospray ionization source probe assembly with detection in
the positive mode polarity. Samples were purified using the preparative TLC procedure (see
below) and diluted 1600-fold with 50% aqueous ACN before introduction into the spectrom-
eter using a direct infusion method via the on-board syringe pump at 3 uL/min.

Early Studies of 1,3-Dibutyl-2,4,5-Trifuryl-Imidazolium Acetate (DBTFIM-Ac) Synthesis

by Reaction of Furil (or Furoin) with N-Butylamine, Acetic Acid, and Formaldehyde

Reactions were performed using batch method-IV described by Zimmermann et al. (2010). N-
Butylamine (2.0 mmole), AcOH (1.0 mmole), and HCHO (1.0 mmole) were added to a 10 ml
reaction tube and reacted 30 min at 0 °C. This solution was then added to a solution containing
1.0 mmole furil (or furoin) in 2.5 ml ACN. Next, 400 μl aliquots of the furil and furoin
reaction solutions were added to each of five Shimadzu HPLC 1.5 ml glass screw cap vials.
Each vial had its screw thread wrapped twice around with Poly-Temp PTFE tape (0.5″ medium
density) to prevent escape of volatile contents from the capped vials (soln. wt. loss ≤0.15%).
The reaction vials were heated at 80 °C in a Pierce Reacti-Therm aluminum block heater for
0 h, 0.5 h, 1 h, 2 h, 24 h, and stored at −80 °C until analyzed using TLC (Fig. 1).

Time Course of DBTFIM-Ac Synthesis from Furoin, N-Butylamine, Acetic Acid,

and Formaldehyde

The reaction solution was prepared by adding nBA (5.0 mmole), AcOH (2.5 mmole), HCHO
(2.5 mmole), and a furoin solution (2.5 mmole in 6.25 ml ACN) in the order listed to a glass
test tube. Aliquots (400 μl) of this solution were immediately transferred to PTFE wrapped
1.5 ml HPLC vials that (as described earlier) were capped, heated at 80 °C, and stored until
analyzed by HPLC.

Time Course of DBDFIM-Ac Synthesis from Furfural, N-Butylamine, Acetic Acid,

and Formaldehyde Catalyzed by EMIM-Ac

Reaction solutions were prepared by adding nBA (0.6 mmole), AcOH (0.3 mmole), HCHO
(0.3 mmole), and EMIM-Ac (1.2 mmole), furfural (1.2 mmole) in the order listed to PTFE
Imidazolium-Catalyzed Synthesis of an Imidazolium Catalyst 203

wrapped 1.5 ml HPLC vials that (as described earlier) were capped, heated at 80 °C (0-48 h),
and stored until analyzed by HPLC. Imidazolium products (DBDFIM and DBTFIM) and the
furoin intermediate were not formed in similar control reactions (80 °C, 24 h) in which EMIM
catalyst was either absent or replaced with an equal volume of acetonitrile or DMF.

Effect of Reactant Ratios on DBDFIM-Ac Synthesis from Furfural, N-Butylamine, Acetic

Acid, and Formaldehyde Catalyzed by EMIM-Ac

Furfural (1.2 mmole) and EMIM-Ac (1.2 mmole) were reacted with 20%, 40%, 50%, 60%,
80%, and 100% of the stoichiometric amounts of nBA, AcOH, and HCHO. The respective
mmoles of nBA were 0.24, 0.48, 0.60, 0.72, 0.96, 1.2, and the respective mmoles of AcOH and
HCHO were 0.12, 0.24, 0.30, 0.36, 0.48, 0.60. Reaction solutions were prepared by adding the
above amounts of nBA, AcOH, HCHO, EMIM-Ac, and furfural in the order listed to PTFE
wrapped 1.5 ml HPLC vials that (as described earlier) were capped, heated at 80 °C, and stored
until analyzed by HPLC.

TLC Purification of Imidazolium Products for Mass Analysis

DBDFIM-Ac was synthesized from furoin, nBA, AcOH, and HCHO at 60 °C (24 h)
using the method described previously under early studies of DBTF-Im synthesis from
furoin. A sample of the product was diluted tenfold and streaked across a Merck
HPTLC RP-18 W plate. The plate was then developed using methanol/0.2 M ammo-
nium acetate in water (55/45 v/v), and dried 15 min in the hood air flow. The plate was
developed a second time using water, dried 15 min in the hood air flow, and then
developed a third time using acetone (DBDFIM Rf = 0.23). The area of the plate
containing the UV absorbing imidazolium product was scraped off the plate, placed
in a Centrex microfiltration tube, eluted twice using 500 μl of methanol / 0.2 M
ammonium acetate (85/15 v/v), and dried twice in vacuo in a CentriVap centrifugal
evaporator at 40 °C after adding back methanol. The identity of imidazolium product
was confirmed by electrospray mass spectrometry (DBDFIM expected m/z = 313.19,
found m/z = 313.32).
DBDFIM-Ac and DBTFIM-Ac were also synthesized from furfural, nBA, AcOH, HCHO,
and EMIM catalyst at 80 °C (24 h) using the method described under the time course of
DBDFIM-Ac synthesis from furfural. The identities of the imidazolium cations that had been
isolated by TLC were confirmed by electrospray mass spectrometry: DBDFIM (expected
m/z = 313.19, found m/z = 313.38); DBTFIM (expected m/z = 379.20, found m/z = 379.36).
The TLC purification method was the same as described earlier, except that the TLC plate was
developed using ACN/0.2 M ammonium acetate (6/5 v/v) DBDFIM Rf = 0.22; DBTFIM Rf =
0.16).
In addition we examined the ability of DBDFIM-Ac and EMIM-Ac to catalyze the
synthesis of 1,3-dipentyl-4,5-difuryl-imidazolium acetate (DPDFIM-Ac) and 1,3-dipentyl-
4,5-trifuryl-imidazolium acetate (DPTFIM-Ac) from furfural, n-pentylamine, AcOH, and
HCHO at 80 °C (24 h) using the method described under the time course of DBDFIM-Ac
synthesis from furfural. The identities of the DPDFIM and DPTFIM cations isolated by
TLC were confirmed by electrospray mass spectrometry: DPDFIM (expected m/z =
341.22, found = 341.28); DPTFIM (expected m/z = 407.23, found m/z = 407.23). TLC
purification method was the same as described earlier, except that the TLC plate was
204 Weber A.L., Rios A.C.

developed using ACN/0.2 M ammonium acetate (3/2 v/v) DPDFIM Rf = 0.2; DPTFIM
Rf = 0.07).

Preparation and Column Purification of DBDFIM-Ac

N-Butylamine (5.0 mmol), AcOH (3.0 mmol), and 37% aqueous HCHO (2.5 mmol) were
added as listed to a 5 ml reaction vial and reacted at 0 °C for 30 min. This solution was
added to a solution of furoin (2.5 mmol in 6.25 ml ACN) and reacted at 80 °C for 4 h. The
reaction product was concentrated to 1 ml volume in vacuo in a CentriVap centrifugal
evaporator. Saturated sodium bicarbonate (150 μl) was added and a 0.4 ml aliquot was
applied to a Supelco Discovery-DSC-18 column (5 g in 20 ml tube). The column was pre-
conditioned with MeOH and eluted with 18 ml water, 18 ml acetone, 18 ml MeOH, and
18 ml 0.1 M ammonium acetate in MeOH. The first 6 ml of the 0.1 M ammonium acetate/
MeOH solution was collected and dried extensively in vacuo in a rotary evaporator. The
structure of DBDFIM-Ac was confirmed using 1D and 2D proton/ carbon nuclear mag-
netic resonance spectroscopy and electrospray mass spectrometry. 1H NMR (500 MHz,
DMSO-d6) δ 10.10 (s, 1H), 8.02–7.98 (m, 2H), 6.93 (d, J = 3.5 Hz, 2H), 6.73 (dd, J = 3.5,
1.8 Hz, 2H), 4.26 (t, J = 7.3 Hz, 4H), 1.72–1.63 (m, H), 1.28 (h, J = 7.4 Hz, 4H), 0.86 (t,
J = 7.4 Hz, 6H); 13C NMR (126 MHz, DMSO-d6) δ 173.88, 146.56, 139.40, 138.31,
123.50, 123.48, 115.53, 112.48, 48.99, 31.23, 24.86, 19.22, 13.66; ESI-MS (+): Calculat-
ed MW for DBDFIM = 313.41, found m/z = 313.38. QNMR analysis using 1,3,5-
trimethoxybenzene as an internal standard showed the purified preparation contained
89–93% DBDFIM-Ac.

Results

DBDFIM-Ac Synthesis from Furil and Furoin

To develop an understanding of the chemistry of the imidazolium synthesis pathway described

in Scheme 1, we initially examined the synthesis of DBDFIM-Ac by reacting furil and furoin
with nBA, AcOH, and HCHO in acetonitrile. Our method was based on batch method (IV)
used by Zimmermann et al. (2010) that yielded imidazolium salts from an aqueous solution of
glyoxal (an α-ketoaldehyde), nBA, HCHO, and acetic acid. As shown in Fig. 1, we discovered
that furoin (an α-hydroxyketone) gave a much higher yield of DBDFIM-Ac than furil. This
reaction also gave high yields of DBDFIM-Ac when carried out for 9 days at 25 °C. The
identity of DBDFIM-Ac was confirmed by electrospray mass spectrometry and 1H NMR. The
nature of the dehydrogenation process needed to produce DBDFIM-Ac from the α-
hydroxyketone (furoin) is unknown. However, as described earlier there have been several
reports of imidazole synthesis from α-hydroxyketones.
Since the above results supported the direct synthesis of DBDFIM-Ac from furoin, nBA,
HCHO, and acetic acid, we next measured the time course of DBDFIM production from furoin,
nBA, HCHO, and AcOH in acetonitrile at 80 °C. Figure 2a shows the HPLC profile of furoin
and derived reaction products at 0.5 h monitored at 270 nm. Figure 2b shows the time course of
product formation from furoin, nBA, HCHO, and AcOH in acetonitrile. In the first 0.5 h of
reaction there is a rapid decrease in furoin concentration that is accompanied by formation of (a)
DBDFIM and (b) unidentified transient products U1 and U2. A small amount of furil also forms
Imidazolium-Catalyzed Synthesis of an Imidazolium Catalyst 205

Fig. 1 TLC separation of DBDFIM and other products from the reaction of furoin or furil with n-butylamine,
acetic acid, and formaldehyde at 80 °C. TLC using ACN/0.20 M ammonium acetate (60/40 v/v) showed
unknown-1 and unknown-2 to be different substances

before the first measurement at 0.5 h and then decreases. Furil, U1, and U2 could be reaction
intermediates in DBDFIM synthesis, because their formation and disappearance coincide with
the production of DBDFIM. However, our earlier observation that DBDFIM-Ac synthesis is
slow and inefficient with furil compared to furoin suggests that furil is not an intermediate in
DBDFIM synthesis. The synthesis of DBDFIM and unidentified products U4 and U5 is
complete at about 3 h. DBDFIM-Ac appears to be stable under the reaction conditions.
At 7 h the DBDFIM yield was 62.5% (based on formaldehyde) estimated using QNMR
and HPLC. When the reaction was performed under anaerobic conditions in 1 ml glass
Wheaton vacuoles, the imidazolium salt yield was 90% that of the reaction in the capped
1.5 ml Shimadzu vials containing air. TLC analysis showed that furoin alone dissolved in
ACN was stable when heated at 80 °C for 4 h under aerobic and anaerobic conditions (±
15 mM acetic acid).
The discovery that DBDFIM-Ac could be synthesized directly from furoin (an α-
hydroxyaldehyde) led us to propose the simpler pathway shown in Scheme 2 for the
synthesis of DBDFIM from furfural, nBA, HCHO, and AcOH. In this revised pathway
EMIM catalyzes the benzoin condensation of furfural to give the furoin intermediate (Liu
et al. 2012) that then reacts with nBA, HCHO, AcOH to produce DBDFIM. To
determine if these two reactions could occur concurrently, we examined the overall
functioning of the complete pathway, which is the one-pot EMIM catalyzed synthesis
of DBDFIM-Ac from furfural, nBA, HCHO, AcOH. No solvent was used in our studies
of imidazolium synthesis from furfural because all the reactants were liquid, and Liu’s
synthesis of furoin from furfural was solvent-free (Liu et al. 2012).
206 Weber A.L., Rios A.C.

Fig. 2 a. HPLC separation of DBDFIM and other products from the reaction of furoin (350 mM), nBA
(700 mM), AcOH (350 mM), and HCHO (350 mM) at 80 °C for 0.5 h in acetonitrile. b. Time course study
of the same multicomponent reaction

DBDFIM-Ac Synthesis from Furfural

In our first study of imidazolium synthesis from furfural we reacted stoichiometric and lower
amounts of nBA, HCHO, AcOH with a fixed quantity (1.2 mmol) of furfural and EMIM-Ac.
As shown in Fig. 3 the reaction yielded two imidazoliums: the desired product, DBDFIM-

Scheme 2 Imidazolium synthesis pathway

Imidazolium-Catalyzed Synthesis of an Imidazolium Catalyst 207

Ac, and the side product, 1,3-dibutyl-2,4,5-trifuryl-imidazolium acetate (DBTFIM-Ac),

depicted in Scheme 2. The identities of DBDFIM (m/z-313) and DBTFIM (m/z-379) were
confirmed by electrospray mass spectrometry. During imidazolium synthesis, formalde-
hyde becomes the C2-carbon of DBDFIM; whereas, furfural’s aldehyde becomes the C2-
carbon of DBTFIM. In Fig. 3 the stoichiometric reaction is marked with an asterisk.
Unexpectedly, the stoichiometric reaction did not produce the highest yield of DBDFIM-
Ac. Instead the best yield of DBDFIM-Ac was observed when 50% of the stoichiometric
amounts of nBA, AcOH, HCHO were reacted with furfural (mmoles respectively = 0.6,
0.3, 0.3, 1.2-furfural). Above 50% of the stoichiometric amounts of nBA, AcOH, and
HCHO there is a sharp decrease in the yields of the furoin intermediate and imidazolium
products (DBDFIM-Ac, DBTFIM-Ac) and a coincident increase in unreacted furfural.
These observations suggest that when the amount of nBA, AcOH, and HCHO exceeds
50% of their stoichiometric amount, one or more of these reactants interferes with EMIM-
catalyzed synthesis of furoin required for imidazolium synthesis.
To explore the chemistry of imidazolium synthesis from furfural we next examined
the time course of DBDFIM synthesis. This reaction used the optimal ratio of reactants
determined in the Fig. 3 study. Figure 4a shows the HPLC separation of furfural and
derived reaction products at 10 h monitored at 270 nm. Figure 4b shows the time course
of the synthesis of DBDFIM and other products from the EMIM-Ac catalyzed reaction of
furfural, nBA, HCHO, and AcOH at 80 °C. In the first 5 h of reaction there is a rapid
decrease of furfural concentration that is accompanied by formation of (a) furoin, and (b)
furil and unidentified products U1 and U2. Since furil, U1, and U2 were shown earlier to
be transient products in the synthesis of DBDFIM from furoin (see Fig. 2b) these are
furoin-derived products that could be involved in DBDFIM synthesis. Unidentified

Fig. 3 The effect on imidazolium synthesis of reacting less than stoichiometric amounts of n-BA, AcOH, and
HCHO with the furfural and EMIM-Ac held constant at 1.2 mmol. The stoichiometric reaction marked with an
asterisk in Fig. 3 contained: nBA (1.2 mmol), AcOH (0.6 mmol), HCHO (0.6 mmol), and furfural (1.2 mmol)
208 Weber A.L., Rios A.C.

Fig. 4 a. HPLC separation of DBDFIM and other products from the reaction of furfural (1.2 mmol), nBA
(0.6 mmol), AcOH (0.3 mmol), and HCHO (0.3 mmol) catalyzed by EMIM-Ac (1.2 mmol) at 80 °C (10 h). b.
Time course study of the same multicomponent reaction

product U3 which is found in the zero-time reaction but not the furfural reagent also
undergoes rapid decrease in the first 5 h of reaction. U3’s rapid formation (possibly
during sample preparation at 25 °C) suggests it might be the addition product of furfural
with the C2-carbon of EMIM. DBDFIM, DBTFIM, and U5 appear to be stable products
of the reaction that ends in 30 h. At 48 h the DBDFIM yield was 33.0% (based on
formaldehyde) estimated using QNMR and HPLC. Imidazolium products (DBDFIM and
DBTFIM) and the furoin intermediate were not formed in similar control reactions
(80 °C, 24 h) in which EMIM catalyst was either absent or replaced with an equal
volume of acetonitrile or DMF.

Catalytic Activity of the DBDFIM-Ac Imidazolium Product

To establish the catalytic activity of the DBDFIM-Ac product, purified DBDFIM-Ac

and commercial EMIM-Ac were each tested as catalysts for the synthesis of the
structurally related 1,3-dipentyl-4,5-difuryl-imidazolium acetate (DPDFIM-Ac) and its
side product 1,3-dipentyl-4,5-trifuryl-imidazolium acetate (DPTFIM-Ac) from furfural,
Imidazolium-Catalyzed Synthesis of an Imidazolium Catalyst 209

n-pentylamine, formaldehyde, and acetic acid at 80 °C (24 h). HPLC analysis showed
that DBDFIM-Ac and EMIM-Ac both catalyzed the synthesis DPDFIM-Ac and
DPTFIM-Ac. The DPDFIM-Ac yield using DBDFIM-Ac was about 70% its yield using
EMIM-Ac.

Discussion

Chemistry Our studies demonstrate that an imidazolium salt (EMIM-Ac) can catalyze the
solvent-free, one-pot synthesis of another catalytic imidazolium salt, (DBDFIM-Ac). As
shown in Fig. 4b this synthetic process is a concurrent two-reaction process: (1) EMIM-Ac
catalyzed furoin synthesis followed by (2) furoin reaction with nBA, HCHO, and AcOH to
give DBDFIM-Ac. The synthetic capability of this process derives from (1) the surprising
ability of simple imidazolium salt of a weak base (EMIM-Ac) to catalyze the benzoin
condensation of furfural to furoin in the presence of a considerable amount of protic molecules
that would be expected to quench formation of the imidazolium carbene intermediate needed
for catalysis (Clairmont et al. 2015), (2) the anaerobic synthesis of DBDFIM-Ac from furoin
(an α-hydroxyketone) reacted with nBA, HCHO and AcOH, (3) the ability of the EMIM-Ac to
act as both catalyst and solvent, and (4) the stability of imidazolium products under the
reaction conditions. The chemistry of this model of imidazolium-catalyzed imidazolium
synthesis is simpler than the model reported earlier by Clairmont et al. (2015) because here
imidazolium synthesis from furfural proceeds via furoin, rather than formaldehyde derived
sugars which can undergo isomerization, dehydration, aldol-retro-aldol reactions, and Maillard
degradation reactions under the reaction conditions. However, Clairmont’s model used form-
aldehyde which is a more prebiotically plausible reactant than furfural. Presumably under
prebiotic conditions furfural could have formed by dehydration of ketopentoses (Choudhary
et al. 2011) derived from formaldehyde.
The formation of imidazolium catalysts from the reaction of amines with sugars (Clairmont
et al. 2015) or sugar-derived furfural (this study) suggests that related Maillard sugar-amino
acid reactions could generate imidazolium salts capable of catalyzing Maillard transformations
(aldehyde benzoin condensations and oxidations), thereby influencing the chemical dynamics
of the Maillard process.
The development of an imidazolium model capable of sustained autocatalytic growth in the
presence of water probably requires the synthesis of an amphiphilic imidazolium (Lin et al.
2011; Jungnickel et al. 2008) that could catalyze self-synthesis while bound to a hydrophobic
resin in a column. Periodic elution of the column with fresh reactants should enable continued
synthesis and accumulation of imidazolium catalyst and removal of waste products (Wang and
Chen 2015; Yan et al. 2016). Related benzimidazolium salts possessing N-(C12-alkyl)-substit-
uents have been shown to catalyze the benzoin condensation in the presence of water
(Iwamoto et al. 2006).

Prebiotic relevance In addition to their ability to catalyze self-synthesis from an aldehyde, an

amine, formaldehyde, and acetic acid, imidazolium salts have other structural and functional
properties that make them attractive prebiotic molecules. First, the Radziszewski reaction is
capable of producing a variety of imidazolium salts possessing different N1,N3,C4,C5-ring
substituents. This structural complexity comes from (1) the large number of amines that can be
used for the synthesis of the N1,N3-substituents of the imidazolium ring (e.g. amino acids,
210 Weber A.L., Rios A.C.

peptides, aniline, alkylamines) (Davidek et al. 1991; Velisek et al. 1992; Clairmont et al. 2015;
Zimmermann et al. 2010), and (2) the many carbon substrates (1,2-dicarbonyls (e. g. glyoxal)
and α-hydroxyketones (e.g. sugars, furoin) that can be used for the synthesis of the C4,C5-
substituents of the imidazolium ring (Zimmermann et al. 2010; Clairmont et al. 2015; Siddiqui
et al. 2005). The Radziszewski reaction is also capable of producing large imidazolium
polymers from glyoxal, formaldehyde, and a diamine (e.g. lysine) (Lindner 2016; Saxer et al.
2018). Moreover, azolium (thiazolium and imidazolium) catalysis is not limited to the benzoin
condensation (Enders 2007). For example, azolium salts have been shown to catalyze oxidation
reactions that model biological pyruvate oxidative decarboxylation, the energy-transducing
process that yields acetyl-CoA from pyruvate, and connects glycolysis to the citric acid cycle
(Knappke et al. 2012; Kageyama and Murata 2005; Guin et al. 2008; Kiran et al. 2013).

Acknowledgements The authors thank Esther Varon for technical assistance in this study. This investigation
was supported by a grant (NNX15AL19G) from the Exobiology Program of the National Aeronautics and Space
Administration. ACR was supported by Exobiology Program grant, NNH17ZDA001N-EXO.

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