Reduced reactivity of amines against nucleophilic substitution via reversible reaction with carbon dioxide

Article abstract of DOI:10.3390/molecules21010024

The reversible reaction of carbon dioxide (CO₂) with primary amines to form alkyl-ammonium carbamates is demonstrated in this work to reduce amine reactivity against nucleophilic substitution reactions with benzophenone and phenyl isocyanate. The reversible formation of carbamates has been recently exploited for a number of unique applications including the formation of reversible ionic liquids and surfactants. For these applications, reduced reactivity of the carbamate is imperative, particularly for applications in reactions and separations. In this work, carbamate formation resulted in a 67% reduction in yield for urea synthesis and 55% reduction for imine synthesis. Furthermore, the amine reactivity can be recovered upon reversal of the carbamate reaction, demonstrating reversibility. The strong nucleophilic properties of amines often require protection/de-protection schemes during bi-functional coupling reactions. This typically requires three separate reaction steps to achieve a single transformation, which is the motivation behind Green Chemistry Principle #8: Reduce Derivatives. Based upon the reduced reactivity, there is potential to employ the reversible carbamate reaction as an alternative method for amine protection in the presence of competing reactions. For the context of this work, CO₂ is envisioned as a green protecting agent to suppress formation of n-phenyl benzophenoneimine and various n-phenyl-n-alky ureas.

Full text of DOI:10.3390/molecules21010024

Article
Reduced Reactivity of Amines against Nucleophilic
Substitution via Reversible Reaction with
Carbon Dioxide
Fiaz S. Mohammed and Christopher L. Kitchens *
Received: 6 November 2015 ; Accepted: 13 December 2015 ; Published: 23 December 2015
Academic Editor: Jason P. Hallett
Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC 29634, USA;
fiaz.mohammed@chbe.gatech.edu
*
Correspondence: ckitche@clemson.edu; Tel.: +1-864-656-2131
Abstract: The reversible reaction of carbon dioxide (CO ) with primary amines to form
2
alkyl-ammonium carbamates is demonstrated in this work to reduce amine reactivity against
nucleophilic substitution reactions with benzophenone and phenyl isocyanate. The reversible
formation of carbamates has been recently exploited for a number of unique applications including
the formation of reversible ionic liquids and surfactants. For these applications, reduced reactivity of
the carbamate is imperative, particularly for applications in reactions and separations. In this work,
carbamate formation resulted in a 67% reduction in yield for urea synthesis and 55% reduction for
imine synthesis. Furthermore, the amine reactivity can be recovered upon reversal of the carbamate
reaction, demonstrating reversibility. The strong nucleophilic properties of amines often require
protection/de-protection schemes during bi-functional coupling reactions. This typically requires
three separate reaction steps to achieve a single transformation, which is the motivation behind Green
Chemistry Principle #8: Reduce Derivatives. Based upon the reduced reactivity, there is potential
to employ the reversible carbamate reaction as an alternative method for amine protection in the
presence of competing reactions. For the context of this work, CO is envisioned as a green protecting
2
agent to suppress formation of n-phenyl benzophenoneimine and various n-phenyl–n-alky ureas.
Keywords: carbamate; urea; benzophenoneimine; green chemistry
1
. Introduction
It has been previously reported that primary and secondary amines react with CO to produce
2
thermally reversible alkylammonium alkylcarbamates as seen in Scheme 1 [1–7]. The CO reacts
2
with one primary amine to form carbamic acid, which then further reacts with free amine to form
the carbamate product. This mechanism has been extensively studied in literature with a variety
of applications in different fields [8–12]. For example, the reversible amine to carbamate transition
exhibits a significant change in the ionic character from non-ionic to ionic upon CO reaction, which
2
has been employed in systems referred to as reversible ionic liquids, reversible surfactants, and
switchable solvents [8,13–19]. These systems have included CO reaction with guanidines and
2
amidines reaction with alcohols as two-component systems and primary or secondary amines as
single component systems. In these systems, the solvent property changes can be quite appreciable,
changing in character from that of hydrophilic methanol to that of hydrophobic chloroform [8,14,15].
The potential implications of such tunable solvent properties are widespread in the realm of reactions
and separations, where a change in solvent properties can induce a complete phase separation and facile
recovery of products, catalysts, or unreacted reagents. This was initially demonstrated by Jessop et al.
with the reversible protonation of DBU (1,8-diazabicyclo-[5.4.0]undec-7-ene) in the presence of an
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alcohol and CO2 [8]. In the unprotonated state, the DBU/alcohol mixture is considered non-polar and
is completely miscible with decane. The addition of CO induces DBU protonation and switch to a
2
polar nature and phase separation from the non-polar decane phase. Specific potential applications
that have entertained the use of switchable solvents or reversible ionic liquids have included oil
extractions [20] CO capture [17
,
21] styrene polymerization [15
,22], Claisen-Schmidt condensation,
2
Heck reaction [13] Michael addition [13 15] cellulose acetylation [23] and nanomaterial processing [18],
,
to name a few. In each of these applications, amine reactivity can become an impeding issue [13].
Scheme 1. Reaction scheme of reversible alkylammonium carbamate formation from coupling of
carbon dioxide and a secondary amine.
In other work, reversible surfactants use the same chemistry as the switchable solvents
or reversible ionic liquids to create and break emulsions or form gels with many potential
applications [15,24]. Similarly, the reversible reaction of CO with amines have been demonstrated
2
during the development of ordered laminar materials comprised of amino-terminated silanes [25].
The formation of the hybrid material could not be possible if the absence of the carbamates. Other
studies have used the reversible reaction to dramatically dictate the product selectivity during the
intramolecular hydroaminomethylation of ethyl methallylic amine by reducing the nucleophilicity of
the nitrogen atom [26]. Eckert and coworkers [27] used CO expanded liquids at 30 bar to increase the
2
yield of primary amine synthesis in the hydrogenation reactions of benzonitrile and phenylacetonitrile
with NiCl /NaBH in ethanol. The CO induced carbamate formation prevented side reactions by
2
4
2
precipitating the desired product from solution as a carbamate, thus simplifying the purification and
increasing the yield. However, the protected carbamate was not used in any further coupling reactions.
In each of these applications, CO reaction is beneficial in protecting the amine from undesired
2
product formation.
Protecting groups provide a vital role within the field of organic synthesis, enabling the coupling
of various organo-functional groups in the presence of a competing group [28]. This protection also
needs to be stable under a broad range of reaction conditions and both moderately and selectively
cleavable. Thus, choosing the right type of protective group is of primary significance, especially in the
presence of amino containing compounds that tend to be very reactive, basic in nature, and form strong
hydrogen bonds. In addition to sulfonamides and amides, carbamates are the most popular and widely
used protection mechanism utilized for amino groups. Such protecting groups primarily include
carbobenzoxy (CBZ), di-tertiary butoxy carbonyl (Di-t-BOC) [29], and 2-(trimethylsilyl)ethylsulfonyl)
(SES) [30] groups as well as other less common groups, such as borane [31]; each having their own
set of advantages and disadvantages. The t-BOC and Di-t-BOC protecting groups, for example, are
utilized quite frequently in literature due to the stability during catalyzed nucleophilic substitutions
and catalytic hydrogenation reactions [32]. However, de-protection requires strong acids, long reaction
times and has shown to generate t-butyl cations that then require scavengers to prevent undesirable
side reactions [33]. Likewise, regeneration of a CBZ protected amine is achieved by acidolysis, catalytic
hydrogenation, or reduction with dissolved metals. In light of these hazards, the use of milder reagents
and reaction conditions has been an area of significant potential improvement [34,35], building upon
the principles of Green Chemistry. Despite the recent advancements in protection/de-protection
mechanisms for amines, these traditional methods are widely lacking in both material and energy
efficiency, adding to the cost and/or use of corrosive reagents.
Only recently has the concept of using CO2 as a simpler, greener approach to amine
protection/de-protection arisen [36–38]. Peeters et al. demonstrated CO as a reversible amine-protecting
2

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agent in selective Michael additions and acylations [36]. Specifically, the reaction of primary amines
was inhibited in favor of normally less reactive sulfonamides, cyclic secondary amines, or -ketoesters
β
for the Michael addition and complete inhibition of benzylamine acylation was achieved, effectively
favoring alcohol conversion without significant byproduct. Ethier et al. investigated the solvent effect
and addition of other bases in addition to DBU on the protection of benzylamines with CO [37].
2
In each case, protection of the amine was achieved in the presence of a competitive reaction and
removal of the CO protecting group was achieved; however, the reactivity of the de-protected amine
2
was not examined.
This work further explores the use of the reversible CO chemistry as a unique method of
2
protecting amines during simple coupling reactions. All reactions were carried out with (1) the
non-protected amine; (2) the carbamate analogs formed in solution via reaction with gaseous CO ; and
2
(3) with the de-protected amine regenerated through a thermal treatment of the carbamate. Significant
differences between this work and those of Peeters et al. and Ethier et al. are the lack of a competing
reaction and measurement of reactivity following de-protection. The lack of a competing reaction is
significant because it measures the decreased reactivity rather than the competitive reactivity.
2
. Results and Discussion
2
.1. Synthesis of n-Alkyl, n-Phenyl Urea
Urea formation via amine coupling with isocyanates has been well-studied and
characterized [39,40]. The urea synthesis in this work showed 95% yield from propylamine,
while other amines achieved comparable yields of 85% from hexylamine, 91% from decylamine,
and 90% from octadecylamine (Table 1). Once protected in the carbamate form, the reactivity was
significantly reduced for the shorter chained amines with an average decrease of 62%. After the
heat treatment, de-protection of the propyl, hexyl and decyl amine was successful based on the
increase in urea yield to values comparable to the non-protected amine. This demonstrates the
reversibility of the carbamate protection and requirement of no pressurization or separate reaction
conditions. The observed lower product yields for the de-protected amines are attributed to incomplete
de-protection of the carbamates along with a loss of starting material during de-protection due to the
inherent volatilities of the propyl and hexylamine. TGA showed carbamate degradation temperatures
higher than their amine conjugates, thus resulting in a loss of starting material during thermal amine
regeneration process (Figure S6). Decylamine, with its low volatility and ease of carbamate reversal
displayed the best results, with a 93% urea yield from the de-protected amine comparable to that of
the pure or un-protected amine (91%). The octadecyl carbamate showed the lowest reduction in yield
and the poorest recovery in the de-protected amine reactivity. This was not an expected result as a
protection/de-protection cycle had been achieved separately for the octadecyl amine. A significant
difference was that the octadecyl-carbamate formation resulted in a white precipitate, however the
de-protection regenerated the soluble amine analog. We hypothesize that the long alkyl chains and
precipitation inhibited the complete formation of the carbamate and resulted in insufficient protection.
FTIR of the isolated ureas demonstrated high purity through the absence of carbamate or
other reaction byproducts for all three scenarios (non-protected, protected and de-protected). In
each FTIR spectra (Figure S1), the characteristic carbonyl (C=O) and secondary amine (N-H)
absorbance associated with urea formation are consistent within all isolated products while the
´1
C-H (2800–3000 cm ) absorption levels correlate very well to the alkyl chain backbone length.
The three states of amine (non-protected, protected and de-protected) all produced an isolated urea
product displaying similar absorbance bands (Figure S1). This indicates that the products obtained
were spectrally identical and not side products due to residual carbamate presence. The urea purity
1
was further determined by H-NMR, displaying chemical shifts characteristic to our desired products
(
Figures S2 and S3). The main differences in spectra were the chemical shifts at 1.3 ppm attributed to

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the longer alkyl backbones of hexyl and decylamine, while integration of the peaks further evidenced
its structure and purity.
Table 1. Percentage yields of the n-phenyl–n-alkyl ureas of for pure, protected and de-protected amine.
Percentage Yield (%)
Amine
n
Non-Protected
Protected
De-Protected
Propylamine
Hexylamine
Decylamine
1
4
8
95
85
91
90
28
20
38
69
85
80
93
72
Octadecylamine
16
m
The urea melting temperatures (T ) were determined by DSC (Table 2). All measured values
correlated well with literature values and possessed small melting temperature ranges, indicating high
purity [41]. The n-propyl urea exhibited the highest melting point and crystallization temperature
despite the shortest carbon chain, and highest volatility. Similarly, the propyl and hexyl carbamates
showed an increase in the decomposition onset temperature due to the stronger charged carbamate
interactions present. The ureas contain hydrogen bonding donors (NH ) and hydrogen bonding
2
acceptors (C=O). The shorter alkyl chains contribute less steric hindrance and thus, a higher degree
of hydrogen bonding occurs. As the chain length increases, the alkyl chain disrupts the urea-urea
˝
hydrogen bonding and order, thus reducing the melting point, as seen with n-hexyl urea (68–69 C).
˝ ˝
As the alkyl chain increases, an expected T increase from 82 C for decylamine to 95 C for stearyl
m
amine is observed, which is due to increases in energy demand for the onset of melting for higher
molecular weight urea.
Table 2. n-Phenyl, n-alkyl urea melting points and crystallization temperatures determine from DSC.
˝
˝
Entry
MP ( C)
Recrystalization Temp. ( C)
n-phenyl, n-propyl urea
n-phenyl, n-hexyl urea
n-phenyl, n-decyl urea
n-phenyl, n-stearyl urea
112–114
68–70
81–83
95–97
89
47
61
84
m
Figure 1 displays a typical DSC curve used to determine T for each urea isolated. From the image,
we can further conclude urea purity consistency throughout each amine state. As with the FTIR data,
the protected and de-protected samples all provide isolated products which are chemically identical.
Figure 1. DSC spectra of n-propyl urea isolated from all three amine starting materials. Ramp
˝
˝
˝
rate = 5 C per minute to 140 C followed by equilibration to 60 C and repeated heating.

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2
.2. Synthesis of n-Propyl, Benzophenone(BP) Imine
Titanium(IV) isopropoxide is a low cost mediator in BP imine synthesis [42
–
46]. According to
Figure 2, the initial BP concentration of 0.45 M is slowly reduced to 0.26 M after 3 h and finally 0.11 M
after 24 h as the reaction proceeds. Gas chromatography (GC) was used to determine an overall
yield of 75% for the non-protected amine while a 25% yield is obtained for the protected and 50% for
de-protected propylamine. Once again, a similar trend is seen with the de-protected amines falling
short of the original product yield, which is attributed to the incomplete reversal of carbamates or
propylamine volatilization during the de-protection process.
Figure 2. Plot of benzophenone (BP) concentration determined via gas chromatography (GC) for the
non-protected, protected and de-protected propylamine reactions at 3, 6 and 24 h.
Although FTIR is not commonly used as a powerful quantitative tool, it was used to confirm the
presence of our imine species, as well as, calculate the BP conversion. Figure 3 shows the strongly
´
1
´1
absorbing C=N shift to 1620 cm from the C=O at 1660 cm of the original BP [47]. This shift in
absorbance demonstrates that the desired imine species was obtained during the BP-propylamine
1
reactions and this was further evidenced via H NMR and GC-MS.
Figure 3. FTIR of pure BP (dashed) compared to isolated BP imine product (solid).
The qualitative analysis was conducted over a period of 12 h, during which time ATR-FTIR
spectra of aliquots of the reaction vessels were collected and analyzed to confirm the appearance of the
imine product. As the reaction proceeds forward, the concentration of imine in the reaction solution
will increase until equilibrium has been reached. By analyzing the absorbance ratio of C=O to C=N, the
percentage of imine in the reaction vessel was determined (Table 3). These calculated values correlate

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very well to the percentage conversion obtained via GC and support our initial hypothesis that CO is
2
a viable tool for the protection and inhibition of free primary amines to undergo coupling reactions.
Table 3. Determined BP conversion from GC analysis compared to BP conversion calculated from IR
spectral C=N/C=O absorbance ratio.
Sample
Time (h)
Calculated IR Conversion (%)
Conversion from GC (%)
Non-protected
Non-protected
Protected
3
12
3
35
55
16
26
33
65
18
Protected
12
20 *
*
denotes a value that was estimated using Figure S7.
In a separate set of experiments, imine formation was observed to take place without the presence
of mechanical stirring (Figure S7). Here, the benzophenone, Ti catalyst and propylamine were
combined in 1.5 mL GC vials and monitored in-situ with the absence of any a titanium complex
intermediates. The percentage conversion correlated very well despite running the reaction in separate
vials with maximum conversions identical to those obtained above in Figure 2. The non-protected
reaction reaches a 75% equilibrium conversion after 15 h, while the protected propylamine yields a
2
5
5% equilibrium conversion after 36 h. The de-protected sample obtains an equilibrium conversion of
0% after 5 h, a phenomenon that has been consistent throughout this work. Confirmed by FTIR, a
distinct reduction in CH and CH absorption provides evidence to support the loss of starting amine
2
3
concentration during de-protection. An alternative explanation for the reduction in imine and urea
yield using the de-protected amines is the formation of isocyanate side products during the thermal
treatment [48]; however, this theory is not strongly supported.
In the presence of methanol, CO will preferentially react with the alcohol to form an alkylcarbonic
2
acid that then reacts with the amine to form methyl carbamates, as opposed to the alkylammonium
carbamates obtained under aprotic conditions [49]. The resulting carbonic structure has a larger energy
requirement to cleave the methyl group and release the carbon dioxide. It is hypothesized that the
reduced BP conversion for the de-protected reactions could be due to the increased difficulty to reverse
the protection as the protic methanol solvent interacts with the carbamate.
Lastly, an explanation into the formation of ureas and benzophenoneimine in spite of CO induced
2
carbamate protection needs to be discussed. For example, the 25% conversion of BP to the imine
does not represent a complete protection of the propyl amine. According to Salmi et al. [45], the
reductive amination of BP proceeds through an imine species with no observable titanium complex
intermediates. Hence, the complexation of BP with the Ti is not a cause for the observed reduction in
BP concentration, and this conversion is attributed to reactivity of the amine with the BP. Furthermore,
control experiments in the absence of propylamine showed negligible loss in BP concentration, further
supporting a residual amine reactivity under CO vs. complexing of BP to Ti as the source of BP
2
conversion. We conclude that the conversion of starting material under protected conditions is
primarily due to the equilibrium which exists between the carbamates and the amine (Scheme 1).
As the amine is converted to urea/imine, the equilibrium can shift towards the reactants, resulting
in more conversion of the starting material. This theory explains the formation of the urea/imine
under the carbamate protection mechanism and an investigation into the kinetics of the carbamate
reactivity can also provide useful information on the degree of protection. By fully understanding the
relationship that exists between carbamates and the amine-CO system, we can calculate expected
2
yields of the product based on the equilibrium constant of the carbamate formation.

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3
. Materials and Methods
3
.1. General Amine Protection
The required quantity of amine was added to a round-bottom flask before the addition of any
other component. A CO atmosphere was then introduced into the closed vessel via a CO gas cylinder
2
2
equipped with a low pressure regulator for approximately 5 min resulting in the exothermic formation
of solid white powders. The reaction solvent was then added with additional CO being bubbled
2
through the solution for a further 3 min. The original volume of the solution was made up with
pure solvent after the CO bubbling in order to preserve concentrations. The reactions with protected
2
amines were carried out under a CO atmosphere.
2
3
.2. General Amine De-Protection
Carbamate solutions of the alkylamines were de-protected using indirect heat and thermostat
control with stirring. An ice-bath cooled condenser was attached to the top of the reaction vessel while
a steady stream of nitrogen was introduced to aid the reversal. This was carried out for 10 min, after
which fresh solvent was added to maintain the reaction concentration after nitrogen saturation. This
procedure was used in attempt to convert carbamates back to the original amines. The de-protected
amines were then employed in the urea/imine synthesis to ensure complete de-protection and no loss
of reactivity.
3
.3. General Characterization
An aliquot of the reaction mixture (1.5 mL) was taken from each reaction vessel and injected
into an Agilent 7695A GC using the Agilent 7683B automatic liquid sampler (Agilent Technologies,
˝
Santa Clara, CA, USA). The inlet temperature was set at 300 C with a pressure of 16 psi, the oven at
8
˝
˝
˝
˝
0 C with a heating rate of 20 C/min to 250 C. The FID was set at 300 C. A calibration curve for
benzophenone (BP) was created by plotting the integral of the BP peak vs. known concentrations of BP
= 14.5 min). Melting points were determined from DSC spectra obtained using a Thermal Analysis
SDT Q600 (TA Instruments, New Castle, DE, USA) equipped with alumina pans. A steady heating
(R
t
˝
˝
rate of 5 C/min was maintained to 350 C with a nitrogen purge of 100 mL/min. IR spectra were
collected on a Nexus 870 spectrometer (Nicolet Instrument Corporation, Madison, WI, USA) with a
´
1
˝
4
cm resolution using 64 scans. A fixed angle single reflection 60 hemispherical Ge crystal plate,
equipped with an ATR pressure clamp, was placed in a sample compartment. The output signal was
1
collected using a deuterated triglycine sulfate (DTGS) room temperature detector. H-NMR spectra
were obtained on a Bruker 300 MHz in CDCl (Bruker Biospin Corporation, Billerica, MA, USA).
3
3
.4. Synthesis of n-Alkyl, n-Phenyl Urea
Exactly 50 L (0.0545 g, 0.46 mmol) of phenyl isocyanate was added dropwise to a solution of
µ
˝
alkylamine (0.92 mmol) in 2 mL of dry CHCl at 0 C. The resulting solution was stirred for 60 min
3
at room temperature and then precipitated into 25 mL of pentane. The product was isolated as a
white powder via filtration and washed with several portions of pentane before being dried under
˝
vacuum at 50 C. The products isolated from the alkylcarbamates were alternatively re-dispersed in
dry CHCl and underwent thermal treatment to remove any residual carbamates. The ureas were then
3
re-crystallized in pentane again and isolated via filtration to determine yield (Scheme 2a).
3
.5. Synthesis of n-Propyl, Benzophenone(BP) Imine
Propylamine (5 mmol) was added to 5 mL of dry methanol, followed by 2.5 mmol benzophenone
(BP) and 3.3 mmol titanium(IV)-isopropoxide. The solution was stirred under nitrogen at room
temperature while aliquots were taken at 3, 6 and 24 h for GC analysis and ATR-FTIR monitoring.

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Alternatively, the reaction was separated into 4 GC vials and sampled in-situ without stirring. Each GC
vial represented a reaction vessel that was used to monitor the reaction kinetics (Scheme 2b).
Scheme 2. Reaction scheme showing the pathways for n-phenyl, n-alkyl urea synthesis in CHCl3 (
and benzophenoneimine synthesis in methanol (b).
a);
4
. Conclusions
In conclusion, we have shown that the reaction of CO with alkyl amines reduced the amine
2
reactivity resulting in reduced urea and imine yields for multiple primary amines. Performing the
reaction in the absence of a competing reaction demonstrates a true decrease in reactivity, rather than
preferentiality. Reversible carbamate formation via gaseous CO alone shows potential as a simple,
2
“green” alternative compared to traditional methods that require harsh chemicals and more energy
intensive reaction conditions; adhering to the major strategies of green chemistry which promote
reduced solvent and energy use, inherently safer reagents, and reduced number of transformations.
Despite the novelty, the temperature dependence of the reverse reaction does introduce
limitations. The ability to efficiently protect and de-protect the amine and the solubility of the
carbamates in the reaction media are also potential limitations. In future work, this protection
mechanism will be implemented in a competitive reaction where amine functionality is required
post protection for a separate coupling reaction. This will test the limits and efficiency of the proposed
protection/de-protection technique. Also, this technique will be applied to high pressure systems in
an attempt to dictate and shift the carbamate equilibrium to favor the protection. The energy input to
maintain higher pressures may increase, but it is offset by the reduction in solvents for conducting the
three separate steps in traditional protection methods.
We anticipate that the results from this work will encourage chemists to not only design greener
routes for amine protection/de-protection mechanisms, but also to learn about the many advantages
that carbamate chemistry has to contribute to safer lab and industrial practices.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
2
1/1/24/s1.
Acknowledgments: This work was funded by the American Chemical Society. Authors would like to
acknowledge Paul Hernley for his experimental contributions to the study.
Author Contributions: F.M. and C.K. conceived and designed the experiments; F.M. performed the experiments,
analyzed the data and drafted the paper. C.K. oversaw the entire research study and coordinated the redaction of
the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
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