Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso-scale flow reactors

Article abstract of DOI:10.3762/bjoc.11.262

The continuous flow synthesis of a range of organic solutions of N,N-dialkyl-N-chloramines is described using either a bespoke meso-scale tubular reactor with static mixers or a continuous stirred tank reactor. Both reactors promote the efficient mixing of a biphasic solution of N,N-dialkylamine in organic solvent, and aqueous sodium hypochlorite to achieve near quantitative conversions, in 72-100% in situ yields, and useful productivities of around 0.05 mol/h with residence times from 3 to 20 minutes. Initial calorimetric studies have been carried out to inform on reaction exotherms, rates and safe operation. Amines which partition mainly in the organic phase require longer reaction times, provided by the CSTR, to compensate for low mass transfer rates in the biphasic system. The green metrics of the reaction have been assessed and compared to existing procedures and have shown the continuous process is improved over previous procedures. The organic solutions of N,N-dialkyl-N-chloramines produced continuously will enable their use in tandem flow reactions with a range of nucleophilic substrates.

Full text of DOI:10.3762/bjoc.11.262

Continuous formation of N-chloro-N,N-dialkylamine solutions
in well-mixed meso-scale flow reactors
A. John Blacker* and Katherine E. Jolley
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 2408–2417.
Institute of Process Research and Development, School of Chemistry
and School of Chemical and Process Engineering, University of
Leeds, Woodhouse Lane, Leeds, LS2 9JT, Leeds, UK
doi:10.3762/bjoc.11.262
Received: 13 October 2015
Accepted: 19 November 2015
Published: 02 December 2015
Email:
A. John Blacker* - j.blacker@leeds.ac.uk
This article is part of the Thematic Series "Sustainable catalysis".
Guest Editor: N. Turner
* Corresponding author
Keywords:
amine; biphasic; chloramine; chlorination; continuous flow chemistry;
CSTR; static mixer; sodium hypochlorite; tube reactor
© 2015 Blacker and Jolley; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The continuous flow synthesis of a range of organic solutions of N,N-dialkyl-N-chloramines is described using either a bespoke
meso-scale tubular reactor with static mixers or a continuous stirred tank reactor. Both reactors promote the efficient mixing of a
biphasic solution of N,N-dialkylamine in organic solvent, and aqueous sodium hypochlorite to achieve near quantitative conver-
sions, in 72–100% in situ yields, and useful productivities of around 0.05 mol/h with residence times from 3 to 20 minutes. Initial
calorimetric studies have been carried out to inform on reaction exotherms, rates and safe operation. Amines which partition mainly
in the organic phase require longer reaction times, provided by the CSTR, to compensate for low mass transfer rates in the biphasic
system. The green metrics of the reaction have been assessed and compared to existing procedures and have shown the continuous
process is improved over previous procedures. The organic solutions of N,N-dialkyl-N-chloramines produced continuously will
enable their use in tandem flow reactions with a range of nucleophilic substrates.
Introduction
N-Chloramines provide a versatile and reactive class of reagents bonds in the presence of acid and visible light to form hetero-
for use in electrophilic amination and other reactions. N-Chloro- cycles [9,10]. Furthermore they have also been used for chlori-
N,N-dialkylamines have been shown to offer a broad range of nation of aromatics in the presence of acid [11], and as reagents
products from reactions with i) unsaturated C–C bonds to give in the syntheses of natural products [12,13].
amines [1-3] and heterocycles [1,4]; ii) Grignard and
organozinc reagents to give amines [1]; iii) aldehydes to give Despite their versatility as reagents, the exothermicity and insta-
amides [5-7]; iv) base to give imines [8]; v) alkyl and aryl C–H bility that occurs in both their formation and reaction, has
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reduced the interest in their use for reasons of process safety. NaOH (Scheme 1). Such separation of biphasic mixtures is
Isolation of many N-chloramines is unadvisable with reports of known in continuous systems, for example membrane-based
unpredictable and rapid decomposition [11,14-16].
separators [26,27].
N-Chloramines are prepared conventionally by reaction of the
amine precursor with an electrophilic chlorine source [14].
Despite its atom efficiency use of chlorine gas is undesirable
due to its toxicity and strong oxidising properties, making it
highly hazardous and operationally difficult to use. In addition,
the hydrochloric acid byproduct requires additional processing
to neutralise and separate it. N-Chlorosuccinimide is used
Scheme 1: Two-phase reaction of N,N-dialkylamine and sodium
hypochlorite.
frequently in the laboratory because it is a relatively stable solid Mixing is a key parameter for reactions in multiphasic systems
that is easily weighed and added to reactions [3,17], however, it and characterisation of material flows within different contin-
has a low atom economy, poor economics, and requires sep- uous reactors is widely studied by both modelling and experi-
aration of the succinimide byproduct [18]. The tert-butyl ment [28,29]. The rate of reaction of NaOCl and amines at high
hypochlorite (t-BuOCl) reagent is also used regularly, but is pH is very fast with a second order rate constant, kobs of
similarly expensive, wasteful and hazardous [14,19-21]. On the 1.52 × 105 L·mol−1·min−1 reported for dimethylamine [30]. In
other hand sodium hypochlorite (NaOCl) is an inexpensive this case it is the rate of mass transfer of the reagents, parti-
byproduct of chlorine manufacture, and offers a safer, greener tioned between the two liquid phases that limits the rate of
source of electrophilic chlorine for producing N-chloramines product formation, rather than the chemical rate of reaction
[11,14,22]. Reaction times can, however, be long [14,23,24], between the two species. Continuous liquid biphasic reactions
and yields low [25]. Zhong et al. have reported a process using are usually poorly mixed within micro-scale reactors, as low
NaOCl to generate t-BuOCl in situ for chloramine formation, fluid velocities and frictional wall effects cause laminar flow
applying the methodology to a broad range of substrates in high and phase separation into alternating organic–aqueous
yields [20].
segmented flow; whilst meso-scale reactors are much better
suited, and provide more accurate and reliable information for
Published literature on chloramine formation is limited to batch scale-up. Interaction of the reactants occurs only at the phase
procedures, however, the use of continuous processes could interface, so efficient mixing increases the surface area and
offer significant advantages. Use of continuous flow reactors to promotes product formation. Within batch or continuous stirred
achieve steady-state allows precise control over the reaction tank reactors an increase in mixing intensity is achieved with
parameters to improve safety, selectivity, productivity and optimised impellor design and speed, alongside a reactor
consistency. Reduced reactor volumes compared to conven- designed to disrupt the flow and increase turbulence. Within
tional batch reactors limit the quantity of reacting material at meso-scale tubular reactors the addition of in-line aids such as
any one time; particularly important for the preparation of split and recombination streams [31,32], or static mixers
hazardous or unstable products. Furthermore smaller volumes [32,33], can enhance mixing and mass transfer between phases.
with higher surface areas enable faster heat removal and better Phase-transfer catalysts (PTCs) can also be used to promote
temperature control to limit unwanted side reactions. Further reactions across phase boundaries [31], their use would,
kinetic control is achieved with reactant concentrations, feed however, incur additional financial costs for the reaction, and
rates, mixing regime and residence time resulting in higher also the need for purification and removal of the catalyst from
product yields.
the reaction solution.
Results and Discussion
Herein we report the use of different types of bespoke contin-
uous reactors for preparing different N-chloro-N,N-dialkyl- Calorimetry
amines. The use of these materials in forming a range of In view of the potential dangers involved in making chlor-
different nitrogen containing products via a cascade/tandem amines we began our studies with calorimetric analysis. The
procedure will be reported elsewhere. This atom efficient proce- formation N-chloromorpholine was studied by feeding 1.1 M
dure, with sodium hydroxide and water the only byproducts, NaOCl (aq) into a 1 M morpholine (aq) at a rate of 1 g/min. The
should have better green metrics than other methods. Using calorimeter jacket temperature was set at −15 °C, and power
biphasic reaction conditions with the amine dissolved in a water compensation used to maintain the reactor at 5 °C. 20 mL of the
immiscible, organic solvent such as toluene enabled facile sep- NaOCl solution were added to 20 mmol of morpholine over
aration of the organic soluble product from the water soluble 20 min, and after subtracting the feed solution temperature
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Beilstein J. Org. Chem. 2015, 11, 2408–2417.
(Q Dose) from compensatory power (Q Comp) the total was the continuous reactors employed in this work, with increased
2.76 W. For this calibrated calorimeter this equates to −1.47 kJ surface area-to-volume ratio, allows effective heat dissipation
which gives a heat of reaction, ΔHr = −73.4 kJ·mol−1 for the under ambient conditions.
formation of N-chloromorpholine (Figure 1). Calculation of the
heat of reaction by bond forming/bond breaking calculation, Continuous reactor
according to mechanisms proposed in the literature, give a ΔHr A nylon/PTFE tubular reactor was constructed that incorpo-
of −72 kJ·mol−1 (Supporting Information File 1) [30].
rates static mixers for enhanced mixing of the biphasic reaction
solution, made of the acetal homopolymer, Delrin® that are
Figure 1 shows the calorimetric trace for the formation of solvent and oxidant resistant [34]. The set-up comprised one
N-chloromorpholine. Following the addition of NaOCl (aq) pump for the organic phase (amine/toluene) and one for the
there is a small delay in the reaction which may be mixing aqueous phase (NaOCl/water). The feeds were connected via a
related. A rapid exotherm then occurs with 1.37 kJ energy stainless steel T-piece to tubing (1/4 inch OD, 3/16 inch ID)
released continuously over the 20 minute feed. When the containing static mixer tubes (1/8 inch ID, 3/16 inch OD) along
NaOCl (aq) addition is stopped there is a further release of the flow channel (Figure 2). The length of the reactor and
0.09 kJ energy over 2 minutes indicating a small accumulation number of static mixer inserts were adjusted to vary the resi-
of heat. Analysis of the crude reaction product shows no side dence time, thus maintaining sufficient flow rate to give effec-
products, and no decomposition of the N-chloromorpholine tive mixing.
product.
Initial experiments using toluene and an aqueous dye were used
When the same reaction was carried out using a toluene–water to assess static mixer performance. Figure 3 shows the solu-
biphasic system, the calorimeter trace was more complex with tions being pumped simultaneously into a T-piece with equal
mass transfer effects making interpretation difficult (Supporting flow rates. As the solution progresses into the tube containing
Information File 1).
the static mixers, it can be seen to be a well-mixed emulsion.
Shortly after emanating from the mixed region, the biphase
The calorimetric analysis shows chloramine formation to be an separates into a segmented flow before being collected into a
energetic process with a significant associated exotherm illus- flask.
trating the need for efficient temperature control during the
reaction to ensure a safe process. In batch it would be neces- Initial reactions looked at the effect of increasing the number of
sary to cool the reaction with an ice bath or similar, however, static mixers within the reactor and also increasing residence
Figure 1: Calorimeter trace for the single phase reaction of morpholine (aq) and NaOCl (aq). Q Comp: compensatory power, Q Total: total power,
Q Dose: power delivered by dosing of room temperature NaOCl (aq) to cooled reaction solution. Energy: heat energy.
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Figure 2: Meso-scale static mixer set-up for continuous N-chloramine formation. (a) Pumps, (b) reagent solution reservoirs, (c) reactor tube
containing static mixers, (d) collection vessel, (e) back pressure regulator (75 psi).
Figure 3: Effect of static mixers on biphasic solution.
time by decreasing the flow rate of reagents. The progress of the
reaction was studied to determine the point at which steady state
is achieved and to assess the consistency of the reaction over
several reactor volumes (Figure 4). The reaction reaches steady
state after 6 minutes (2 residence times) with fairly consistent
conversion achieved thereafter. The N-chloromorpholine yield
was measured by direct sampling of the toluene solution and
measuring by quantitative 1H NMR.
Figure 4: Progress of reaction for continuous formation of N-chloro-
morpholine. Morpholine (toluene) 0.9 M 1 mL/min, NaOCl (aq) 0.9 M,
1.1 mL/min, 6 mL total reactor volume, of which 0.8 mL is static
mixers. Residence time = 2.9 min. Conversion refers to composition of
organic phase of reaction solution.
Table 1 entry 1 shows the poor conversion observed using the Substrates
T-piece alone, whilst higher conversions are seen with The formation of a range of N-chloro-N,N-dialkylamines was
increased static mixed volume. Table 1 entry 2 shows higher investigated. Some were found to react relatively slowly, partly
chloramine formation with increased residence time (Tres) as a for the mass transfer reasons discussed above, and possibly for
result of lower flow rates, with a maximum 89% conversion at a electronic and steric reasons as well. The tube reactor did not
Tres of 20 min. Even at flow rates of 0.15 mL/min there appears conveniently allow sufficient residence times for full conver-
to be intimate mixing of the aqueous–organic phases. Both sion of amine to chloramine to be achieved, and in such cases a
intense mixing and long residence times are required because continuous stirred tank reactor (CSTR), able to provide longer
the N-benzylmethanamine partitions mainly in the organic residence times, was used instead (Figure 5 and Figure 6).
phase with KD [organic]/[aqueous] = 28.8, causing the reaction
to be limited by the mass transfer rate. For example mixing in Table 2 shows reaction parameters investigated for the reaction
the T-piece alone gives 11% conversion with N-benzyl- of different amines: residence time, reactor volume, number of
methanamine, but 46% with 1,4-morpholine; also 65% conver- static mixers and molar equivalents of NaOCl. Formation of
sion is seen with 0.8 min of intense mixing of N-benzyl- N-chloromorpholine and N-chloropiperidine (Table 2, entries 1
methanamine with NaOCl, whilst 68% is seen with 1,4-morpho- and 2) proceeded with high yields under short reaction times
line mixed for half this time, because it partitions more using the static mixers. N-chloro-N-methyl-p-toluenesulfon-
favourably into the aqueous phase with KD = 0.01.
amide and N-chloro-N-benzylmethanamine proceeded with
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Beilstein J. Org. Chem. 2015, 11, 2408–2417.
Table 1: Effect of reactor parameters on chloramine formation.a
Entry
Product
NaOCl
(equiv)
Mixed volume
(mL)
Total RV
(mL)
Tres
(min)
Amine conv.
(%)b
0c
0c
0.8
1.6
<0.1
<0.05
11
39
57
65
6
6
6
3
3
3
1
1.1
1.1
1.2d
3
6e
12f
20g
41
65
69
78
89
2
3
1.6
6
0c
0.8
<0.1
6
<0.05
3
46
68
1.1
aTres = residence time, RV = reactor volume. Reaction conditions: 1 M amine in toluene and 1.1 M NaOCl (aq) at equal flow rates of 1 mL/min, room
temperature. bSteady state conversion by NMR vs internal standard. cT-piece only. dFlow rates = 2.5 mL/min. eFlow rates = 0.5 mL/min. fFlow rates =
0.25 mL/min. gFlow rates = 0.15 mL/min.
Figure 5: CSTR set-up for N-chloramine formation. (a) Syringe pump, (b) collection vessels, (c) reactor (50 mL), (d) stirrer plate: stirring rate
1200 rpm.
good yields in both the tube reactor and CSTR, however, for the
tube reactor 1.5 equiv NaOCl were required for complete reac-
tion of N-methyl-p-toluenesulfonamide, and 20 min residence
time was required for high yields of N-chloro-N-benzylmethyl-
amine. Due to the low solubility of N-methyl-p-toluenesulfon-
amide in toluene the tube reactor was susceptible to blockage.
This was overcome using EtOAc as the organic phase, and gave
more consistent results. Formation of N-chlorodibutylamine
proceeded slowly within the tube reactor and the longer resi-
dence times leant themselves to the CSTR. Table 2 entry 8
shows the need for 2 equiv NaOCl with 20 min residence time
to give 35% conversion of the chloramine product with the
tubular reactor. However, the conversion was improved
markedly using the CSTR and enabled use of only 1.1 equiv of
NaOCl to give quantitative formation of the product. The reac-
tion of dibenzylamine with NaOCl proceeds slowly within the
CSTR achieving only 40% conversion in 50 min, which may
Figure 6: Interior of 50 mL CSTR.
reflect its lower reactivity, since the partition coefficient is
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Table 2: Formation of secondary chloramines.a
Entry
1d
Product
KD
Reactor type
Static mixers
Reactor vol.
(mL)b
Tres
(min)
Amine conv.
(%)c
Yield
(%)c
0.01
6 (0.8)
4 (1.6)
4
4
100
100
84
94
2e
0.84
Static mixers
3f
4
28.9
28.9
Static mixers
CSTR
6 (1.6)
50
3
97
100
50
100
72–98g
5
6
28.8
28.8
Static mixers
CSTR
6 (1.6)
50
20
25
89
87
100
100
7h
8
118
118
Static mixers
CSTR
4 (1.6)
50
20
50
35
Not determined
100
100
9
114
CSTR
50
50
40h
Not determined
aKD = [amine] in organic/[amine] in aqueous phase. Reaction conditions: Equal flow rates of amine and NaOCl solutions used. 1 M amine in toluene
and 1.1 M NaOCl (aq) were used. Reactions conducted at room temperature. bStatic mixed volume in parentheses. cDetermined by NMR vs internal
standard. dNaOCl (aq) 2.2 M, flow rate 0.5 mL/min, amine 1 M in toluene, flow rate 1 mL/min. e1.5 M NaOCl (aq). fEtOAc solvent instead of toluene
used due to solubility of amine. gLow solubility of starting material in toluene caused problems with amine feed giving variation in yields. g2 M NaOCl
(aq) used. h40% N-chlorodibenzylamine and 60% residual dibenzylamine observed by 1H NMR, no other products observed.
similar to that of dibutylamine. The productivities of N-chlor- and 3 [20]. There are also improvements to the total mass inten-
amine formation are in the range of 0.04–0.06 mol/h.
sity of the flow procedure, primarily by avoiding work-up and
purification procedures. The mass efficiency remains low, but is
comparable to literature procedures. Whilst increasing the reac-
Green metrics
A key driver within the chemical industry is the need for tant concentrations is possible, the safe removal of the heat of
greener, more sustainable processes. In order to assess the reaction must be considered, moreover the flow process is much
sustainability of the continuous process for chloramine forma- more productive than batch. Nevertheless the N-chloramine
tion described in this publication, the metrics of the reaction solution that is generated should be used directly, so is ideally
were assessed and compared with existing literature procedures coupled with a second flow process, and the results of this will
[35]. The results are summarised in Table 3.
be reported elsewhere.
The yields of the continuous N-chloramine process were high, Conclusion
and comparable to literature batch procedures. The atom The facile synthesis of N,N-dialkyl-N-chloramines is described
economy of our process was increased compared to the use of using either a tubular reactor with static mixers or a continuous
N-chlorosuccinimide [3], or NaOCl/t-BuOH, Table 3, entries 2 stirred tank reactor; both are able to promote efficient mixing of
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Table 3: Comparison of green metrics for different chloramine formation procedures.
Entry
1a
2b
3c
4d
5e
Amine
N-chloro
succinimide
Chlorine source
NaOCl
NaOCl/ t-BuOH
NaOCl
NaOCl
Reactor
Flow
Batch
TBME, H2O
H2O, brine
100
Batch
Et2Of
H2O
100
Batch
H2O
Et2O
100
Flow
Reaction solvent
Work-up solvents
Conversion
Yield
toluene, H2O
toluene, H2O
–
–
100
94
100
84
100
90
88
Reaction mass
efficiency
57.73
74.94
18.17
18.17
1.73
63.42
53.94
37.5
46.37
54.69
80.3
63.44
75.25
12.39
8.43
60.24
75.25
15.09
15.09
1.66
Atom economy
Mass intensity:
total
Mass intensity: reaction
7.56
33.71
2.16
Mass intensity: reaction
chemicals
2.03
1.58
Mass intensity: reaction
solvents
16.43
–
5.54
31.55
46.58
6.85
3.96
13.43
–
Mass intensity: work-up
29.94
aSee Table 2, entry 3. bReference [20]. cReference [36]. dReference [11]. eSee Table 2, entry 1. fDCM has also been used for reactions of other
amines with NCS [3].
the biphasic reaction solution. Those amines which partition solution was determined by GC analysis using an Agilent HP
mainly in the organic phase required longer reaction times to 6890 with FID (Supporting Information File 1). Calorimetry
compensate for the reduced mass transfer between the organic experiments were carried out using HEL AutoMATE parallel
and aqueous phases, and good yields with useful productivities reactors with HEL WinISO 2225 and HEL IQ 1.2.16 software.
were achieved for most. The green metrics of the reaction have For the tube reactor, Harvard syringe pumps (model 981074) or
been assessed and compared to existing procedures for chlor- JASCO PU-980 HPLC pumps were connected via a syringe and
amine formation, and have shown the continuous process is im- 1.5 inch, 21 guage disposable needle to PTFE tubing with 1/16
proved over previous procedures. Work to expand the scope of inch OD. The 1/16 inch stainless steel T-piece and stainless
N-chloramines, and their subsequent use in flow reactions with steel 1/16 inch to 1/4 inch increasing connector were obtained
alkenes to make amines, aldehydes to make amides, and base to from Swagelok. The reactor tube comprises of PTFE tubing 1/4
make imines is ongoing.
inch OD and in-line plastic static mixers supplied by Nordson
EFD (3/16 inch OD, mixer element diameter 1/8 inch, 3.5 inch
length). For the CSTR, the same Harvard syringe pumps were
Experimental
All reagents were used as received from suppliers without used along with PTFE tubing with 1/8 inch OD.
purification. Sodium hypochlorite solution 10–15% available
General procedure for N-chloramine forma-
chlorine was purchased from Sigma-Aldrich. The accurate
NaOCl concentration was determined by titration (Supporting tion using the tube reactor and static mixers
Information File 1) and diluted to the required concentration The required number of static mixers (3/16 inch OD, 1/8 inch
with distilled water. CDCl3 purchased from Sigma-Aldrich was mixing element diameter 3.5 inch length) was inserted into a
used for NMR analysis. NMR spectra (1H and 13C) were length of 1/4 inch PTFE tubing to give the overall required
obtained on either a Bruker Advance 500 MHz, 400 MHz or a reactor volume. The reactor was connected to 1/16 inch tubing
Bruker DPX 300 MHz spectrometer. NMR spectra were refer- via a 1/4–1/16 inch reducing adapter. The tubing was split with
enced to either TMS or CHCl3. The partitioning of the amine a T-piece to 2 pumps (either piston or syringe pumps). A 1 M
reagents in the organic phase of a biphasic organic/aqueous solution of amine in toluene was prepared and fed via pump 1 at
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Beilstein J. Org. Chem. 2015, 11, 2408–2417.
the required flow rate. A 1.1 M solution of aqueous NaOCl was (0.84 M, 84%) by separation of the organic phase form the
fed via pump 2 at the required flow rate. The reaction solution aqueous phase of the reaction solution. The yield of product
was flowed through the reactor and collected in residence time was determined by NMR analysis as in the typical procedure for
fractions. The organic phase was separated from each fraction volatile products. The toluene solution was analysed by NMR
to avoid further interaction with the NaOCl solution. The and data matches that reported in the literature [17]. 1H NMR
organic phase was analysed by 1H NMR. For non-volatile prod- (CDCl3, 500 MHz) δ ppm 3.69 (br s, 4H, CH2OCH2), 3.12 (br
ucts yields were obtained by removal of toluene from the s, 4H CH2NClCH2); 13C NMR (CDCl3, 125 MHz) δ ppm 67.72
organic phase of each residence time fraction and weighing the (CH2OCH2), 63.03 (CH2NClCH2).
resulting product. For volatile products yields were obtained by
1H NMR analysis. 100 μL or the organic phase was weighed N-Chloropiperidine
and analysed by 1H NMR. The ratio of toluene/starting ma- Prepared according to the general procedure using the tube
terial/product and mass of 100 μL of the solution was used to reactor with 4 static mixers, a 4 mL reactor volume and a resi-
determine the N-chloramine concentration in the solution. From dence time of 4 min, 1.5 M NaOCl (aq) at 0.5 mL/min and 1 M
this the yield of N-chloramine in the full organic phase could be piperidine in toluene at 0.5 mL/min. Due to the high volatility
determined.
of N-chloropiperidine the product was not isolated and was
instead obtained as a solution in toluene (0.94 M, 94%) by sep-
aration of the organic phase from the aqueous phase of the reac-
tion solution. The yield of product was determined by NMR
General procedure for N-chloramine forma-
tion using the CSTR
Through the lid of a 50 mL jacketed glass vessel containing a analysis as in the typical procedure for volatile products. The
stirrer bar was inserted 2 lengths of 1/8 inch PTFE tubing toluene solution was analysed by NMR and data matches that
connected to syringe pumps. A third length of tubing was reported in the literature [17]. 1H NMR (CDCl3, 300 MHz) δ
inserted so that it ended flush with the base of the lid to act as ppm 3.49–2.63 (br m, 4H, CH2NClCH2), 1.84 (quin, J = 5.8
an overflow tube out of the reactor into a collection vessel. The Hz, 4H, 2 x CH2CH2CH2), 1.75–1.32 (br m, 2H,
reactor was secured on a stirrer plate.
NCH2CH2CH2); 13C NMR (CDCl3, 125 ppm) δ ppm 64.00 (2 ×
CH2NCl), 27.68 (2 × CH2CH2NCl), 23.07 (CH2(CH2)2NCl).
A 1 M solution of amine in toluene was prepared and fed via
pump 1 at the required flow rate. A 1.1 M solution of aqueous N-Benzyl-N-chloromethanamine
NaOCl was fed via pump 2 at the required flow rate. The reac- Prepared according to the general procedures. 1) Tube reactor
tion solution was flowed into the reactor, and once full was with 4 static mixers, a 6 mL reactor volume and a residence
eluted from the reactor via the overflow tube and collected. The time of 3 min, 1.1 M NaOCl (aq) at 0.15 mL/min and 1 M
solution was collected in residence time fractions. The organic N-benzylmethylamine in toluene at 0.15 mL/min. 2) CSTR with
phase was separated from each fraction to avoid further inter- a reactor volume of 50 mL, and residence time of 25 min. 1.1 M
action with the NaOCl solution. The organic phase was NaOCl (aq) at 1 mL/min and 1 M N-benzylmethylamine in
analysed by 1H NMR. For non-volatile products yields were toluene at 1 mL/min were used. Due to the volatility of
obtained by removal of toluene from the organic phase of each N-benzyl-N-chloromethanamine the product was not isolated
residence time fraction and weighing the resulting product. For and was instead obtained as a solution in toluene (1 M, quanti-
volatile products, yields were obtained by 1H NMR analysis. tative yield) by separation of the organic phase from the
100 μL or the organic phase was weighed and analysed by aqueous phase of the reaction solution. The yield of product
1H NMR. The ratio of toluene/starting material/product and was determined by NMR analysis as in the typical procedure or
mass of 100 μL of the solution was used to determine the volatile products. The toluene solution was analysed by NMR
N-chloramine concentration in the organic solution. From this and data matches that reported in the literature [17]. 1H NMR
the yield of N-chloramine in the full organic phase could be (CDCl3, 300 MHz) δ ppm 7.32–7.28 (m, 5H, CHAr), 3.99 (s,
determined.
2H, CH2), 2.88 (s, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ
ppm 139.37 (CAr), 128.58 (2 × CHAr), 128.49 (2 × CHAr),
127.32 (CHAr), 55.85 (CH2), 35.68 (CH3).
N-Chloro-1,4-morpholine
Prepared according to the general procedure using the tube
reactor with 2 static mixers, a 6 mL reactor volume and a resi- N-Chloro-N-methyl-p-toluenesulfonamide
dence time of 4 min, 2.2 M NaOCl (aq) at 0.5 mL/min and 1 M Prepared according to the general procedures. 1) Tube reactor
morpholine in toluene at 1 mL/min. Due to the high volatility of with 4 static mixers, a 6 mL reactor volume and a residence
N-chloromorpholine and its reported instability the product was time of 3 min, 1.5 M NaOCl (aq) at 1 mL/min and 1 M
not isolated and was instead obtained as a solution in toluene N-benzylmethylamine in EtOAc at 1 mL/min. 2) CSTR with a
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Beilstein J. Org. Chem. 2015, 11, 2408–2417.
reactor volume of 50 mL, and residence time of 25 min. 1.1 M
NaOCl (aq) at 1 mL/min and 1 M N-benzylmethylamine in
toluene at 1 mL/min were used. The product was isolated for
each reactor volume by separation of the organic phase for each
reactor volume of solution and removal of the solvent by rotary
evaporation to give a white solid (1 reactor volume gives
666 mg, 3.0 mmol, quantitative yield). NMR data matches that
reported in the literature [37]. 1H NMR (CDCl3, 500 MHz) δ
ppm 7.82 (d, J = 8.4 Hz, 2H, CHAr), 7.42 (d, J = 8.4 Hz, 2H,
CHAr), 3.09 (s, 3H, NCH3), 2.48 (s, 3H, Ar-CH3); 13C NMR
(CDCl3, 125 MHz) δ ppm 145.75 (CAr), 129.80 (2CHAr),
129.78 (2 CHAr), 128.28 (CAr), 45.51 (NCH3), 21.70 (ArCH3).
Supporting Information
Supporting Information File 1
Details of the titration method for determination of NaOCl
strength, determination of amine partition coefficients, GC
analytical conditions and calorimetry.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-262-S1.pdf]
Acknowledgements
The research for this work has received funding from the Innov-
ative Medicines Initiative joint undertaking project Chem21
under grant agreement no. 115360, resources of which are
composed of financial contribution from the European Union’s
Seventh Framework Programme (FP7/2007-2013) and EFPIA
companies in kind contribution.
N-Chloro-N,N-dibutylamine
Prepared according to the general procedures. 1) Tube reactor
with 4 static mixers, a 4 mL reactor volume and a residence
time of 20 min, 2 M NaOCl (aq) at 0.1 mL/min and 1 M di-
butylamine in toluene at 0.1 mL/min. 2) CSTR with a reactor
volume of 50 mL, and residence time of 50 min. 1.1 M NaOCl
(aq) at 0.5 mL/min and 1 M dibutylamine in toluene
0.5 mL/min were used. The product was isolated for each
reactor volume by separation of the organic phase for each
reactor volume of solution and removal of the solvent by rotary
evaporation to give a colourless oil (1 reactor volume gives
8.17 g, 50 mmol, quantitative yield). NMR data matches that
reported in the literature [17]. 1H NMR (CDCl3, 300 MHz) δ
ppm 3.07–3.02 (m, 4H, 2 × NClCH2), 1.85–1.74 (m, 4H, 2 ×
NCH2CH2CH2), 1.54–1.45 (m, 4H, 2 × CH2CH3), 1.11–1.05 (t,
J = 7.4 Hz, 6H, 2 × CH3); 13C NMR (CDCl3, 125 MHz) δ ppm
64.04 (2 × CH2NCl), 30.01 (2 × CH2CH2NCl), 20.03 (2 ×
CH2(CH2)2NCl), 13.90 (2 × CH3).
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