Using iSUSTAIN to validate the chemical attributes of different approaches to the synthesis of tacn and bridged (bis)tacn ligands

Article abstract of DOI:10.1039/c6gc01896c

Using green chemistry principles, alternative approaches for the synthesis of commercially important aza-macrocyclic tacn and (bis)tacn derivatives have been investigated to determine the step average and overall efficiency of these synthetic methods. Based on analytical metrics derived from the iSUSTAIN toolkit, the Richman-Atkins route for the synthesis of tacn (1) was found to be the more efficient; however an alternate route was shown to be preferable for the synthesis of (bis)tacn (2) compounds. The outcome of this study documents the importance of rigorous analysis of synthetic procedures for such aza-macrocyclic compounds in terms of their green chemistry attributes, in order to delineate how alternative synthetic methods can be ranked, more innovative procedures selected to improve productivity and yield, and synthetic methods deployed to achieve greater levels of waste reduction, reduced use of hazardous chemicals and lower environmental impact.

Full text of DOI:10.1039/c6gc01896c

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Using iSUSTAIN™ to validate the chemical
attributes of different approaches to the synthesis
of tacn and bridged (bis)tacn ligands†
Cite this: DOI: 10.1039/c6gc01896c
C. J. Coghlan,‡ E. M. Campi, W. R. Jackson and M. T. W. Hearn*
Using green chemistry principles, alternative approaches for the synthesis of commercially important aza-
macrocyclic tacn and (bis)tacn derivatives have been investigated to determine the step average and
overall efficiency of these synthetic methods. Based on analytical metrics derived from the iSUSTAIN™
toolkit, the Richman–Atkins route for the synthesis of tacn (1) was found to be the more efficient;
however an alternate route was shown to be preferable for the synthesis of (bis)tacn (2) compounds. The
outcome of this study documents the importance of rigorous analysis of synthetic procedures for such
aza-macrocyclic compounds in terms of their green chemistry attributes, in order to delineate how
alternative synthetic methods can be ranked, more innovative procedures selected to improve pro-
ductivity and yield, and synthetic methods deployed to achieve greater levels of waste reduction, reduced
use of hazardous chemicals and lower environmental impact.
Received 12th July 2016,
Accepted 31st July 2016
DOI: 10.1039/c6gc01896c
www.rsc.org/greenchem
hazardous reagents and solvents in the manufacture and appli-
cation of chemical products.2
Introduction
Development of new green chemical approaches for the syn-
Initially, the assessment of the “greenness” of a specific
thesis of organic and inorganic compounds is now an chemical reaction was based on the use of a single Green
increasingly important part of modern chemistry. Besides the Chemistry metric, such as the atom economy (AE), the
direct commercial and economic impact, the adoption of E-factor, the effective mass yield or the mass intensity.3 More
green chemistry principles accrues a wide range of benefits, recently, the focus has shifted to the development of more
including minimisation of waste, reduction in eco-pollution, unified metrics to analyse multiple steps in a reaction
and the potential for higher yields through the use of fewer sequence, utilising the AE and E-factor as well as the stoichio-
synthetic steps. At its core, Green Chemistry encompasses metric factor (SF) and reaction mass efficiency (RME).4,5
atom efficiency, energy conservation, waste minimisation and Further development of unified metric concepts has led to the
the use of safe and renewable reagents and solvents. The inclusion of a material recovery parameter (MRP) which, when
twelve principles of Green Chemistry, eloquently defined over combined with the above parameters, enables each reaction
20 years ago by Anastas and Warner in their seminal text1 have sequence to be graphically represented as pentagons whose
been concisely transcribed into the frequently quoted dictum: data depend on the degree of recovery of solvents and auxiliary
Green chemistry efficiently utilizes (preferably renewable) raw materials. Combinations of these data and graphical represen-
materials, eliminates waste and avoids the use of toxic and/or tations with relevant synthesis trees or plans has provided an
avenue to achieve improved assessment of the “greenness” of
chemical reaction strategies, often presented as radial hexa-
gons.6 Moreover, inclusion of environmental impact para-
meters, based on “benign indices”, coupled with radial
Centre for Green Chemistry, School of Chemistry, Monash University, Clayton, VIC,
3800, Australia. E-mail: milton.hearn@monash.edu
†Electronic supplementary information (ESI) available: The ESI and Appendix A
pentagram analysis (with the results also presented as hexa-
includes: 1. Supplementary experimental procedures: This section provides the
grams) provides a de novo way to achieve a more comprehen-
essential information related to the experimental synthetic procedures required
sive assessment of the “greenness” of particular synthesis
plans.
The power of such approaches has been demonstrated for
systems such as the 2 step routes to phenol and aniline and
also from phenol to aspirin.7 Moreover, these approaches
enable greater emphasis to be placed on safety, as well as
to be able to input the data into the iSUSTAIN toolkit and allow analysis of the
reactions. 2. An Appendix showing overall the synthetic routes and associated
spreadsheets for the consolidated iSUSTAIN data. 3. Compiled tables of results
and associated excel spreadsheets for preparation of spider charts for compari-
sons of the different synthetic routes. See DOI: 10.1039/c6gc01896c
‡Present address: School of Chemistry and Physics, Centre for Advanced Nano-
materials, The University of Adelaide, Adelaide, SA, 5005, Australia.
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economic and ecological drivers. The impact of these classes) and the process steps (including temperature, time,
approaches on life cycle analysis has been exemplified in a equipment count and the number of steps that involve
variety of case study reports, mainly from the chemical and addition or removal of materials). The process control and
pharmaceutical industry with the results depicted as penalty reaction safety are also analysed through a series of iterative
points (EcoScale)8 or hexagons (BASF).9 Various companies questions to determine the levels of hazard associated with the
have further developed methods to suit their specific needs. reaction. Once the data are entered each variable is analysed in
For example, GlaxoSmithKline have developed a guide for terms of a series of metrics (based on a mathematical formal-
green solvent selection,10
(FLASC™)11 and a comprehensive guide for reagent selection 12 principles of Green Chemistry.
a life cycle assessment tool ism to assess the extent of sustainability) aimed at each of the
(based on reaction class) which summarises their strategies for
The use of iSUSTAIN™ has been advocated in circum-
sustainable practices.12 Similarly, Pfizer Inc. has developed stances linking Green Chemistry and Sustainability as a
solvent and reagent selection guides based on Green Chem- research and development tool19–23 The deployment of the
istry concepts13 while a tool called “Eco-footprint” has been iSUSTAIN™ toolkit, along with a discussion of the metrics,
developed to assess the impact of both manufacturing and specifically developed for its use and their inherent assump-
eco-design parameters, the results being displayed as spider- tions, have been described by Koster and Cohen.24 employing
web charts.14 In addition to such individual company strat- an esterification reaction as exemplar, to illustrate the use of
egies, general strategies have been suggested for medicinal the iSUSTAIN toolkit. A related system called “Green Star” has
chemists.15 Another novel process performance metric has been developed by Ribeiro, again scoring against each of the
been proposed recently by Roshangar to quantify the environ- 12 principles, but with a focus on relatively simple reactions
mental impact of producing a specific pharmaceutical target for the purpose of teaching laboratory experiments.25 The
product.16 The key metrics focus on the impact of E-factors nature of the trade-offs that need to be recognised when
and process complexity with the aims to ensure that compari- iSUSTAIN™ is employed has been highlighted through com-
sons related to “relative process greenness” are meaningful.
parison between the production of lactic acid by either a
Recently, Clark and co-workers have brought all of the chemical route from acetaldehyde or from a fermentation
above methodologies and analytical techniques together into a route from a carbohydrate in water.21 The former, using
“holistic” approach to metrics for the pharmaceutical indus- acetaldehyde and HCN is by far less benign in every aspect as
try.17 A comprehensive toolkit has been proposed to measure shown by iSUSTAIN™, however the fermentation process is
the “green credentials” of existing and new synthetic tech- significantly more energy intensive.
niques. The methodology involves a hierarchy of web-based
With regard to multi-step synthesis of heterocyclic com-
toolkits from zero pass (screening reactions) and first pass pounds, there have however not been any comprehensive
(promising reactions) to pilot scale then third pass (manufac- reports to date of the use of freely available tools, such as the
turing scale) with green, amber and red flags assigned to each iSUSTAIN™ toolkit, to evaluate (against the 12 principles of
of the criteria assessed. The first two levels focus on classical Green Chemistry) reactions in a complex synthesis pathway
Green Chemistry metrics (yield, AE, RME), the choice of sol- involving several steps, as well as alternative routes to the
vents and health and safety issues (i.e. hazardous chemicals/ target compounds. This article reports new findings relevant
solvents). The first pass level also focuses on the use of cata- to the use of the iSUSTAIN™ toolkit with such compounds,
lysts, use of critical elements (i.e. risk of depletion), energy with the task logic exemplified with an important class of aza-
consumption, availability of reagents and general applicability macrocycles of wide application utility.
of transformations. One key aim of this toolkit is to act as an
educational tool for the use of green and sustainable and its bridged analogues, (bis)tacn (2), have a broad range of
chemistries. applications in biomimetic and catalytic systems such as syn-
Aza-macrocycles, such as 1,4,7-triazacyclononane (tacn) (1)
The iSUSTAIN™ toolkit was developed for just this purpose thetic laccases and nucleases due to their ability to co-ordinate
by Cytech Industries, Sopheon and John Warner at Beyond multiple metal ions.26–30 They have application as chelating
Benign18 and has been available on line since 2010.19 The agents, magnetic resonance imaging (MRI) contrast reagents
inputs for this generally applicable assessment tool are the and NMR shift reagents.26,31,32 They exhibit high stability con-
process data for 12 metrics which are waste prevention, atom stants for transition metals such as divalent copper, nickel
economy, safe raw materials, product, solvents and process, and zinc ions, with the bridged (bis)tacn ligands having values
energy efficiency, renewables, catalysis, biodegradability, >10.33–35 These ligands have also found application in
process control, and process complexity. The output of the protein purification using immobilised metal affinity chrom-
program is 12 separate scores (from 0 to 100) for these atography (IMAC)36–38 and in the modelling of enzyme active
12 metrics based on Green Chemistry principles, with the data sites.30,39,40 We have recently reported the use of both tacn (1)
presented as a spider graph. The scores for each principle are and (bis)tacn (2) as ligands for the more benign and efficient
based upon user input, with information required for the purification of tagged recombinant proteins using IMAC.41,42
materials employed in the specific reactions (in terms of mass,
Conceptually, the synthesis of tacn (1) and (bis)tacn com-
percentage recovered and reusability percentages), all products pounds (2) can be achieved in several ways, using different
and by-products produced in the reaction (mass and weight starting materials, reagents and conditions. This makes the set
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of reactions an ideal target for analysis using the iSUSTAIN™ compounds (2). Using the iSUSTAIN™ toolkit, analysis of the
toolkit. The scores against each of the 12 principles of Green performance of the reactions against the 12 principles of
Chemistry make it possible to accurately assess the strengths Green Chemistry was carried out and the results are shown in
and weaknesses of the attributes of each reaction procedure. the tables and Fig. 1–3 below. Additional supporting infor-
They also provide in-depth information about each particular mation is found in the ESI and Appendix A.†
reaction enabling comparison of the “greenness” of several
In order to input all relevant data, several assumptions had
alternative methods to produce the same target products. To to be made. Since not all of the synthesised compounds had
document the utility of the iSUSTAIN™ toolkit in the synthesis full eco-toxicological or risk data available, a close compound
of heterocyclic compounds, we report, herein, a strategy that analogue was thus chosen. For example, since the eco-toxico-
can be followed to evaluate reactions in alternative pathways logical data for tri(tosyl)tacn (4) was not available, related data
involving several step syntheses of the target products, tacn (1) for 1,4,7,10-tetratosyl product (1,4,7,10-tetraazacyclododecane
and the (bis)tacn compounds (2).
(tos4cyclen)) was employed as these two compounds have
octanol–water partition coefficient log P values of similar mag-
nitude. Similarly, α,α′-dibromo-m-xylene was used for the ana-
lysis of the reactions 9 and 12 with the intermediates (10) and
(12) respectively, whilst 1,3-diaminopropane was used for reac-
tion 14 via the intermediate (14). Additionally, as the amount
of each recovered solvent was ≥80%, this value was employed.
A more detailed discussion follows below with all input data
and related information found in the ESI and Appendix A.†
Results and discussion
Retrosynthetic analysis for target A, tacn (1) and target B, the
bridged (bis)tacn (2) (Scheme 1) shows that both compounds
conceptually can be prepared from either the amine (3) or the
amino alcohol (6). The reaction scheme (Scheme 2) outlines in
detail the various synthetic routes for tacn (1) and the (bis)tacn
Scheme 1 Retrosynthetic analysis for the two target molecules, tacn
(1) and the bridged (bis)tacn (2) compounds.
Fig. 1 Average scores for the preparation of tacn (1) using method 1
(Richman–Atkins route) and method 2 (alternate route).
Scheme 2 Summary of synthetic routes to tacn (1) via the Richman–Atkins route from (3) or the alternative route from (6) and to the (bis)tacn com-
pounds (2) via tacn orthoamide (10), Boc2tacn (12) or the tetratosyl compound (7).
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Tacn synthesis (Richman–Atkins route; reactions 1–3)
Tacn (1) is commonly synthesised by the Richman–Atkins
route43,44 shown in Scheme 2. Refinements to this method in
this laboratory have led to a one-pot procedure involving con-
current tosylation of the three amino groups of diethylene–tri-
amine (3), followed by cyclisation using 1,2-dibromoethane,
which gave in our hands at the 0.35 mol scale, a 66% yield of
tri(tosyl)tacn (4). The tri(tosyl)tacn (4) was detosylated in a
subsequent step using the conventional concentrated sulphu-
ric acid method43,44 with the product then converted to the 3
HCl salt of tacn (5) in 80% yield. The tacn free base (1) was
then isolated in 72% yield. The overall yield of tacn (1) from di-
ethylenetriamine (3) was 38%.
Through use of the iSUSTAIN™ toolkit, each synthesis step
of the Richman–Atkins route to tacn (1) from (3) was assessed
for its total sustainability and efficiency. The results are shown
in Table 1 and the average scores illustrated in the spider chart
shown in Fig. 1. The reactions were assessed by their average
scores and their overall efficiency. An example of this assess-
ment is illustrated by the ‘safe solvent’ principle. Steps 1 and 2
both use ‘safe solvents’, e.g. water and toluene, and have
efficiency scores of 80 and 85 respectively. The third step,
however, only had an efficiency score of 50. This outcome
leads to an average efficiency score of 72, but when the
efficiency scores are multiplied together they gave an overall
efficiency percentage of 34%. Clearly, the overall efficiency
would be improved by replacing the solvent (toluene) with an
even safer solvent.
Fig. 2 Average scores for the preparation of (bis)tacn compounds (2)
using method 1 (from tacn (1) via tacn orthoamide (10)), method 2 (from
tacn (1) via Boc2tacn (12)), and method 3 (alternate route from the
aminoalcohol 6).
The relatively poor atom economy of the Richman–Atkins
reaction sequence is the result of the need to use reagents in
excess and the need for multiple tosyl protection and de-
protection steps, which are required to avoid high dilution
conditions or the use of metal templating procedures if a
product in acceptable purity and yield is to be obtained. These
constraints also impact upon the renewability of the reaction
Fig. 3 Average scores for the preparation of (bis)tacn (2) using method
1 (from diethylenetriamine (3) via tacn (1) and tacn orthoamide (10)); or
using method 2 (from diethylenetriamine (3) via tacn (1) and Boc2tacn
(12)), and via method 3 (alternate route from the aminoalcohol (6)).
Table 1 iSUSTAIN scores for the two synthetic routes to tacn (1): steps 1–3 for Richman–Atkins route are for reactions 1–3, Scheme 2 and steps
1–5 relate to the alternate route and are for reactions 4–7 and reaction 3, Scheme 2
Richman–Atkins route to tacn (1)
Alternate route tacn (1)
Steps
Steps
Average
Overall
Average
Overall
Principles
1
2
3
efficiency (/100) efficiencya (%)
1
2
3
4
5
efficiency (/100) efficiencya (%)
Waste prevention
Atom economy
Safe raw materials
Safe product
Safe solvents
Energy efficiency
Renewables
70
55
85
25
80
0
55 75 67
20 27
75 80 80
50 50 42
85 50 72
29
1
51
6
34
0
0
55
65
85
25
80
35
0
80
40
55
25
75
0
65
75
50
25
40
100
0
55 75 66
20 41
75 80 82
50 50 35
85 50 66
12
0
37
0
10
0
0
5
5
0
0
0
0
0
0
0
0
0
0
27
0
0
0
Process complexity
Catalysis
Biodegradability
Process control
Safe process
55
85
10
40 70 55
28
75 75 53
15
0
6
80
58
12
30
0
25
75
0
25
40
75
25
40 70 51
15
75 75 45
3
0
1
80
39
3
0
0
0
0
100 100 80 93
80
54
100 100 100 100 80 96
90
49
90 80 83
48 48 50
85
47
70
55
90 80 83
48 48 51
Score
a The overall efficiency percentages are the product of the scores for steps 1–3 for the Richman–Atkins route and steps 1–5 for the alternate route.
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materials, as many of these reagent materials cannot be detosylation of 4; again both steps would benefit from the use
readily recovered after the reaction is completed. Obviously, of a catalyst.
solvents are easier to recover and recycle than spent chemical
The low overall energy efficiency score of this sequence is
solids, however a balance must be achieved since recovering mainly associated with the cyclisation step, the detosylation
multiple litres of water used in the first step, for example, may step and the conversion of the tacn salt to the free base 1
not be desirable from an energy consumption point of view. In (these steps all had a score of zero). The first step requires
the second and third steps of this Richman–Atkins route, no maintaining the reaction at 0 °C for two hours, which only
catalysts were utilised. However, the detosylation of 4 to give incurs a minor penalty, and the third step, the conversion of 8
the HCl salt 5 requires heating 4 for three days at 120 °C using to 9, is carried out at room temperature overnight and does
an excess of concentrated H2SO4. If a suitable recyclable cata- not incur any penalty. These results, however, do not discrimi-
lyst were to be employed, such as the poly(vinylsulfonic acid)- nate between the energy inputs required for holding the reac-
grafted solid acid catalysts,45 it could possibly decrease the tion at 90 °C for 4 days for the synthesis of the tri(tosyl)tacn
thermal input (as heat) required and the time, which would (4) (route 1) or the reflux for 6 h required for route 2. Thus, the
lead to an increase in productivity. This conclusion reflects the tosylation and cyclisation steps using this alternate route 2
strength of iSUSTAIN™ as it actively points out where a reac- required a reaction at 0 °C for two hours and a reaction in
tion sequence can be improved.
acetonitrile at reflux for only six hours, and thus are much less
The average efficiency score of the Richman–Atkins reaction energy intensive than 90 °C for four days.
sequence based on each of the Green Chemistry metrics of
If the various steps are considered individually, the
“atom economy”, “energy efficiency”, “renewables” and “cataly- efficiency scores of the 5 steps in this alternate pathway are 49,
sis” was less than 30. In contrast, the average efficiency score 46, 55, 48 and 48, respectively, with an average efficiency score
based on each of the Green Chemistry metrics of “safe raw of 50. This is the same average score as found using the
materials”, “safe solvents”, “process control” and “safe Richman–Atkins route to 1. However, the overall synthesis has
process” was more than 70. If each step is considered individu- only a efficiency percentage of 3% which is significantly lower
ally, the efficiency score for the first step in the pathway was than 12% found for the previous method. This outcome can
54, whilst the second and third steps both scored 48, with an be attributed to the extra steps required for this reaction
average efficiency score of 50. The overall efficiency was then pathway, five steps versus three for the Richman–Atkins
determined from the product of these values (similar to the method, which uses a one-pot method for the synthesis of
determination of the overall yield of a synthetic pathway). tri(tosyl)tacn (4). However, the alternative method 2 has the
Based on this assessment, the overall efficiency percentage for advantage of generating the di(tosyl) compound 9, which has
the Richman–Atkins synthetic route to tacn (1) was thus 12%.
a single free –NH group which can be further functionalised.
(Bis)tacn synthesis
Tacn synthesis via an alternate route; (reactions 3 and 4–7)
Synthesis of (bis)tacn compounds (2) from tacn (1) (reac-
An alternate method for the preparation of tacn (1) is shown in tions 8–10 or reactions 11–13). The first method (reactions
Scheme 2, and involves the tosylation of compound 6 (75% 8–10) for the synthesis of the (bis)tacn compounds used
yield) followed by ring closure with benzylamine to give the the tricyclic orthoamide,48,49 (1,4,7-triazatricyclo[5.2.1.04,10
]
N-benzyl-di(tosyl)tacn (8) (62% yield).46,47 Reductive elimin- decane, (10)) as the precursor for the bridged compounds
ation of the benzyl group gave di(tosyl)tacn (9) in 92% yield, (Scheme 2). The orthoamide, produced in 64% yield from tacn
which was detosylated to give the hydrochloride salt of tacn (5) (1), was allowed to react with the dihalide 15 to produce the
in 84% yield. The overall yield of tacn (1) was 26%. The bis(amidinium) salt 11. There are two methods to convert the
di(tosyl) compound 8 is a particularly useful intermediate bis(amidinium) salt 11 to the desired (bis)tacn salt 2, the first
since two of the nitrogen groups are protected by tosyl groups, being a hydrolytic workup with NaOH, resulting in isolation of
allowing the remaining free –NH group to be selectively func- the (bis)tacn as the free base. The second method converts the
tionalised. A further advantage of the di(tosyl) compound 8 is bis(amidinium) salt 11 to the corresponding HCl salt in a
that it can also be reacted with a bi-functionalised bridging single step after reflux in concentrated HCl overnight. The tacn
group to give a tosyl-protected (bis)tacn such as compound 14 orthoamide (10) route to (bis)tacn compounds is a commonly
(reaction 9 in the scheme).
used route49 and usually generates high yields of the salt,
The iSUSTAIN™ toolkit was used to evaluate this alternative greater than 70%. The dihalides used in step 2 of this route
reaction sequence against the 12 principles of Green Chem- were the 1,2-, 1,3- and 1,4-α,α′-dibromo-xylenes as well as ana-
istry. The results are shown in Table 1 and the average scores logues of the 1,3- compound with substituents in the aromatic
illustrated in the spider chart Fig. 1. Prominent weaknesses ring. The 6 HCl salts of the (bis)tacn compounds 2 were
associated with this synthetic pathway are the metrics for obtained in our hands with yields in the range of 52–75%,
energy efficiency, and the lack of renewables and a suitable cat- with overall yields of 33–48% from tacn (1).
alysis, which all showed an average efficiency score less than
The second method involves selective protection of two of
30. The detosylation step of 9 to 5 requires the same reaction the secondary amine groups of the tacn (1) with Boc groups,
conditions as used in the Richman–Atkins method for the giving Boc2tacn (12) in 54% yield. The reaction also gives a
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small amount of the fully protected compound, Boc3tacn
(18%), but this is easily separated from the target product
using a citric acid wash workup. Di-protection is useful as it
prohibits the bridging compound, a dihalide 15, from binding
more than once to a single tacn or multiple ligands binding to
the same tacn molecule. This method also involves a simpler
workup as conversion to the HCl salt and removal of the Boc
groups are carried out in a single step without reflux to give
the desired (bis)tacn salt 2.50 The dihalides used in step 2 of
this route were 1,3-α,α′-dibromo-o-xylenes with substituents in
the aromatic ring. The 6 HCl salts of the (bis)tacn compounds
2 were obtained in 48–78% yield, with an overall yield of
26–42% from tacn (1). It is also possible to use the tos2tacn (9)
as described above but the resulting (bis)tacn compound 14
will now have tosyl protecting groups, which require harsh
removal conditions as described previously for the synthesis of
the tacn salt 5.
The iSUSTAIN™ toolkit was again used to assess various
reaction sequences against the 12 principles of Green Chem-
istry. The results are shown in Table 2 with the average scores
illustrated as the spider chart (Fig. 2). The synthesis of tacn
orthoamide (10) uses safer solvents and is a less complex
method than the synthesis of Boc2tacn (12) which, however, is
far more energy efficient, more efficient in terms of waste pre-
vention and atom economical. The average score for the first
step in the two routes is slightly higher for the Boc2tacn (12)
product (59 compared to 50). In comparison, preparation of
the bridged (bis)tacn is more efficient from tacn orthoamide
(10), with the average score being 55 compared to 48 from
Boc2tacn (12). Moreover, the former route is more atom econo-
mical, uses safer solvents and has less process complexity.
Overall, when comparing the routes from tacn orthoamide
(10) and from Boc2tacn (12), the main differences are that the
Boc2tacn (12) route is more complex (average efficiency score
28 compared to 58) but is more energy efficient (average
efficiency score 48 compared to 0). However, the score for
average efficiency on the “green-ness” scale of each 2 step
route is 53 for both routes, and the overall efficiency of these
two routes is also identical (28% efficient). Combining this
result with the highest overall score for the synthesis tacn (1)
described above (method 1, 12%), the overall efficiency score
for the preparation of (bis)tacn (2) from diethylenetriamine (3)
was approximately 3% (see below).
(Bis)tacn compounds (2) synthesis using alternate route
(reactions 4, 14, 15). A third alternate method47 for the prepa-
ration of (bis)tacn compounds is shown in Scheme 2. The tosy-
lated compound 7 was used to prepare the tosyl-protected
bridged compound 14. Here, ring closure is achieved using the
diamino-compound 16, which also builds in the bridge in the
same step. This method requires heating under reflux for 10
days,46 however this time frame can be improved using micro-
wave techniques. The tosyl-protected alkyl bridged (bis)tacn
compounds 14 were prepared in 71–81% under the standard
conditions. The use of microwave heating was investigated
with these bridges and found to be successful. Reaction at
160–180 °C for 20 to 40 minutes gave the tosyl-protected
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(bis)tacn compounds 14 in 56–91% yield. Detosylation gave the alternate method is far more efficient than either the tacn
the 6 HCl salts of the (bis)tacn compounds 2 in 76–90% yield, orthoamide (10) or Boc2tacn (12) methods due to the efficiency
with a yield of 56–71% for the two steps. The overall yield of cost associated with making these compounds.
(bis)tacn (2) from the linear starting material 6 was 47–59%.
The benefit of this type of green chemical analysis is that it
The results from this iSUSTAIN™ analysis are shown in clearly demonstrates where reaction improvements can be
Table 2 with the average scores illustrated in the spider chart made. In the case of the synthesis of tacn (1), the removal of
Fig. 2. This method does not perform well in terms of the the tosyl groups required in both methods would benefit
energy efficiency, renewables, process complexity and the cata- greatly from the availability of a recyclable catalyst, and this
lysis categories. The low energy efficiency is due to the need to would lead to increased energy efficiency and potentially a
reflux at high temperatures for long periods of time for both greater atom economy. A substitute for the tosyl group which
the cyclisation step (reaction 14) and the detosylation step could be more easily removed would also be beneficial.
(reaction 15). The energy score for the 10 day reflux for step 2
can be improved from 0 to 60 by using microwave heating. The
use of a catalyst for these reactions to reduce reaction time and
heat requirements would be beneficial for steps 2 and 3.
Acknowledgements
The synthetic route to (bis)tacn compounds from com- Financial support from Novo Nordisk A/S and from the Austra-
pound 6 performs well in the safe solvent, process control and lian Research Council for Linkage Grant funding which
safe solvent categories in comparison to the other methods. included a scholarship (to CJC) is gratefully acknowledged.
However, the 10 day reflux step drops the energy efficiency
rating significantly. The main advantage of this method is that
it only requires three steps from starting material to final
product, with the steps having a green efficiency score of 49,
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