Photocatalyic Appel reaction enabled by copper-based complexes in continuous flow

Article abstract of DOI:10.3762/bjoc.14.251

A copper-based photocatalyst, Cu(tmp)(BINAP)BF₄, was found to be active in a photoredox Appel-type conversion of alcohols to bromides. The catalyst was identified from a screening of 50 complexes and promoted the transformation of primary and secondary alcohols to their corresponding bromides and carboxylic acids to their anhydrides. The protocol was also amendable and optimized under continuous flow conditions.

Full text of DOI:10.3762/bjoc.14.251

Photocatalyic Appel reaction enabled by copper-based
complexes in continuous flow
Clémentine Minozzi, Jean-Christophe Grenier-Petel, Shawn Parisien-Collette
and Shawn K. Collins*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2730–2736.
Department of Chemistry and Centre for Green Chemistry and
Catalysis, Université de Montréal, CP 6128 Station Downtown,
Montréal, Québec, H3C 3J7, Canada
doi:10.3762/bjoc.14.251
Received: 09 July 2018
Accepted: 12 October 2018
Published: 30 October 2018
Email:
Shawn K. Collins* - shawn.collins@umontreal.ca
This article is part of the thematic issue "Reactive intermediates part I:
radicals".
* Corresponding author
Keywords:
Guest Editor: T. P. Yoon
Appel; continuous flow; copper; halides; photocatalysis
© 2018 Minozzi et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A copper-based photocatalyst, Cu(tmp)(BINAP)BF4, was found to be active in a photoredox Appel-type conversion of alcohols to
bromides. The catalyst was identified from a screening of 50 complexes and promoted the transformation of primary and secondary
alcohols to their corresponding bromides and carboxylic acids to their anhydrides. The protocol was also amendable and optimized
under continuous flow conditions.
Introduction
Synthetic photochemistry and photocatalysis continues to influ- ported that photocatalysis could be used to promote the
ence molecular synthesis [1-4]. In exploring photochemical re- alcohol→halide conversion using low catalyst loadings of a ru-
activity manifolds, there exists the potential to discover new thenium-based catalyst (Ru(bpy)3Cl2, 1 mol %) in the absence
methods to construct important molecular fragments, as well as of PPh3 as a reductant (Figure 1) [8]. The method possesses nu-
revamp traditional chemical transformations. One such process merous advantages (wide functional group tolerance, no forma-
is the Appel reaction [5], which employs PPh3 and an electro- tion of oxidized phosphine byproducts [9-14], mild reaction
philic halogen source to promote the formation of an organic conditions and visible-light irradiation), which should be easily
halide from the corresponding alcohol (Figure 1) [6,7]. The embraced by the synthetic community. To further develop the
Appel reaction is representative of a host of transformations that photochemical alcohol→halide transformation, the use of alter-
require stoichiometric reagents to effect a functional group native photocatalysts based upon more abundant metals
change of an alcohol. In 2011, Stephenson and co-workers re- was envisioned [15-18]. Specifically, our group has demon-
2730

Beilstein J. Org. Chem. 2018, 14, 2730–2736.
strated that heteroleptic Cu(I) complexes [19-21] have signifi-
cant potential as photocatalysts that can promote a variety of
mechanistically distinct photochemical transformations includ-
ing single electron transfer (SET), energy transfer (ET), and
proton-coupled electron transfer (PCET) reactions [22-26].
Herein, the evaluation of Cu(I)-complexes for photocatalytic
Appel reactions and demonstration in continuous flow is de-
scribed.
Results and Discussion
The first step in identifying a heteroleptic diamine/bisphos-
phine Cu(I)-based photocatalyst for the conversion of an
alcohol to bromide involved screening a wide variety of struc-
turally varied complexes. Our group has previously demon-
strated that the nature of each ligand influences the physical and
photophysical properties as well as catalytic activity of the re-
sulting catalyst (Figure 2) [27].
A library of 50 different catalysts was evaluated in the conver-
sion of alcohol 1 to bromide 2 (Figure 2 and Figure 3). Several
homoleptic complexes were not evaluated due to problematic
Figure 1: Alcohol→bromide functional group transformations.
Figure 2: Ligands used in the library generation of heteroleptic copper(I)-based complexes for photocatalysis.
2731

Beilstein J. Org. Chem. 2018, 14, 2730–2736.
Figure 3: Evaluation of the library of copper-based complexes in photocatalytic alcohol→bromide conversion. Reactions irradiated with 394 nm light
(pink) or 450 nm (blue). Front entries without an indicated phosphine ligand pertain to homoleptic Cu(diamine)2BF4 complexes and are colored in
lighter blue. Entries without a color indicate reactions which could not be performed due to solubility or overoxidation of the complex.
oxidation or low solubility. Reactions were irradiated at either modest yields. Also, BINAP and Xantphos-based catalysts
394 nm (purple LEDs) or 450 nm (blue LEDs), depending on tended to afford higher yields of 2, while amongst the diamines,
the UV–vis absorption characteristics of the photocatalysts [28]. the triazole-based complexes were almost all efficient at provid-
Stephenson and co-workers had previously reported that a pri- ing 2 (54–87% yield, not including dppf-based complexes).
mary alcohol structurally similar to 1 underwent conversion to Interestingly, the best catalyst for the transformation
the corresponding bromide in 96% yield upon irradiation in the (Cu(tmp)(BINAP)BF4, 99% of 2) was a poor catalyst for a pre-
presence of Ru(bpy)3Cl2 (1 mol %). The screening for a suit- viously reported photoredox reaction [27]. It should be noted
able copper-based catalyst was performed under identical reac- that Cu(tmp)(BINAP)+ possesses an excited state reduction
tion conditions whereby the Ru-based photocatalyst was substi- potential of −1.93 V vs. SCE, much greater than that of
tuted for the Cu-based complex. Control reactions performed in Ru(bpy)3+2 (−0.81 V vs SCE), albeit the copper complex has a
the absence of light or in the absence of catalyst at either 394 or much shorter excited state lifetime (≈4 ns vs ≈1100 ns for
450 nm revealed no conversion to the bromide. From the Ru(bpy)3+2). The excited state reduction potential should match
results, none of the homoleptic complexes promoted the favorably with CBr4 (E½ = 0.30 V vs SCE) in DMF [29]. Note
alcohol-to-halide conversion (1→2, see the light blue entries in that many of the corresponding homoleptic copper-based
the front row of Figure 3). While many of the heteroleptic com- sensitizers were ineffective at promoting the Appel-type reac-
plexes promoted the reaction, some trends were apparent. In tion.
general, amongst the phosphines the dppf-based complexes
were poor catalysts, while when considering the diamine With conditions in hand for the formation of the bromides, dif-
ligands the dq and bathophenthroline catalysts provided poor to ferent alcohols were converted to their corresponding halides
2732

Beilstein J. Org. Chem. 2018, 14, 2730–2736.
(Table 1). As shown previously, a benzyl-protected alcohol 1
could be transformed to the corresponding bromide 2 in 99%
yield, respectively (Table 1, entry 1). The corresponding bro-
mide of citronellol (4) was also formed in high yield (91%,
Table 1, entry 2). A long chain methyl ester 5 was also toler-
ated under the reaction conditions (98% of the bromide,
Table 1, entry 3). The corresponding dibromide could be
formed from 1,9-nonadiol (6) in quantitative yield (99%,
Table 1, entry 4). A sulfur-containing alcohol 7 was smoothly
converted to its bromide in 99% yield (Table 1, entry 5). An
allylic alcohol 8 having a cis-olefin underwent alcohol-to-halide
conversion in 89% yield and was isolated as a 1:1 mixture of cis
and trans isomers (Table 1, entry 6). Finally, a racemic second-
ary alcohol 9 was easily transformed to the corresponding
racemic bromide (99%, Table 1, entry 7).
Table 1: Photocatalytic conversion of alcohols to bromides in batch.
entry
1
alcohol
yield (%)a
99
1
4
2
91
Following the optimization of the catalyst structure and explo-
ration of scope, the batch reaction conditions were then trans-
ferred to continuous flow (Table 2). Initially, an experimental
set-up using a previously reported reactor for purple LEDs was
selected for the reaction [30,31]. Following injection of the
reaction mixture with a target residence time of 60 min, only
traces of the desired bromide 2 were observed. Extending the
residence time to 120 or 240 min increased the yield to
32–53%, but significant quantities of the starting alcohol 1 and
the corresponding formate ester 3 were observed. Using tetra-n-
butylammonium bromide (TBAB) as the halide source did not
improve the yield, but resulted in larger amount of the formy-
3
4
5
5
6
7
98
99
99
6
7
8
9
89b
99
aYield determined by isolation via chromatography. bIsolated as a
1:1 mixture of cis and trans isomers.
Table 2: Photocatalytic conversion of alcohol 1 to bromide 2 in continuous flow.
entry
halide source
Tres (min)
flow rate (μL/min)
recovered 1 (%)a
yield 2 (%)a
yield 3 (%)a
1
2
3
4
5
NaBr
NaBr
NaBr
TBAB
NaBr
60
216
110
54.2
110
110
89
47
45
–
<5
53
<5
–
120
240
240
240
32
23
63
–
21
–
91(83)b
aYield determined by analysis of 1H NMR. bYield determined by isolation via chromatography.
2733

Beilstein J. Org. Chem. 2018, 14, 2730–2736.
lated product 3 (Table 2, entry 4). A possible explanation for
the increased yield of 3 when using TBAB could be due to
slower displacement of leaving group by the “bulkier” source of
bromide. In attempting to extend the residence time, the flow
rate of the reaction mixture was decreased. Knowing that faster
flow rates can improve mixing and reaction rates [32], an addi-
tional reactor was placed in line and the residence time of
240 min was repeated but with an increased flow rate
(110 μL/min, Figure 4 and Table 2 entry 5). Gratifyingly, the
desired bromide 2 was isolated in 91% yield.
Table 3: Photocatalytic conversion of alcohols to bromides in continu-
ous flow.
With optimized flow conditions in hand for the formation of
bromides in continuous flow, five different alcohols were con-
verted to their corresponding halides (Table 3). The benzyl-pro-
tected alcohol 1 could be transformed to the bromide in
83% yield (Table 3, entry 1), as was citronellol (4, 83% yield,
Table 3, entry 2). A methyl ester 5, allylic alcohol 8 and
racemic secondary alcohol 9 could all undergo conversion to
their corresponding bromides in 240 min using the continuous
flow protocol (Table 3, entries 3 to 5).
entry
1
alcohol
yield (%)a
83
1
4
2
83
The continuous flow protocol was also applicable to the synthe-
sis of anhydrides, which has also been previously reported by
Stephenson and co-workers [33]. The carboxylic acid 10
was submitted to a flow protocol using the optimized
Cu(tmp)(BINAP)BF4 catalyst, CBr4 (1 equiv) and 2,6-lutidine
as base with a residence time of 20 min (Scheme 1). The an-
hydride derived from p-methoxybenzoic acid was isolated in
90% yield.
3
4
5
8
85
86
5
9
86
aYield determined by isolation via chromatography.
Figure 4: Experimental set-up for the photocatalytic conversion of alcohols to bromides. PFA tubing is wrapped around purple LEDs (394 nm) and
fans are placed underneath reactors to maintain cooling.
2734

Beilstein J. Org. Chem. 2018, 14, 2730–2736.
Scheme 1: Copper-based photocatalysis for photocatalytic synthesis of an anhydride.
2. Albini, A.; Fagnoni, M., Eds. Handbook of Synthetic Photochemistry;
Wiley-VCH: Germany, 2010.
Conclusion
In summary, a heteroleptic copper-based photocatalyst
Cu(tmp)(BINAP)BF4 was discovered for the photochemical
Appel-type conversion of alcohols to bromides, as well as
carboxylic acids to their anhydrides. The protocol was highly
efficient and could be adapted to continuous flow using purple
LED reactors. The batch and continuous flow processes were all
made possible due to the ability to screen highly modular
copper-based complexes for photocatalysis.
3. Rackl, D.; Kreitmeier, P.; Reiser, O. Green Chem. 2016, 18, 214–219.
doi:10.1039/C5GC01792K
4. Lima, C. G. S.; de M. Lima, T.; Duarte, M.; Jurberg, I. D.; Paixão, M. W.
ACS Catal. 2016, 6, 1389–1407. doi:10.1021/acscatal.5b02386
5. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801–811.
doi:10.1002/anie.197508011
6. Weiss, R. G.; Snyder, E. I. Chem. Commun. 1968, 1358–1359.
doi:10.1039/C19680001358
7. Weiss, R. G.; Snyder, E. I. J. Org. Chem. 1971, 36, 403–406.
doi:10.1021/jo00802a009
8. Dai, C.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat. Chem. 2011,
3, 140–145. doi:10.1038/nchem.949
Supporting Information
9. Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; John
Wiley & Sons, 1999; p 689.
Supporting Information File 1
Experimental details and compound characterization.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-251-S1.pdf]
10.Fujisawa, T.; Iida, S.; Sato, T. Chem. Lett. 1984, 13, 1173–1174.
doi:10.1246/cl.1984.1173
11.Mukaiyama, T.; Shoda, S.-i.; Watanabe, Y. Chem. Lett. 1977, 6,
383–386. doi:10.1246/cl.1977.383
12.Benazza, T.; Uzan, R.; Beaupère, D.; Demailly, G. Tetrahedron Lett.
1992, 33, 4901–4904. doi:10.1016/S0040-4039(00)61228-5
13.Benazza, T.; Uzan, R.; Beaupère, D.; Demailly, G. Tetrahedron Lett.
1992, 33, 3129–3132. doi:10.1016/S0040-4039(00)79831-5
14.Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131,
13930–13931. doi:10.1021/ja906520p
Acknowledgements
The authors acknowledge the Natural Sciences and Engi-
neering Research Council of Canada (NSERC), the NSERC
CREATE program in Continuous Flow Science, the Canadian
Foundation for Innovation for financial support for continuous
flow infrastructure and the Centre in Green Chemistry and Ca-
talysis (CGCC) for funding. Ms. Vanessa Kairouz is thanked
for assistance with the continuous flow infrastructure.
15.Zhao, Y.; Antonietti, M. ChemPhotoChem 2018, 2, 720–724.
doi:10.1002/cptc.201800084
See for an alternative route to convert alcohols to iodides in the
absence of catalyst.
16.Reiser, O.; Kachkovskyi, G.; Kais, V.; Kohls, P.; Paria, S.; Pirtsch, M.;
Rackl, D.; Seo, H. Chem. Photocatal. 2013, 139–150.
doi:10.1515/9783110269246.139
ORCID® iDs
Shawn K. Collins - https://orcid.org/0000-0001-9206-5538
17.Higgins, R. F.; Fatur, S. M.; Shepard, S. G.; Stevenson, S. M.;
Boston, D. J.; Ferreira, E. M.; Damrauer, N. H.; Rappé, A. K.;
Shores, M. P. J. Am. Chem. Soc. 2016, 138, 5451–5464.
doi:10.1021/jacs.6b02723
References
1. Stephenson, C. R. J.; Yoon, T. P.; MacMillan, D. W. C., Eds. Visible
Light Photocatalysis in Organic Chemistry; Wiley-VCH: Hoboken, New
Jersey, 2018.
18.Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2016, 138, 15527–15530.
doi:10.1021/jacs.6b08792
2735

Beilstein J. Org. Chem. 2018, 14, 2730–2736.
19.Hernandez-Perez, A. C.; Collins, S. K. Acc. Chem. Res. 2016, 49,
1557–1565. doi:10.1021/acs.accounts.6b00250
20.Hernandez-Perez, A. C.; Collins, S. K. Angew. Chem., Int. Ed. 2013,
52, 12696–12700. doi:10.1002/anie.201306920
21.Knorn, M.; Rawner, T.; Czerwieniec, R.; Reiser, O. ACS Catal. 2015, 5,
5186–5193. doi:10.1021/acscatal.5b01071
22.Beatty, J. W.; Stephenson, C. R. J. Acc. Chem. Res. 2015, 48,
1474–1484. doi:10.1021/acs.accounts.5b00068
23.Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113,
5322–5363. doi:10.1021/cr300503r
24.Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81,
6898–6926. doi:10.1021/acs.joc.6b01449
25.Arias-Rotondo, D. M.; McCusker, J. K. Chem. Soc. Rev. 2016, 45,
5803–5820. doi:10.1039/C6CS00526H
See for energy transfer.
26.Gentry, E. C.; Knowles, R. R. Acc. Chem. Res. 2016, 49, 1546–1556.
doi:10.1021/acs.accounts.6b00272
See for proton-coupled electron transfer.
27.Minozzi, C.; Caron, A.; Grenier-Petel, J.-C.; Santandrea, J.;
Collins, S. K. Angew. Chem., Int. Ed. 2018, 57, 5477–5481.
doi:10.1002/anie.201800144
28.See Supporting Information File 1 for tabular data on reaction yields.
29.Fukui, K.; Morokuma, K.; Kato, H.; Yonezawa, T. Bull. Chem. Soc. Jpn.
1963, 36, 217–222. doi:10.1246/bcsj.36.217
30.Parisien-Collette, S.; Cruché, C.; Abel-Snape, X.; Collins, S. K.
Green Chem. 2017, 19, 4798–4803. doi:10.1039/C7GC02261A
31.Parisien-Collette, S.; Collins, S. K. ChemPhotoChem 2018, 2,
855–859. doi:10.1002/cptc.201800096
32.Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T.
Chem. Rev. 2016, 116, 10276–10341.
doi:10.1021/acs.chemrev.5b00707
33.Konieczynska, M. D.; Dai, C.; Stephenson, C. R. J. Org. Biomol. Chem.
2012, 10, 4509–4511. doi:10.1039/c2ob25463h
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(https://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.14.251
2736