Dr Ali Dabbous

Dr Eloïse Colson

Debargha Chakravorty

Dr Jean-Marie Mouesca

Christian Lombard

Sylvain Caillat

Dr Jean-Luc Ravanat

Dr Fabien Dubois

Dr Fabrice Dénès
email: fabrice.denes@unibe.ch

Prof Philippe Renaud

Dr Vincent Maurel
email: vincent.maurel@cea.fr

Fine Tuning of Quantum Dots Photocatalysts for the Synthesis of Tropane Alkaloid Skeletons

Several types of Quantum Dots (QDs) (CdS, CdSe and InP, as well as core-shell QDs such as type I InP-ZnS, quasi type-II CdSe-CdS and inverse type-I CdS-CdSe) were considered for generating α-aminoalkyl free radicals. The feasibility of the oxidation of the N-aryl amines and the generation of the desired radical was evidenced experimentally by quenching of the photoluminescence of the QDs and by testing a vinylation reaction using an alkenylsulfone radical trap. The QDs were tested in a radical [3+3]annulation reaction giving access to tropane skeletons and that requires the completion of two consecutive catalytic cycles. Several QDs such as CdS core, CdSe core and inverted type I CdS-CdSe core-shell proved to be efficient photocatalysts for this reaction. Interestingly, the addition of a second shorter chain ligand to the QDs appeared to be essential to complete the second catalytic cycle and to obtain the desired bicyclic tropane derivatives. Finally, the scope of the [3+3]-annulation reaction was explored for the best performing QDs and isolated yields that compares well with classical iridium photocatalysis were obtained.

Introduction

Visible light photoredox catalysis with transition metal complexes (mainly based on Ir and Ru complexes) and organic photocatalysts has developed rapidly during the last two decades, resulting in impressive development in the field of organic synthesis. [1][2][3][4][5][6][7] Besides, semiconductor quantum dots (QDs) start to appear as efficient photocatalysts for CO2 reduction [8][9][10] and H2 production, [11][12][13] as well as at promoting synthetic organic transformations, as demonstrated by some of us [14] and several others groups, [15][16][17][18][19][20][21][22] relying in the majority of cases on CdS and CdSe QDs.

The different main types of core and core-shell QDs structures used in photoredox catalysis are presented in Figure 1. The efficiency of the charge transfer between the QDs and a substrate (electron donor or acceptor) primarily depends on the accessibility to the charge carriers delocalized in the QDs.

In the case of core QDs (Figure 1A), both hole (h) and electron (e) can reach the surface and are well accessible to substrates. The main limitation for the charge transfer is the short lifetime of photoexcited QDs due to charges recombination (typically 10-20ns in core QDs). In the case of coreshell structured QDs (Figure 1B-1E) the distribution of the charges depends on the alignment of the energy bands edge of the core and the shell. According to this alignment in the core-shell QDs, the core-shell structures of interest in this study are classified into four main types: type-I (Figure 1B), inverted type-I (Figure 1, C), type-II (Figure 1D) and quasi type-II (Figure 1E). [23,24] In type-I QDs, such as InP-ZnS, the band gap of the core is smaller than that of the shell, and the position of the energy bands of the band gap of the core falls within that of the shell (Figure 1B). This makes the generated charge carriers localized in the core of the type-I QDs and consequently can induce difficult accessibility during the charge transfer process. On the opposite, in the inverted type-I QDs, such as CdS-CdSe [25][26][27] the band gap of the core is larger than that of the shell, and the energy bands edges of the shell are aligned within that of the core (Figure 1C)). In such a case, the generated charges are expected to be delocalized in the outer shell of the QDs, which can enhance their interaction with the substrates. In the case of type-II core-shell QDs (or quasi type-II [25] ), the valence band edge of the core is aligned within the band gap of the shell, and the conduction band edge of the shell falls within the band gap of the core (type II, Figure 1D) or very close to the conduction band of the core (quasi-type II, such as CdSe-CdS) (Figure 1E). The hole is maintained in the core of the QDs and is less accessible to substrates, while the electron is localized in the outer shell (type II) or delocalized between the core and the shell (quasi type II) and is more accessible to substrates. This can result in a better charges separation, with longer lifetimes (up to 200 ns [28] ). Simple CdS and CdSe QDs have been used for multiple C-C bond formation as exemplified by the decarboxylative radical addition to styrene reported by Krauss, [29] and the cascade cyclisation reaction of difluorochlorides reported by Feng. [30] A few other QDs structures were investigated in order to improve the reactivity of the photogenerated electrons in C-C bond formation reactions following reductive pathways. QDs made of semiconductors with more reductive conduction band edge levels, such as ZnSe and CuInS2, were reported for the C-C bond formation by reduction of aryl halides [31] and for the removal of protecting groups. [32] The use of CdSe-CdS quasi type-II QDs (Figure 1E) enabled Peng and co-workers to achieve the reduction of imines [33] and the pinacol coupling of aldehydes and ketones [34] with outstanding turnover numbers (TON > 4 × 10 5 ). Scheme 1. Photoredox catalyzed reactions using quantum dots.

Since the seminal work of Weix and Krauss on the QDs-photocatalyzed alkylation of aldehydes (Scheme 1A), [29] the vast majority of QDs-photocatalyzed C-C bond formation reactions following oxidative pathways still rely on core CdSe or CdS QDs for providing the photogenerated holes with an appropriate reactivity for the targeted reaction. For instance, Li-Zhu Wu and co-workers reported recently examples of C-C bond formation reactions [35][36][37] based on a dual one-electron oxidation of tertiary amines and alkenes (Scheme 1B). In another seminal work, Weiss and co-workers reported the α-vinylation of N-arylamines (Scheme 1C) with core CdS [38] and later Pillaï and co-worker reported the same reaction with type-I core-shell InP-ZnS QDs (see Scheme 1 and Figure 1). [39] Besides this unique example of reaction reported with two different types of QDs, up to now, no investigation was reported about the photocatalysis of such an oxidative pathway reaction using different core-shell QDs structures (see Figure 1) that would induce either a better charge separation (such as type-II or Quasi type-II QDs) or localize both charge in the outer shell in order to make them more reactive (such as inverted type-I QDs).

Recently, our groups reported a unique photoredox catalyzed synthesis of tropane and related alkaloid skeletons via a radical [3+3]-annulation process (Scheme 1D). [40] The reaction involves two successive photocatalyzed one-electron oxidation of an arylamine to generate α-aminoalkyl radicals (Scheme 1D).

The limited number of QDs structures investigated up to now for reactions following an oxidative pathway prompted us to perform a systematic study of several types of QDs to perform the radical [3+3]-annulation. We report here that several different types of QDs are suitable for this transformation and that enhanced reactivity can be achieved by QD ligand exchange.

Result and discussion

A. Charge transfer between QDs and 1-phenylpyrrolidine (1a) At first, three types of core QDs, CdS, CdSe and InP were considered for generating the α-aminoalkyl free radical by comparing the reported potentials of the valence band edge of the QDs to the DFT computed one-electron oxidation potential of the N-arylamine model substrate 1-phenylpyrrolidine (1a) (Table 1). The one-electron oxidation potential of 1a was computed to be E°= +0.57 V vs. SCE (+0.81 V vs. NHE) in acetonitrile as a solvent and E°= +0.64 V vs. SCE (0.88 V vs. NHE) in trifluorotoluene (TFT), which was selected in this study as a less volatile alternative to dichloromethane. The reported values for the valence band of CdS QDs vary between +1.24 V vs SCE [41] to +1.66 V vs SCE [38] for CdS QDs and between +0.66 and +1.20 V vs SCE for CdSe QDs depending on their size and their surface ligands. [42] The valence band edge of InP QDs was estimated to be +1.09V vs. SCE [39,43] and +1.75 V vs.SCE [39,43] . Overall, as presented in Table 1, the valence band of CdS, and InP QDs are higher than +1.00 V vs. SCE, so they have a good driving force (typically > 0.4 V) for the oxidation process. For CdSe QD the position of the valence band can be as low as 0.66 V vs. SCE so the driving force can range from 0.56 V down to 0.02 V and might be too low for the one-electron oxidation. Table 1. Comparison between Valence Band (VB) edge redox potentials and the redox potential of 1a computed by DFT (TFT as a solvent).

QDs VB (V vs. SCE) E°(1a +• /1a V vs. SCE) Driving Force (V) CdS 1.24 [41] -1.66 [38] 0.64 > 0.60 CdSe 0.66 [42] -1.20 [42] 0.64 > 0.02 InP 1.09 [43] -1.75 [39] 0.64 > 0.45

Then the QDs considered for this study, including core CdS [44] , CdSe [45] , InP [46] (simply called CdS, CdSe, InP in the text) different types of core-shell QDs type I InP-ZnS [46] (called InP-ZnS), quasi type-II CdSe-CdS [47] (called CdSe-CdS) and inverted type-I CdS-CdSe [26,27]

B. Low scale photocatalysis (1 µmol of 1a) Vinylation and [3+3] annulation involving 1a

The QDs were first tested with the one-step α-vinylation reaction previously reported by MacMillan with an Ir(III)-based complex, [48] then later by the Weiss and Pillai groups using CdS QDs [38] and InP-ZnS QDs, [39] respectively. This well-established reaction proceeds via a radical mechanism closely related to that of the first cycle of the [3+3] annulation reaction. The oxidation of 1a to the corresponding aminyl radical cation, followed by deprotonation, ultimately generates an α-aminoalkyl radical that reacts with the 2-phenylethenylsulfone radical trap. All different QDs were tested in trifluorotoluene (TFT) with 1a (1 µmol) and the radical trap (1.1 µmol). The concentration of the QDs in each reaction was set based on their calculated extinction coefficient (see SI table S.3) and targeting an absorbance close to 1.

CdS, CdSe and CdS-CdSe were tested first. CdS QDs functionalized with their native oleate surface ligands possess a high extinction coefficient close to 10 6 m -1 cm -1 (see SI table S.3), which offers the possibility of using a low catalytic loading (0.1 mol%). They afforded the vinylated pyrrolidine 2 in 49% after 4 h of irradiation at 455 nm (Table 2, Entry 1), which is similar to the yield reported by Zhang et al [38] (50% using 0.5 mol% CdS QDs after 7.5 h of irradiation). CdSe QDs (0.5 mol%) gave 2 in 51% yield upon irradiation at 528 nm for 4 hours ( the results reported by Pillai [39] (52 % after 10 hours of irradiation). For all the studied QDs, our attempts to increase the irradiation time (up to 22 hours) only led to a degradation of the vinylation product 2, which was attributed to an over-oxidation leading to by-products, as proposed by Zhang et al. [38] Table 2. Screening the activity of the QDs. All the reactions are run on the 0.001 mmol scale in TFT. The reaction products 2, 3a and 4a are quantified by UHPLC-MS by comparison with authentic samples. The ability of the QDs to photocatalyze a [3+3] annulation reaction involving two consecutive redox neutral cycles was investigated next. For this purpose, 1a (1 μmol) was allowed to react with ethyl 2-((phenylsulfonyl)methyl)acrylate (1.1 equivalents) under the reaction conditions developed for the alkenylation reaction. For all studied QDs, 24 h of irradiation provided the intermediate allylated pyrrolidine 3a in 42%-59% yields (Table 2). Interestingly, formation of the desired bicyclic product 4a was observed with CdS, CdSe, CdS-CdSe and CdSe-CdS QDs (Table 2, entries 1-4), albeit in low yields (≤15%). Reactions with InP or InP-ZnS QDs stopped at the allylated product 3a without formation of bicyclic 4a even after 48 hours of irradiation. Based on these initial results, we decided to optimize the QDs by modifying the ligand layer.

Entry

Enhancing QDs photocatalytic activity by partial or complete ligand exchange with shorter ligands

The QDs were prepared with long-chain ligands such as oleate or oleylamine on their surface, which can hinder the access of the reaction substrate to the QDs [49] . It was reported by Zhang et al. [38] that a partial exchange of oleate ligands on CdS QDs with shorter n-octyl phosphonate ligands enabled to increase the initial rate of the vinylation reaction by a factor of 2.3. This was attributed to disorder in the ligand layer created by the presence of two different ligands, that helps the substrate to reach the surface of the QDs (Figure 3A). Moreover, Wang at al. [50] and Weidman et al. [51] reported that QDs surrounded by shorter ligands, or by a blend of ligands of two different sizes, are better dispersed.

The effect of the partial exchange of oleate with shorter octyl phosphonate ligands was first investigated for CdS and CdSe core QDs on the reaction leading to the tropane framework 4a. The partial exchange was obtained by adding n-octyl phosphonic acid (n-C8H17PO3H2) to the QDs one hour before performing the photocatalytic reaction, without further treatment. Under these conditions, a strong increase of photocatalytic performance was observed for CdS and CdSe QDs. The yield of 4a increased from 12% to 75% by treating the CdS QDs with 380 equivalents of n-C8H17PO3H2 and from 6% to 73% by treating CdSe QDs with 300 equivalents of n-C8H17PO3H2 (Figure 3B). For CdS QDs, the reaction kinetics is presented in Figure 3C. Complete consumption of the starting material 1a occurs within 10 hours of irradiation. Formation of the mono-allylated intermediate 3a was reached after 9 hours while formation of 4a needed 24 hours of irradiation to reach its maximum. Then, the CdS QDs were tested for successive uses with only one initial treatment with n-C8H17PO3H2.

The first and second runs provided 4a in 73% yield and 75% yield respectively. However, the third run showed a decreased yield of 63% (see also SI section S.6).

Encouraged by the spectacular enhancement obtained with CdS and CdSe QDs for the formation of 4a, the partial ligand exchange was tested for other types of QDs for the vinylation leading to 2 and the annulation leading to 4a. The results are summarized in Table 3 (Table 3, entries 1-7). For core CdS and CdSe QDs, the partial exchange of oleate with n-octylphosphonate ligands lead also to a significant improvement for the vinylation reaction. The use of 0.1 mol% CdS QDs treated with n-C8H17PO3H2 (380 eq) led to 2 in 68% yield after 3 h of irradiation (Table 3, entry 1) compared to 49% after 4 h for the non-modified QDs (Table 2, entry 1). This result compares well with the yield obtained by Zhang et al.

after modifying the QDs surface with a similar addition of n-octylphosphonate ligands (60% yield using 0.5 mol% catalytic loading). The quantum yield (QY) was measured by ferrioxalate actinometry (see SI section S.7.3) to be 0.18%, a value comparable to that reported by Zhang et al. (0.22%). [38] Similarly, CdSe QDs treated with 300 equiv of n-C8H17PO3H2 afforded the vinylated product 2 in 70 % yield (Table 3, entry 2) compared to 51% for the non-modified QDs (Table 2, entry 2). Beside CdS and CdSe QDs, CdS-CdSe QDs also exhibited a strong enhancement of their photocatalytic activity for both reactions (Table 3, entry 3). The use of CdS-CdSe QDs (0.5 mol%) treated with 400 eq of n-C8H17PO3H2 resulted in high yields for both reactions (74% for 4a and 69% for 2) (Table 3 entry 3) comparing with 15% (4a) and 51% (2) yields obtained with the non-modified QDs (Table 2, entry 3). These last results show that the partial ligand exchange with n-C8H17PO3H2 is not limited to oleate coated QDs (CdS, CdSe) but is also efficient when the initial ligand is oleylamine (CdS-CdSe).

The use of 0.5 mol% of CdSe-CdS treated with 400 equivalents of n-C8H17PO3H2 lead to a very slight yield improvement for 2 (33%, Table 3, entry 4) compared to the reference reaction (30%, Table 2, entry 4). The annulation reaction gave a mixture of 3a (42%) and 4a (13%) (Table 3, entry 4) similar to the one observed without ligand exchange (Table 2, entry 4). The use of 0.7 mol% of InP QDs treated with 500 eq of n-octylamine (Table 3, entry 5) provided no change relative to the native InP QDs (Table 2, entry 5) for both reactions. For InP-ZnS QDs, the addition of a shorter ligand was tested by adding octylamine to oleylamine capped QDs (Table 3, entry 6) and by adding n-C8H17PO3H2 to oleate capped QDs (Table 3, entry 7). For both catalysts, the vinylation reaction leading to 2 proceeded with similar yields, 44% and 46% respectively, as the one with unmodified catalysts (Table 2, entries 6 and 7).

Attempts to run the annulation process provided exclusively the allylated pyrrolidine 3a with slightly higher yields (48% and 45%, resp. vs. 42% and 38% without ligand exchange). These results suggest that InP-ZnS QDs are promising catalysts to perform the simple allylation reaction. This selectivity may tentatively be attributed to the limited reducing power of their conduction band [39,43] that does not allow the final reduction of the bicyclic α-ester radical (see discussion of the mechanism, vide infra).

At last, complete ligand exchange was tested for CdS and CdSe QDs using 500 equivalents of phosphonopropanoic acid (HO2C(CH2)2PO3H2). The use of HO2C(CH2)2PO3H2 was reported to transfer QDs into water using dimethylformamide as an intermediate polar solvent. [52] After treatment with HO2C(CH2)2PO3H2, CdS and CdSe core QDs could be dispersed in acetonitrile (ACN) and then their photocatalytic activity was tested (Table 3, entries 8 and 9). The vinylation reaction gave 2 in 67% and 71% using CdS and CdSe, respectively. The annulation reaction gave, after 24 h of irradiation, 4a in a 74% and 72% yield using CdS and CdSe QDs, respectively. However, it was observed that after 24 hours of reaction under light irradiation in acetonitrile, the phosphonopropanoate coated QDs lost their optical properties (see SI section S6). Their poor stability makes them unsuitable for recycling and they have not been further investigated. In summary, partial exchange of the native oleate and oleylamine ligands at the surface of the CdS, CdSe and CdS-CdSe QDs with the smaller n-octylphosphonate ligand proved to efficiently promote their efficiency for the two reactions under investigation. This effect is particularly impressive in the case of the [3+3] annulation leading to 4a. With all other QDs examined, this ligand exchange process had either no effect or only a limited positive effect on the catalyst efficiencies.

C. Scaling-up the [3+3] annulation

Optimization of the preparation of 4a with CdS, CdSe and CdS-CdSe QDs

After having successfully developed the QDs photocatalyzed protocol on the 1 µmol scale, the scalability of the methodology was investigated with CdS, CdSe, and CdS-CdSe QDs. For this study, the synthesized QDs were modified by ligand exchange with n-octylphosphonic acid according to Table 3 (entries 1-3). The reactions were performed on 0.05 mmol scale in 4 mL of TFT (12.5 mM). The QDs catalyst loading was decreased to set the absorbance in TFT at A = 3.7 to enable a sufficient penetration of light in the reaction vessel. Promising results were obtained with CdS and CdSe QDs with isolated yields of respectively 42% and 56% for the cyclized product 4a (Table 4, entries 1 and 2). Although significantly lower than the yields obtained on 1 µmol scale, these yields were obtained with a lower catalyst loading (0.025 mol% vs. 0.1 mol% for CdS, 0.16 mol% vs. 0.5 mol% for CdSe). A high TON of 1680 was obtained for CdS QDs while CdSe QDs showed a lower efficiency (TON of 350). The reaction run with CdS-CdSe QDs was significantly less clean and 4a was isolated in a low 21% yield after 24 h of irradiation corresponding to TON of 131 (Table 4, entry 3). No significant amounts of starting material or side-product was observed that could explain the low yield of the annulation reaction. Considering these results, CdS QDs which exhibited high yield and good TON at low catalyst loading were selected as the most promising candidate for further optimization of the scale-up process. Although encouraging result was obtained with 0.025 mol% CdS and 1.1 equivalents of the sulfone trap (Table 4, entry 1), the presence of side product 6a not only decreased the yield of the desired cyclized product but also greatly impaired its purification due to the very similar polarity. Since this side product is formed when too little trap is present, the reaction was repeated with 1.4 equivalents of the allylsulfone radical trap (Table 4, entry 4). Under these conditions, formation of both 5a and 6a was observed and the major diastereomer of 4a was isolated in only 27% yield. Next, QDs catalyst loading was doubled while keeping the concentration of substrate unchanged at 12.5 mM. The increase of the absorbance up to 7.4 was well-tolerated and a significant amount of 4a (~50%) was detected by 1 H-NMR analysis of the crude mixture (Table 4, entry 5). However, the presence of 6a did not permit to isolate pure 4a. Increasing the quantity of radical trap to 1.4 equivalents proved beneficial and 4a was isolated in 49% yield (Table 4, entry 6). Unfortunately, the reaction was poorly reproducible and in a duplicate experiment, the major diastereomer was isolated in 36% yield along with 6a (Table 4, entry 7). In the iridium-catalyzed reaction, it was observed that the sulfone radical trap was not stable over long reaction time. [40] While this does not affect the iridium-catalyzed reaction due to short reaction times, it might explain why 6a was formed in most of our reactions. Running the reaction with 2.0 equivalents of the allylic sulfone was performed but led mainly to the formation of the bisallylated product 5a (Table 4, entry 8).

Exploring the scope of radical trap

The iridium photocatalyzed [3+3] annulation process was performed with a series of allylic radical traps such as allyl sulfones (Y = SO2Ph), allyl acetate (Y = OAc) and allyl thioether (Y = S-tert-dodecyl) and best results were obtained with the acetate. [40] Therefore, the influence of the leaving group Y on the radical traps was examined for the CdS and CdSe QDs photocatalyzed [3+3] annulation at 1 µmol scale. The use of an allyl acetate (Y = OAc) instead of an allyl sulfone (Y = SO2Ph) radical trap gave similar results in terms of yields and reaction time (Table 5, entries 1 and 2, 72% and 70% yield vs. Table 3, entries 1 and 2, 75% and 73% yield). The thioether radical trap (Y = S-t-dodecyl) gave desired cyclized product 4a in 55% and 50% yield (Table 5, entries 3 and 4). 1) Reactions were run in a glovebox on the 0.001 mmol scale in 1mL trifluorotoluene and the reaction yield was determined by integrating the UHPLC-MS peaks compared to the peak of the corresponding standard of the reaction products. Time of reaction: 24 hours. Conditions of irradiation: 50 mW LED at 528 nm for CdSe, 10 mW LED at 455 nm for CdS. 2) Reactions were run at 0.05 mmol scale outside the glovebox, irradiation with one Kessil lamp (100 W) for 24 hours in a 8-mL clear glass vial with a screw cap. 3) Same reaction conditions as 2 using a tight Schlenk reaction vessel. 4) Reaction was run at 0.2 mmol scale outside the glovebox, irradiation with two Kessil lamps (100 W) for 24 h in a 20-mL clear glass vial with a screw cap.

The allylic acetate radical trap was further investigated at larger scale (50 μmol) with CdS QDs. The reaction was clean and 4a was isolated in 34% (Table 5, entry 5). In line with previous observations, increasing the trap equivalent number from 1.1 to 1.3 proved beneficial and the isolated yield was raised to 50% (Table 5, entry 6). With the optimized conditions in hand, the reproducibility of the reaction with different batches of QDs was tested and proved to be excellent with 51 and 58% yields (Table 5, entries 7 and 8). Then, the same reaction with the third batch of QDs was run using a tight reaction vessel (Schlenk type) instead of a simple screw type vials but the yield was only marginally better (Table 5, entry 9, 61%). Reducing the catalyst loading to 0.025 mol% induced a significant decrease in yield (Table 5, entry 10). Finally, the reaction was run on 200 μmol scale under our best reaction conditions to afford 4a in 46% yield (Table 5, entry 11) reaching a TON of 920. This result is very close to the one reported for the iridium-catalyzed reaction which gave 4a in 57% yield but with a TON of only 57. [40] Remarkably, it was possible to recycle the CdS QDs and to perform again the reaction a second and a third times at the same scale with only moderate erosion of the yield (Table 5, entries 12 and 13, 42% and 35% respectively).

[3+3]-Annulation with different N-arylamines.

The possibility of expanding the scope of the reaction to other precursors was examined with a short selection of para-substituted N-arylpyrrolidines and N-arylpiperidines, which were found to be suitable partners in the Ir(III) catalyzed reaction. [40] Redox potentials of these precursors were computed by DFT and data are presented in Figure 4. As expected, compared to the non-substituted Nphenylpyrrolidine 1a (+0.64 V vs. SCE in TFT), precursors bearing electron donating groups such as para-methoxy-phenylpyrrolidine 1b, para-methyl-phenylpyrrolidine 1c and the 2-methyl substituted N-phenylpyrrolidine 1d exhibited lower redox potentials (+0.29, +0.50 and +0.48 V vs. SCE). On the opposite, p-carbomethoxy phenylpyrrolidine 1f bearing an electron withdrawing group exhibited a higher redox potential (+0.89 V vs. SCE). A similar trend was observed with N-arylpiperidines: paramethoxy-phenylpiperidine 1h has a lower redox potential (+0.29 V vs. SCE) than the non-substituted phenylpiperidine 1g (+0.66 V vs. SCE), which has a lower potential than pcarbomethoxyphenylpiperidine 1i and p-boropinacolpiperidine 1j, which bear electron withdrawing groups (+1.00 V vs. SCE and 0.72 V vs. SCE). The reactions were carried out first at low scale (1 µmol) in TFT with CdS or CdSe QDs using optimized reaction conditions described in Table 3 (entries 1 and 2) and 24-32 hours irradiation times. The results are collected in Scheme 2. The reaction worked well with the electron-rich paramethoxyphenylpyrrolidine 1b, which has a lower oxidation potential than the parent aniline 1a (see Figure 4), leading to 4b in 55% yield using CdS QDs and 65% using CdSe QDs. Similarly, the reactions using the para-methylphenylpyrrolidine 1c and the 2-methyl substituted N-phenylpyrrolidine 1d worked well leading to the final products 4c and 4d in 38-62% yields. These results are equivalent to those obtained under Ir-photocatalysis. [40] In contrast, p-carbomethoxyphenylpyrrolidine 1f which provides the annulated product in 42% yield under Ir-photocatalysis, [40] did not afford any traces of the desired product with CdS and CdSe QDs dispersed in TFT and 1f was fully recovered after the irradiation period. The DFT calculations for the oxidation potential of 1f in TFT (+0.89 V vs. SCE) is presumably out of reach of photogenerated holes in CdS and CdSe QDs explored in this study.

Next, N-arylpiperidines were tested and reacted similarly to the corresponding N-arylpyrrolidines.

Phenylpiperidine (1g) provided 4g in 72% yield under CdS and 70% under CdSe QDs photocatalysis. A similar yield of 67% was previously reported under Ir-photocatalysis. [40] The electron-rich pmethoxyphenylpiperidine (1h) was converted to 4h in 48% yield with CdS QDs and 64% with CdSe QDs.

As for the pyrrolidine counterpart, the p-carbomethoxyphenylpiperidine reacted neither under CdS QDs nor under CdSe QDs photocatalysis. The N-(p-pinacolborylphenyl)piperidine (1j), a substrate that worked well under Ir-photocatalysis, [40] was examined next. It did not provide the annulated product 4j even though the calculated redox potential (+0.72 V vs. SCE, Figure 4) could have been accessible

for the oxidation using CdS QDs. In that case, side reactions leading to homocouplings products could not be excluded as this kind of reactivity was reported und QDs catalysis. [53] However, 1j was recovered at 40% after 24h of irradiation, so it seems like the redox potential of 1j is too high for the oxidation using photoexcited CdS and CdSe QDs.

Overall [3+3] annulation reactions with substrates having oxidation potentials up to +0.66 V vs. SCE (1a, 1b, 1c, 1d, 1g, 1h) were successful with both CdS and CdS QDs, whereas substrates with oxidation potentials higher than +0.72 V. vs. SCE (1f, 1i, 1j) did not react with photoexcited CdS or CdSe QDs.

Scheme 2. Reaction scope with N-arylamines (1 μmol scale, yields determined by UHPLC-MS).

1 n.d. = not detected.

Reactions were then repeated on 50 μmol scale with N-arylpyrrolidines 1a-1e and the allyl acetate trap (Scheme 3). Products 4a, 4c and 4e were obtained in yields similar to the one obtained under Irphotocatalysis. Lower yields were observed for the formation of 4b and 4e.

Scheme 3. Substrate scope with N-arylpyrrolidines (50 μmol) using CdS QDs. Yields given for the iridium-catalyzed reactions are taken from previous work [40] Scaling-up reactions with N-arylpiperidines was more challenging than expected. N-Phenylpiperidine 1g provided the allylated intermediate 3g (14%) and the tricyclic compound 5g (13%) but none the desired bicycle 4g (Scheme 4). The formation of 5g suggests that the reduction of the first α-ester radical adduct is slow (see mechanism discussed in Scheme 6). Using the sulfone trap allowed to circumvent this problem since fast β-fragmentation of the benzenesulfonyl radical takes place giving the intermediate allylated product 3g without the need for a reduction of the α-ester radical adduct (see mechanistic discussion, Scheme 5). Under these conditions, the desired cyclized product 4g was obtained in 25% yield.

D. Mechanism

Allyl sulfone radical trap can easily be oxidized by the excited QD[+-] to the RC4, this oxidation does not lead to a bicyclic αaminoalkyl radical due the much lower acidity of the bicyclic radical cation RC4 (pKa =58.8) relative to the monocyclic one (RC3 and RC1, pKa=51.4 and 52.7, respectively). RC4 is presumably rapidly converted to RC3 and RC1 via electron transfer process with the corresponding amine 3a and 1a. [40] Scheme 5. Mechanism of the allyl sulfone mediated [3+3]-annulation. Calculated redox potentials in V vs. SCE indicated in blue.

Part of the improvement may be due to modification of interaction of the holes with the shorter phosphonate ligands compared with initial oleate and amine ligands.

Photocatalytic activity of the different types QDs: Insights at the mechanistic redox steps

Our results show a clear variation in both efficiency and product selectivity depending on the QDs used.

Core CdS and CdSe as well as inverted Type-I CdS-CdSe QDs demonstrate the best photocatalytic activity for the production of the bicyclic amines. This can be rationalized by the better accessibility of the charge carriers (mainly holes in our reactions) which are closer to the surface for these two types of QDs (see Figure 1A andC). These QDs were also able to accomplish the different redox processes required at different stages of the catalytic mechanism due to their suitable oxidation and reduction capabilities. Indeed, theses QDs in their various redox forms are expected to be able to oxidize amines 1).

For InP-ZnS QDs, the reaction afforded 3a without producing the final bicyclic amine 4a. This indicates that these catalysts are effective for the first catalytic cycle but not for the second one. The conduction band position of the InP-ZnS QDs was previously estimated to be ECB = -0.9 V vs. SCE using electrochemical measurements. [39,43] This value indicates that the reduction of the α-ester radical R2'

or the benzenesulfonyl (first catalytic cycle) should be easily possible but that the reduction of R4

(second catalytic cycle, Ered = -0.77 V vs. SCE) is challenging for InP-ZnS QDs. Consequently, the first catalytic cycle leading to 3a is effective but the second catalytic cycle leading to 4a cannot be achieved.

The fact that 3a could be produced in fair yield indicated that another reduction process is probably involved to regenerate the catalyst when the oxidation of the 3a takes place (beginning of the second cycle). Presumably, the reduced catalyst QD[-] is able to reduce the acrylate radical trap. This nonproductive process provides the starting QD in its ground state ready to catalyze the first catalytic cycle. The fact that 1a is converted to 3a without formation of noticeable amount of 4a or 5a may also indicate that 3a is less efficiently oxidized by the InP and InP-ZnS QDs than 1a. Since both amines have almost the same oxidation potential, we hypothesized that the oxidation of the more hindered 3a is kinetically disfavored due to a more difficult access to the InP or InP-ZnS QDs catalyst surface.

Conclusion

Core CdS, core CdSe and inverted type I core-shell CdS-CdSe QDs were found to successfully photocatalyze the [3+3]-annulation process involving two successive catalytic cycles leading to tropane derivatives. This is consistent with the good accessibility of the holes in such QDs, which is necessary for the efficient oxidation of the N-arylamine substrates. However, the expected localization of both charges in the outer CdSe shell in inverted type I CdS-CdSe does not increase their reactivity compared to core CdS or CdSe QDs. Highest TON were obtained with core CdS QDs. Using this catalyst, the [3+3]annulation reaction was performed on a scale up to 200 μmol allowing isolation of bicyclic amines closely related to tropanes alkaloids. This work also demonstrates that the photocatalytic activity of QDs for such a complex reaction sequence can be tuned by modification of the QD ligands layer. Partial exchange of the QDs long chain native ligands (oleates and oleylamines) with shorter noctylphosphonate ligands appeared to be strongly beneficial for performing the second step of the [3+3]-annulation reaction and was achieved by addition of n-octylphosphonic acid in the reaction mixture. Interestingly, the use of type I InP-ZnS core-shell QDs enabled to cleanly allylate the N-arylpyrrolidine in fair yield without producing the bicyclic compound. This transformation is hardly achievable using Ir-complex photocatalysts.

Overall this study exemplifies the versatility of QDs as redox photocatalysts by showing that they are able to photocatalyze a complex photoredox one-pot two-steps reaction with yields very comparable to Ir-complex photocatalysts. By playing with the composition of the QDs and their ligands layer, it is possible to modulate their reactivity to perform either one or both steps of the process. Remarkably, QDs require very low catalyst loading and preliminary results indicates that recycling of the catalyst may be envisaged.

Experimental part

Quantum Dots Synthesis

CdS [44] , CdSe [45] , CdSe-CdS [47] , CdS-CdSe [26,27] , InP [46] and oleylamine coated InP-ZnS [46] QDs were synthesized using hot injection methods following literature procedures with few modifications for each type of Quantum Dots. The detailed synthesis procedures and analyses by TEM, UV-vis absorption spectroscopy, and photoluminescence spectroscopy are described in the SI section S-1. Oleate-capped InP-ZnS core-shell QDs were purchased from NN-Labs (Fayetteville, AR, USA).

Photocatalysis

All the one micromole scale photocatalytic reactions were carried out in a 2mL clear glass screw cap HPLC vial under an inert atmosphere in a nitrogen-filled glovebox. All the stock solutions of the reactions' reagents and the QDs were dissolved in degassed solvents placed in the glovebox. The reaction medium was maintained under continuous stirring using a magnetic stirring bar over the complete irradiation time. The reactions were set for irradiation using the home-made irradiation setup connected to Oslon4 power Star LED source of suitable wavelength (See SI section S7). During the irradiation, 30 µL volume aliquots were taken for the analyses at specific intervals of time during the reaction and analyzed by the UHPLC-MS (see SI section S.9).

For the scale up at the 0.05 mmol and 0.2 mmol scales, the reactions were entirely set up in the glovebox in the appropriate reaction vessels (see SI section S.10). Typically, in the reaction vessel equipped with a stirring bar were added the CdS QDs (20 µM in TFT, 1.250 mL, 0.05 mol%) and the OPAc ligands (50 mM in TFT, 0.190 mL, 19 mol%). Additional TFT was added so that the total end volume of the reaction mixture reached 4 mL (12.5 mM, 2.250 mL). The solution was stirred in the dark in the glovebox for 1 h 30. Then, the starting material (1 M in TFT, 50 µL, 0.05 mmol), the radical trap ethyl 2-(acetoxymethyl)prop-2-enoate (0.250 M in α,α,α-TFT, 0.260 mL, 1.3 equiv.) and CsOAc (12 mg, 1.2 equiv.) were added. The vial was tightly closed. A layer of Teflon tape and parafilm was added around the cap. The vial was taken out of the glovebox for irradiation under a 456 nm Kessil lamp (PR160L) for 24 hours (and 525 nm for experiments using CdSe QDs). A ventilator was used. When a Schlenk tube was used, no Teflon tape and/or parafilm was used. The protocol was unchanged when scaling up the reaction to 0.20 mmol, except that two 456 nm Kessil lamps were used opposite to each other, and the reaction time was doubled. The detailed procedure of work-up, purification and analyses of the reaction product can be found in SI section S.10.

Figure 1 .

 1 Figure 1. Energy levels and charges localization in different types of QDs. Upper part: distribution of the charges after the photoexcitation of the different types of QDs. Lower part: conduction and valence bands alignment in the different types of QD. h stands for hole, e for electron, ECB for the energy of the conduction Band, EVB for the energy of the Valence Band and Eg for the band gap energy.

Figure 3 .

 3 Figure 3. Effect of the addition of n-octylphosphonic acid on CdS and CdSe QDs. A) Ligand exchange process. B) Effect on the yield of 4a. C) Reaction kinetics using CdS QDs with the optimal quantity (380 equiv.) of n-octylphosphonic acid.

Figure 4 .

 4 Figure 4. DFT computed one-electron oxidation potentials of N-aryl-pyrrolidines and piperidines. Eox are given in V vs. SCE.

Scheme 5

 5 Scheme 5 shows the reaction mechanism proposed for the catalytic cycles involving Nphenylpyrrolidne 1a and the allyl sulfone trap leading to the bicycle 4a. Under visible light irradiation, the hole in the valence band of the excited QD[+-] is able to oxidize 1a (Eox = 0.64 V vs. SCE in TFT) to its α-amino radical cation RC1, which provides the α-amino radical R1 after deprotonation. Addition of R1 to the allyl sulfone gives the intermediate α-ester radical R2 that undergoes fast β-fragmentation of the benzenesulfonyl radical providing the intermediate allylated pyrrolidine 3a. The first photocatalytic cycle is achieved by reduction of the sulfonyl radical (Ered = +0.46 V vs. SCE) to the sulfinate anion by the reduced form of the quantum dot QD[-]. The second catalytic cycle involves oxidation of 3a by the excited quantum dot QD[+-] affording the radical cation RC3 followed by deprotonation to provide the α-aminoalkyl radical R3. Then R3 undergoes a 6-endo-trig cyclization, leading to the bicyclic α-ester radical R4 (calculated Ered = -0.77 V vs. SCE). Finally, reduction of the radical R4 by the reduced form of the quantum dot QD[-] closes the second catalytic cycle affording after protonation of the ester enolate the bicyclic product 4a. Interestingly, despite the fact that 4a

2.0 2.5 3.0 CdS QDs CdSe QDs CdS-CdSe QDs CdSe-CdS QDs InP-ZnS QDs 1 InP-ZnS QDs 2 I°/I Concentration of 1a (mM) Figure 2. Photoluminescence quenching of the QDs by 1a. Stern-Volmer plots computed from

	the
	photoluminescence plot (see SI 2 for details) of the QDs in presence of 1a (up to 5 mM) in TFT.
	1) Oleylamine capped InP-ZnS QDs. 2) Commercial oleate capped InP-ZnS QDs.

Table 2

 2

, entry 2). Similarly, CdS-CdSe QDs (0.5 mol %) functionalized with oleylamine as surface native ligands provide 2 in 48% yield upon irradiation at 528 nm for 4 hours (Table 2, entry 3). The other types of QDs investigated, namely CdSe-CdS, InP and InP-ZnS exhibited a slower kinetics (see SI Figure S5.1A and S5.1B) and provided 2 in 30%-43% yields after 6 h of irradiation (Table 2, entries 4-6). Noteworthy, the use of the commercially available oleate capped InP-ZnS QDs resulted in 43% yield in 6 hours of irradiation (Table 2, Entry 7), which is close to

QDs type Surface ligands Catalyst loading λirr 1 Vinylation Yield 2 (time) [3+3] Annulation Yield 3a/4a (time)

	1	CdS core	oleate	0.1%	455 nm	49% (4 h)	52%/12% (24 h)
	2	CdSe core	oleate	0.5%	528 nm	48% (4 h)	49%/6% (24 h)
	3	CdS-CdSe	oleylamine 0.5%	528 nm	51% (4 h)	59%/15% (24 h)
		inverted type I
	4	CdSe-CdS	oleylamine 0.5%	528 nm	30% (6 h)	42%/11% (24 h)
		quasi type II
	5	InP core	oleylamine 0.7%	455 nm	40% (6 h)	30%/n.d 3 (24 h)
	6	InP-ZnS type I	oleylamine 0.7%	455 nm	42% (6 h)	42%/n.d. 3 (48 h)
	7	InP-ZnS type I	oleate 2	0.7%	528 nm	43% (6 h)	38%/n.d. 3 (24 h)

1 irradiation power: 528 nm: 50 mW; 455 nm: 10 mW.

2

Commercially available; 3 n.d. = not detected

Table 3 .

 3 Screening the photocatalytic activity of QDs after exchange with shorter ligands. All the reactions are run on the 1 µmol scale in TFT. The reaction products 2, 3a and 4a are quantified by UHPLC-MS by with authentic samples. Conditions of irradiation: 50 mW at 528 nm for CdSe, CdS-CdSe, CdSe-CdS and InP-ZnS (Oleate), 10 mW at 455 nm for CdS, InP and InP-ZnS (Oleylamine).

	Entry QDs type Native	Added shorter	Solvent Catalyst	Vinylation	[3+3] Annulation
			ligand	ligands (equiv)		loading	Yield 2	Yield 3a/4a 1
	1	CdS	oleate	n-C8H17PO3H2 (380)	TFT	0.1%	68% (3 h)	n.d./75% (24 h)
	2	CdSe	oleate	n-C8H17PO3H2 (300)	TFT	0.5%	70% (4 h)	n.d./73% (24 h)
	3	CdS-CdSe oleylamine n-C8H17PO3H2 (400)	TFT	0.5%	69% (4 h)	n.d./74% (24 h)
	4	CdSe-CdS oleylamine n-C8H17PO3H2 (400)	TFT	0.5%	33% (6 h)	42%/13% (24 h)
	5	InP	oleylamine n-octylamine (500)	TFT	0.7%	42% (6 h)	32%/n.d. (24 h)
	6	InP-ZnS	oleylamine n-octylamine (500)	TFT	0.7%	44% (6 h)	48%/n.d. (48 h)
	7	InP-ZnS	oleate	n-C8H17PO3H2 (500)	TFT	0.7%	46% (6 h)	45%/n.d. (24h)
	8	CdS	oleate	HO2C(CH2)2PO3H2 (2) ACN	0.1%	67% (3h)	n.d./74% (24h)
	9	CdSe	oleate	HO2C(CH2)2PO3H2 (2) ACN	0.5%	71% (3h)	n.d./74% (24h)
	1) n.d. = not detected, 2) 500 equivalents of shorter ligand were added with a phase transfer to DMF then to ACN (see main
	text)

Table 4 .

 4 Optimization of the reaction conditions on 0.05 mmol (12.5 mmol) scale using the sulfone trap.

	Entry QDs type	Catalyst	Abs	Radical	Isolated yield of 4a 1 TON	Side product
			Loading		trap
	1	CdS	0.025%	3.7	1.1	42%, α/β 4.5:1	1680	6a
	2	CdSe	0.16%	3.7	1.1	56%, α/β 6:1	350	none
	3	CdS-CdSe	0.16%	3.7	1.1	21%, α/β 4.5:1	131	Unidentified
	4	CdS	0.025%	3.7	1.4	27% (α only)	1080	6a, 5a
	5	CdS	0.05%	7.4	1.1	~50% 2	1000	6a
	6	CdS	0.05%	7.4	1.4	49% (α/β 5:1)	980	none
	7	CdS	0.05%	7.4	1.4	36% (α)	720	6a
	8	CdS	0.05%	7.4	2.0	traces		5a

1)

Irradiation with one Kessil lamp (100 W) for 24 hours (at 456 nm CdS QDs and at 525 nm for CdSe and CdS-CdSe QDs). Experiments performed in TFT with appropriate amounts of OPAc ligands determined in section B-2. Reactions were set-up inside the glovebox and irradiated with one Kessil lamp outside the glovebox. When applicable, 1 H-NMR yield was determined using ethylene carbonate as a standard.

2)

Approximate NMR yield due to unclean reaction; difficulties of purification prevented isolation of the product.

Table 5 .

 5 Radical trap screening at low and higher scale for CdS and CdSe QDs

	Entry QDs	1a (mmol)	cat.load	Abs	Y (equiv)	Yield 4a
	1 1	CdS	0.001	0.1%	1.1	OAc (1.1)	72%
	2 1	CdSe	0.001	0.5%	0.9	OAc (1.1)	70%
	3 1	CdS	0.001	0.1%	1.1	S-t-Do (1.4) 55%
	4 1	CdSe	0.001	0.5%	0.9	S-t-Do (1.4) 50%
	5 2	CdS	0.05	0.05%	7.4	OAc (1.1)	34% α/β 5:1
	6 2	CdS batch 1	0.05	0.05%	7.4	OAc (1.3)	50% α/β 5:1
	7 2	CdS batch 2	0.05	0.05%	7.4	OAc (1.3)	51%, α/β 5:1
	8 2	CdS batch 3	0.05	0.05%	7.4	OAc (1.3)	58%, α/β 5:1
	9 3	CdS batch 3 -Schlenk 0.05	0.05%	7.4	OAc (1.3)	61%, α/β 5.5:1
	10 2	CdS	0.05	0.025%	3.7	OAc (1.3)	42% α/β 3:1
	11 4	CdS 1 st use	0.20	0.05%	7.4	OAc (1.3)	46% α/β 6:1
	12 4	CdS 2 nd use	0.20	0.05%	7.4	OAc (1.3)	42% α/β 4:1
	13 4	CdS 3 rd use	0.20	0.05%	7.4	OAc (1.3)	35% α/β 4:1

  1a (Eox = +0.64 V vs. SCE) and 3a (Eox = +0.68 V vs SCE) and to reduce radical R2' (Ered > -0.29 V vs. SCE) with the acetate trap, or the benzenesufonyl radical (Ered = +0.46 V vs. SCE) with the sulfone trap.

Interestingly, reduction of the radical R4 (Ered = -0.77 V vs. SCE) requires a stronger reducing species than the β-acetoxylated α-ester radical R2' (Ered > -0.29 V vs. SCE). QD[-] states of CdS, CdSe and coreshell CdS-CdSe QDs are expected to be reducing enough to reduce R4 and to close the second catalytic cycle allowing an efficient synthesis of the bicyclic amine 4a. By taking into account a band gap of 2.7 eV for CdS QDs (460 nm), the position of the conduction band and valence band edges of CdS QDs can be estimated to be in the range ECB = -1.5 to -1.04 V vs. SCE and EVB = +1.2 to +1.66 V vs. SCE. Similarly, CdSe QDs having a band gap of 2.3 eV (540 nm) are expected to have a conduction positioned at ECB = -0.64 to -1.1 V vs. SCE and a valence band at EVB = +0.66 to +1.2 V vs. SCE (see Table

Acknowledgements

This work was supported by the Swiss National Science Foundation (project 200021L_182078) and the ANR (project ANR-18-CE93-0004) under the Lead Agency and International Co-Investigator Scheme.

V.M. and J.-M. M. thank the Labex ARCANE (ANR-11-LABX-0003) and CBH-EUR-GS (ANR-17-EURE-0003) for partial funding.

Keywords

Quantum dots; Photoredox catalysis; Alkaloids; Aminium free radicals; Tropanes

Table of contents (ToC) entry:

"CdS core, CdSe core and inverted type I CdS-CdSe core-shell quantum dots proved to be efficient photocatalysts for a two steps [3+3]-annulation reaction giving access to tropane skeletons, whereas InP-ZnS quantum dots stopped after the first step, affording a clean allylation reaction".

Allyl acetate radical trap

When the allylic acetate radical trap is used, the same mechanism is operating, except for the fact that the radical intermediate R2' cannot undergo a radical fragmentation but is rather reduced by QD[-] to its enolate (Ered > -0.29 V vs SCE according to DFT computations), triggering the elimination of an acetate anion. This SET process completes the first catalytic cycle (Scheme 6). Results obtained with the piperidine 1g (Scheme 4) suggest that the lifetime of radical R2' is longer that the one of R2 (Scheme 5) and therefore side reactions such as intramolecular addition to the N-aryl moiety leading to the formation of 5g was observed when the reaction was run with allyl acetate and could be prevented by using the allyl sulfone trap. Scheme 6. Mechanism of the allyl acetate mediated [3+3]-annulation. Calculated redox potentials in V vs. SCE indicated in blue.

Effect of the ligands exchange depending on QDs and on the targeted reaction

Overall the partial (or complete) exchange of ligands for three kinds of QDs, namely core CdS, core CdSe and inverted type I core-shell CdS-CdSe enabled to perform both steps of the [3+3] annulation reaction by unlocking the reactivity of QDs for the second cyclization step (see Table 3), which was otherwise very inefficient (see Table 2). Interestingly, the same ligands exchange brought only a slight improvement for the vinylation reaction (see Tables 2 and3). This suggests that the ligand exchange process specifically helps the cyclization step. The origin of this effect is unclear but the creation of disorder in the ligand layer might provide a better catalyst access to the bulkier and less hydrophobic allylated intermediate product 3a compared to the initial phenylpyrrolidine 1a. Moreover, in these three types of QDs, photogenerated holes are located in the core or the outer shell, which, in both cases is directly in contact with ligands. Other tested core-shell QDs with holes confined in the inner core (CdSe-CdS and InP-ZnS) exhibited no improved reactivity when adding shorter ligands.

DFT computation

All DFT calculations were performed with the ADF (Amsterdam Density Functional) code developed by E. J. Baerends and co-workers [54] using triple-zeta basis sets (no frozen core). Geometry optimizations were performed in vacuo relying on the Generalized Gradient Approximation (GGA) VBP exchangecorrelation (XC) potential (VWN + BP: Vosko, Wilk & Nusair [55] + corrective terms by Becke [56] for the exchange, and Perdew [57] for the correlation) with ADF grid precision 6 throughout. The interaction of the molecules with their polarizable (solvent) environment is computed with the COSMO (COnductorlike Screening Model) [58][59][60] ADF module, representing the solvent as a dielectric continuum. The key parameters for acetonitrile are  = 37.5 (dielectric constant) and R = 2.76 Å (radius of the rigid sphere solvent molecule). For TFT (trifluorotoluene):  = 9.2 and R = 3.48 Å. Absolute redox potentials are then referred to the normal hydrogen electrode (NHE) applying a shift of -4.43 eV defined at pH=0 [61] . The shift between NHE and Calomel (SCE) is set at 0.24 V (i.e. E°SCE = E°NHE -0.24 V).


Linda Marie Ahl
email: linda.ahl@edu.uu.se

Mario Sánchez Aguilar

Uffe Thomas Jankvist

Morten Misfeldt

Johan Prytz

Factors of Influence for Implementing Curriculum Reform: An analysis based on a systematic literature review

Keywords: Mathematics curriculum reform, implementation research, factors of influence

To get an overview of the characteristics of the studies in mathematics education research that explicitly purport to concern implementation, we have conducted a systematic literature review. We report on a subset of twelve papers investigating and discussing factors of influence that are decisive for implementing curriculum reforms. Results show that curriculum change does not occur independently of a change in teachers' concerns, beliefs, views, and images about the nature of mathematics teaching and learning. Also, the school's support level and the innovations' adaption to context are decisive for the implementation outcome. Design for evaluation of curricular reforms may benefit from explicating the supposed main factors of influence and design methods of evaluating their mechanisms.

Introduction

Implementation research, by our working definition, is the systematic inquiry of innovations enacted in controlled settings or in ordinary practice, the factors that influence innovation enactment, and relationships between innovations, influential factors, and outcomes. (Century & Cassata,p. 181) Implementation research (IR) in mathematics education research (MER) has gained momentum during the past few years. Some indications of this fact are that since 2017, a thematic working group (TWG 23) at CERME has been dedicated to the topic, and a new specialized journal-Implementation and Replication Studies in Mathematics Education (IRME)-published its first two issues in 2021. Also, in 2021, a special issue of ZDM was dedicated to the topic of implementation research in MER [START_REF] Koichu | Implementation-related research in mathematics education: The search for identity[END_REF].

Typical issues dealt with in relation to IR in MER concern the use of theoretical constructs from fields such as health science, economics, etc., versus constructs developed specifically for MER; what we should take implementability to mean in relation to IR in MER; to what extent IR should mainly address large scale studies; etc. [START_REF] Jankvist | Illustrating the need for a 'Theory of Change' in implementation processes[END_REF]. When discussing such issues, a natural starting point is to get an overview of the numerosity and type of studies in the MER literature specifically addressing implementation. We have taken on this task by conducting a systematic literature review.

Such a review involved a few delicate considerations on our behalf, not least since a large portion of the research studies in MER may be considered studies addressing some kind of implementation. We settled on two inclusion criteria to avoid a too large number of papers. Firstly, we limited the review to include papers that clearly stated to be dealing with implementation. Secondly, we limited the review to only considering studies published in the top twenty quality-ranked MER journals, following the recent journal categorization by [START_REF] Williams | Journal quality in mathematics education[END_REF]. In this paper, we focus on a smaller subset of the identified studies, consisting of twelve papers that explicitly address factors affecting the enactment of curriculum reform. The research question is: What factors of influence are decisive for the outcome of the implementation of a curriculum reform?

Review methodology

We conducted the literature review using as a starting point the ERIC database. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [START_REF] Moher | Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement[END_REF] were followed to structure our review study. We searched for manuscripts with implement* in the title and/or abstract, journal by journal of our top 20 samples [START_REF] Williams | Journal quality in mathematics education[END_REF]. To ensure that no article had been overlooked, we repeated the search implement* in the title and/or abstract on each of the 20 journals' websites. We found 1,093 peer-reviewed articles fitting the inclusion criteria. The selection of articles followed the four main steps of PRISMA: (1) identification, (2) screening, (3) eligibility, and (4) inclusion [START_REF] Moher | Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement[END_REF]. The literature search was carried out on February 4-5, 2021. We used the software Covidence to manage our systematic review.

Two reviewers screened each paper. The screening was made in two steps. First, we screened the title and abstract. In cases where we were hesitant, e.g., because the abstract did not provide sufficient information, we forward the paper to full-text screening. A total of 138 papers were forwarded to fulltext screening, where papers were included if they fit under [START_REF] Century | Implementation research: Finding common ground on what, how, why, where, and who[END_REF] definition of IR (quoted above). Innovation in the IR definition refers to the practical implementation of ideas resulting from research on improving education [START_REF] Century | Implementation research: Finding common ground on what, how, why, where, and who[END_REF].

Of the 138 papers, 95 remained after the full-text screening. To obtain smaller and more manageable units, these were categorized as: Instructional sequences on mathematical concepts and/or competencies (19), Curriculum materials (21), Professional development (PD) projects (25), and Curriculum reform (30). There are no clear cuts between the categories. An instructional sequence may stem from a new curriculum material implemented through a PD project due to curriculum reform. The category foregrounded in each of the 95 papers was decisive for how the categorization was done.

The data extraction from the papers included general information on the author(s), title, purpose statement(s), country where the study was conducted, research question(s), methods, target group, and results. The specific information about the implementations included what kind of innovation from mathematics education the study concerned, specific or general goals of short term or long term, phase of the implementation studied, stakeholders responsible for the implementation, and identified factors of influence for the implementation outcomes. This paper focuses on the subset of twelve papers explicitly addressing factors of influence for enacting curriculum reform.

IR theoretical constructs applied

One reason to conduct implementation research is to discover factors of influence in the enactment (of the innovation) that are crucial for whether the innovation works [START_REF] Century | Implementation research: Finding common ground on what, how, why, where, and who[END_REF]. Factors of influence are defined as characteristics of four spheres: the innovation, the user, the organization, and the external environment. What constitutes these characteristics varies depending on the context in which the implementation is studied (e.g., hospital, football club, manufacturing industry, etc.). Here, we are interested in the school and why we identify the four categories in the school context.

The innovation: In line with [START_REF] Century | Implementation research: Finding common ground on what, how, why, where, and who[END_REF], we define innovations as "the object or focus for change" (p. 170). In this paper, we are only considering innovations carried out by curriculum reform that stem from ME research. Factors of influence inherent to the innovation are applicability and adaptability to the users and the practice where it will be implemented.

The user: The user in curriculum reform is the teachers since teachers are key players in all educational reforms in the role of agents of change in schools and classrooms. Factors of influence for implementation projects are teachers' level of understanding of the innovation and their mathematical and pedagogical expertise. Also, prior experience, organizational skills, classroom management style, and affective traits such as beliefs, values, attitudes, motivation, self-efficacy, and willingness to try new things are FoI for innovation implementation [START_REF] Century | Implementation research: Finding common ground on what, how, why, where, and who[END_REF].

The organization: The organizational factors of influence that regulate implementation projects originate from a system of decisions made by stakeholders in the school. Examples of organizational factors of influence are decisions on class size, the allocation of resources, the physical space, scheduling, and the organizational structure of teachers' work. Also, the administration, management, and policy-making processes related to the innovation in play are characteristics of organizational factors of influence.

The external environment: Affordances and constraints formed outside the organization (over which the organizations' stakeholders have no influence) that impact innovation enactment are considered factors of influence from the external environment. It is typical for factors of influence that belong to the external environment that stakeholders in the school do not have the power to influence decisionmaking. Economic conditions, infrastructure, and shifting political focus are examples of external influences with the power to influence innovation. It can be tangible things, such as the connections being so bad that it is difficult for PD supervisors to reach out to the schools and policy decisions about the schools' budgets after a change of political power.

Below, we identify which factors of influence are stated as reasons for the success or failure of implementing curriculum reform in the reviewed articles.

Results

Six countries are represented in the sample of the twelve identified papers, explicitly investigating factors of influence for enacting curriculum reform in line with the intended reform. We report on the identified factors of influence country by country, starting with the earliest study, from Brazil in 1991, and ending with the latest, from Bhutan in 2018. After that, we categorize the factors of influence as characteristics of the innovation, the user, the organization, and the external environment. We also categorize the studies as a priori or a posteriori to distinguish whether the study enters with a prior idea of the existence of a specific factor of influence under investigation (a priori) or if the identified factors of influence stem from the empirical investigation (a posteriori).

In Brazil, an a posteriori analysis of the mathematics curricular reform movement in the 1960s concluded that the implementation was not a success [START_REF] D'ambrosio | The modern mathematics reform movement in Brazil and its consequences for Brazilian mathematics education[END_REF]. The reform was built on a transfer of knowledge from a developed to a developing country, which created practical problems such as incorrect translations of curriculum documents. Also, mathematics that the teachers themselves had not studied, such as set theory, was introduced by the curriculum reform. In addition, there was a lack of teacher preparation and textbooks supporting reformed mathematics. Yet, the teachers' beliefs were the most important factor of influence for the failure of implementing a reformed curriculum in Brazil. The reformed ideas about how teaching should be carried out did not align with the teachers' own beliefs about the practice of teaching and learning. D'Ambrosio concludes:

Curriculum change does not occur independently of a change in teachers' beliefs about the nature of mathematics, the nature of mathematics learning and the nature of mathematics teaching." (D'Ambrosio, 1991, p. 84) In Cyprus, a reformed mathematics curriculum was gradually implemented from 1995 in grade 1, the next year in grade 2, and so on until 2000, when grades 1 through 6 were covered. In our sample, two a priori studies show that teachers' concerns and beliefs are influential factors in enacting reformed mathematics [START_REF] Charalambous | Teachers' concerns and efficacy beliefs about implementing a mathematics curriculum reform: Integrating two lines of inquiry[END_REF][START_REF] Christou | Teachers' concerns regarding the adoption of a new mathematics curriculum: An application of CBAM[END_REF]. The reform was implemented without substantial professional development. Instead, a mandated mathematics textbook and a teacher guide were intended to carry the reform ideas to the classroom. Data from a questionnaire with 655 teachers showed that elementary teachers generally felt capable of meeting the demands of reformed mathematics but were concerned about planning the daily work with the new textbook and large student groups [START_REF] Christou | Teachers' concerns regarding the adoption of a new mathematics curriculum: An application of CBAM[END_REF]. [START_REF] Charalambous | Teachers' concerns and efficacy beliefs about implementing a mathematics curriculum reform: Integrating two lines of inquiry[END_REF] report that after five years of reform, the 155 elementary teachers in their study argued that they were not sufficiently acquainted with the reform. In additional interview data from 53 teachers, the opinion that the teacher manual did not convey the underlying philosophy of the reform was put forward. Findings also showed that teachers who were happy with their pre-reform teaching practice tended to be more skeptical of the reformed curriculum. Hence, ignoring teachers' concerns and efficacy beliefs about their pre-reform teaching may hinder successful implementation.

We also found a posteriori analysis from Australia on teachers' implementing a curriculum prescribing thematic teaching [START_REF] Handal | Teaching mathematics thematically: Teachers' perspectives[END_REF]. Interviews with ten teachers in grades 9-10 showed that while the teachers generally appreciated the goals of teaching thematically, they continued to teach procedures topic by topic. According to the teachers, a lack of instructional, curricular, and organizational support hindered the implementation. Also, from Australia, we have an a posteriori study identifying high staff turnover and cultural norms as key factors of influence for implementation failure in an analysis of a transfer of curriculum reform from California to remote areas in Aboriginal communities in Australia [START_REF] Sullivan | Transposing reform pedagogy into new contexts: Complex instruction in remote Australia[END_REF].

So far, we have not reported on any success stories. However, when we turned to the US, we found only one in our sample. A brief report based on a doctoral dissertation shows positive results on student achievement after implementing two innovations, block-scheduling and standards-based curriculum [START_REF] Kramer | An existence proof: Successful joint implementation of the IMP curriculum and a 4 x 4 block schedule at a suburban US high school[END_REF]. The investigated high school thoroughly prepared the year before the reform. Teachers with a special interest in reformed mathematics were hired, comprehensive professional development for enactment in classroom practice was provided, and organizational support for collaboration between colleagues.

In the other five studies from the US, successful enactment is conspicuous by its absence. A study on twelve first-year teachers in grades 8-10 showed that traditional chalk and talk dominated even though the curriculum prescribed reformed teaching with student participation and problem-solving. [START_REF] Laberge | First-year teachers' implementation of the NCTM standards[END_REF]. The teachers had attended teacher education that did not apply standardbased methods. Self-reported factors of influence revealed by a-posteriori methods were lack of time, resources, and support for changing practice. A lack of support for reform was also identified by [START_REF] Stickles | Using instructional logs to study teachers' adaptation to curricular reform[END_REF]. Electronic logs from 50 elementary school teachers were collected. The results showed that teachers roughly fall into three a posteriori caricatures: the conflicted traditionalists, the growing reformists, and the distinguished leaders. The former has trouble adjusting to reform, while the latter takes on the task in an exemplary manner. The vast majority fall in between (80%). These are teachers with the potential to adapt to reform with proper support. Similar factors of influence, the lack of support for changing practice, are revealed through a posteriori analysis by Swars and Chesnutt (2016). Despite a belief in the merit of the standards, lack of familiarity, inadequate content knowledge, limited curricular resources, and a perceived mismatch with English language learners hindered implementation, according to 73 elementary teachers in a large urban high school [START_REF] Swars | Transitioning to the common core state standards for mathematics: A mixed methods study of elementary teachers' experiences and perspectives[END_REF]. Finally, from the US, a summary paper on the enactment of reformed mathematics in K-12 concludes that the challenges with curriculum reform included both the teachers' views of mathematics as a school subject and their existing images of teaching. For successful reform, teachers' existing views of teaching and their teaching images associated with the reform must change [START_REF] Taylor | Implementing the standards: Keys to establishing positive professional inertia in preservice mathematics teachers[END_REF].

Teachers' beliefs were identified as the most important factor of influence for the lack of successful implementation of the reformed curriculum in the last two studies. From China, we have an aposteriori analyzed single case study of a preschool teacher. The teacher had difficulties implementing the curriculum reform due to a conflict between Standards, the curriculum, and her philosophy and teaching style [START_REF] Hu | A case study of the implementation of Chinese kindergarten mathematics curriculum[END_REF]. Finally, in Bhutan, a lack of success due to a misalignment between the intentions in the reformed curriculum and teachers' views of classroom practice is reported from an a posteriori analyzed study of 72 elementary teachers [START_REF] Dolma | Investigating the alignment of Bhutanese mathematics teachers' planned approaches within the context of a reformed curriculum[END_REF].

We summarize the results by distributing the factors of influence on the four spheres: the innovation, the user, the organization, and the external environment.

The innovation:

The innovation needs to be adapted to the context in which it should be implemented. When transferring an innovation to other cultures than the one the innovation was created for, adaptations are necessary [START_REF] D'ambrosio | The modern mathematics reform movement in Brazil and its consequences for Brazilian mathematics education[END_REF][START_REF] Sullivan | Transposing reform pedagogy into new contexts: Complex instruction in remote Australia[END_REF].

The user: Our sample consists of two a priori studies, where teachers' concerns and efficacy beliefs towards reform are investigated [START_REF] Charalambous | Teachers' concerns and efficacy beliefs about implementing a mathematics curriculum reform: Integrating two lines of inquiry[END_REF][START_REF] Christou | Teachers' concerns regarding the adoption of a new mathematics curriculum: An application of CBAM[END_REF]. Nine other a posteriori studies report results supporting that curriculum change does not occur independently of a change in teachers' concerns, beliefs, views, and images about the nature of mathematics learning and teaching [START_REF] D'ambrosio | The modern mathematics reform movement in Brazil and its consequences for Brazilian mathematics education[END_REF][START_REF] Dolma | Investigating the alignment of Bhutanese mathematics teachers' planned approaches within the context of a reformed curriculum[END_REF][START_REF] Handal | Teaching mathematics thematically: Teachers' perspectives[END_REF][START_REF] Hu | A case study of the implementation of Chinese kindergarten mathematics curriculum[END_REF][START_REF] Laberge | First-year teachers' implementation of the NCTM standards[END_REF][START_REF] Stickles | Using instructional logs to study teachers' adaptation to curricular reform[END_REF][START_REF] Sullivan | Transposing reform pedagogy into new contexts: Complex instruction in remote Australia[END_REF][START_REF] Swars | Transitioning to the common core state standards for mathematics: A mixed methods study of elementary teachers' experiences and perspectives[END_REF][START_REF] Taylor | Implementing the standards: Keys to establishing positive professional inertia in preservice mathematics teachers[END_REF]. It should be noted that affective traits such as concerns, beliefs, views, and images are often not very well defined in individual studies.

The organization: Even if the teachers believe in the reformed ideas, this is not enough for successful reform [START_REF] Christou | Teachers' concerns regarding the adoption of a new mathematics curriculum: An application of CBAM[END_REF][START_REF] Handal | Teaching mathematics thematically: Teachers' perspectives[END_REF][START_REF] Laberge | First-year teachers' implementation of the NCTM standards[END_REF][START_REF] Stickles | Using instructional logs to study teachers' adaptation to curricular reform[END_REF][START_REF] Swars | Transitioning to the common core state standards for mathematics: A mixed methods study of elementary teachers' experiences and perspectives[END_REF]. Implementation fails without support structures from the school, providing the teachers with opportunities to understand the intentions of the innovation. Teachers need time and support for planning instruction before launching the reform, as well as support during the implementation. The school also needs to supply sufficient curricular resources that align with the ideas in the reformed curriculum.

The external environment: In the case of implementation, expectations on newly educated teachers and the level of alignment between methods taught in teacher education and required methods in the curriculum that teachers shall teach are influential factors [START_REF] Laberge | First-year teachers' implementation of the NCTM standards[END_REF].

Discussion

We posed the question: What factors of influence are decisive for the outcome of the implementation of a curriculum reform? Our main finding is that changes in accordance with a curriculum innovation do not occur independently of a change in the teachers' concerns, beliefs, views, and images about the nature of mathematics learning and teaching. Most papers highlight affective constructs, such as beliefs and views, as the main factors of influence for the outcome of implementation projects, which may be problematic when analyzing the results of the studies. Not only are affective constructs used and defined differently in the various studies, but this built-in discrepancy also makes it difficult to build on the results in future studies on curriculum adaptations. According to the studies we reviewed, it is not enough that teachers' beliefs are in line with the ideas carried by the innovation. Teachers' curriculum adaptions must be supported by the school organization. The role of the schools' organization is reinforced by the result that even when a majority of the teachers say they are positive towards reform, the change in teachers' beliefs that is supposedly required for a change in teaching practice does not take place, at least not without extensive organizational support. Looking at the matter from the characteristics of the innovation, we see the other side of the same coin. Unless the innovation is adapted, or at least adaptable, to the cultural context and presumably to the system of beliefs and manifested practices of the context of implementation, change is unlikely to occur. Finally, we conclude that the external environment is rarely discussed in our sample.

The main result presented above is in line with a wealth of previous research on curriculum reform and associated teacher change, for example, represented in the theoretical account of the phenomena by [START_REF] Gregoire | Is it a challenge or a threat? A dual-process model of teachers' cognition and appraisal processes during conceptual change[END_REF], the Cognitive-Affective Model of Conceptual Change. According to this model, when teachers' practices are implicated by a reform message, change is likely to occur only when the reform message is seen as a challenge rather than a threat. Seeing it as a challenge depends on appraising one's own cognitive and affective resources as well as the organizational support as sufficient for enacting a practice in line with the reform message. The only example of effective implementation in our sample reinforces this conclusion. In the case reported by [START_REF] Kramer | An existence proof: Successful joint implementation of the IMP curriculum and a 4 x 4 block schedule at a suburban US high school[END_REF], teachers who already believed in the reform ideas were hired and given extensive support in the form of professional development, forums for collaboration, and support in practice. Unfortunately, not all schools can hire teachers who already have the capacity to implement reforms simply because they do not exist. Hence, the approach taken in the project reported by Kramer and Keller appears unrealistic for implementation at a large scale.

Our study is small in scope, which should be kept in mind when reading the results. However, given that our results on the importance of belief alignment and organizational support are indeed in line with previous research, it is surprising to observe so few studies with an a priori approach specifically designed to shed light on the mechanisms of belief change and organizational support. A wellestablished call from external sources [START_REF] Chen | Theory-driven evaluations[END_REF]) and internal [START_REF] Century | Implementation research: Finding common ground on what, how, why, where, and who[END_REF] to educational research is to design for evaluation, explicate the supposed main factors of influence along their mechanisms, and design ways of evaluating these mechanisms. It seems to us that these calls should be taken rather seriously by designers and researchers in the area of curricular reform in order for the field to take further steps toward ensuring effective implementations.

Acknowledgments

This paper is part of grant 2020-04090 under the Swedish Research Council.