Martin Jiskra
email: martin.jiskra@unibas.ch

Lars-Eric E Heimbürger-Boavida

Marie-Maëlle Desgranges

Mariia V Petrova

Aurélie Dufour

Beatriz Ferreira-Araujo

Jeremy Masbou

Jerome Chmeleff

Melilotus Thyssen

David Point

Jeroen E Sonke
email: jeroen.sonke@get.omp.eu

Non-peer reviewed EarthArXiv

Keywords: GEOTRACES, marine mercury, Hg stable isotopes, Mediterranean Sea, Atlantic Ocean, atmospheric deposition, gas exchange, emission, invasion, biota, sediment Non-peer reviewed EarthArXiv

Human exposure to toxic mercury (Hg) is dominated by the consumption of seafood 1,2 . Earth system models suggest that Hg in marine ecosystems is supplied by atmospheric wet and dry Hg(II) deposition, with a 3 times smaller contribution from gaseous Hg(0) uptake 3,4 . Observations of marine Hg(II) deposition and Hg(0) gas exchange are sparse however 5 , leaving the suggested importance of Hg(II) deposition 6 ill-constrained. Here we present the first Hg stable isotope measurements of total Hg (tHg) in surface and deep Atlantic and Mediterranean seawater and use it to quantify atmospheric Hg deposition pathways. We observe overall similar tHg isotope compositions, with median Δ 200 Hg signatures of 0.02‰, lying in between atmospheric Hg(0) and Hg(II) deposition endmembers. We use a Δ 200 Hg isotope mass balance to estimate that seawater tHg can be explained by the mixing of 42% (24 to 50 %, median and interquartile range) atmospheric Hg(II) gross deposition and 58% (50 to 76 %) Hg(0) gross uptake. We measure and compile additional, global marine Hg isotope data including particulate Hg, sediments and biota and observe a latitudinal Δ 200 Hg gradient indicating larger ocean Hg(0) uptake at high latitudes. Our findings suggest that global atmospheric Hg(0) uptake by the oceans is equal to Hg(II) deposition, which has implications for our understanding of atmospheric Hg dispersal and marine ecosystem recovery.

). Dissolved Hg(0) concentrations in surface waters are sporadically measured, and generally show Hg(0) supersaturation [19][20][21] , supporting net Hg(0) evasion. The direction and magnitude of the large air-sea exchange of Hg(0) depends on the aqueous Hg(II) reduction and Hg(0) oxidation rates, and the wind driven air-sea Hg(0) exchange velocity in models 6 . The absence of direct, long-term Hg(0) flux measurements over the ocean and limited

observations of Hg(II) wet and dry deposition to oceans currently provide insufficient constraints for model validation of air-sea Hg(0) exchange, and Hg(II) deposition fluxes. This in turn hampers our capability to predict how Hg levels in the ocean will respond to curbed anthropogenic Hg emissions under the UN Minamata Convention on Mercury, and to climate change 12,22 .

In terrestrial ecosystems, Hg stable isotopes have proven to be instrumental in understanding the relative importance of Hg(II) and Hg(0) deposition [23][24][25] . Atmospheric Hg(0) and Hg(II) in rainfall have different mass-dependent (MDF, δ 202 Hg) and mass-independent isotope fractionation (MIF, Δ 199 Hg and Δ 200 Hg) signatures. Even-Hg MIF (Δ 200 Hg) is thought to be generated exclusively by upper tropospheric and/or stratospheric photochemical reactions 26,27 . Δ 200 Hg is therefore considered as a conservative tracer for atmospheric Hg deposition pathways 28 . So far, Hg stable isotopes in total unfiltered Hg (tHg) in seawater have only been measured in coastal seawater of the Canadian Arctic Archipelago, suggesting that 50% to 80% of tHg originated from coastal erosion and river input 29 . Analysis of particulate Hg (pHg) isotopes at the station ALOHA (22 o N) near Hawaii suggested that atmospheric deposition of Hg(II) from rainfall was an important Hg source to the tropical Pacific surface ocean 30 .

In this contribution we develop and apply a method for tHg isotope analysis of open ocean seawater, characterized by its (sub-)picomolar levels of tHg in all basins 31 , to understand atmospheric supply of Hg to the ocean. We use the new Mediterranean and North-Atlantic tHg and pHg isotope observations together with published atmospheric Hg(II) and Hg(0) and marine pHg, sediment and biota Hg isotope data to show that ocean Hg(0) uptake is relatively more important than currently estimated.

Results and Discussion

Seawater Hg isotope composition

Oligotrophic Mediterranean station K2, 20 km off-shore (Extended Data Figure 2) showed tHg concentrations in June 2017, February and May 2019 (Figure 1a) that are slightly depleted in surface waters (0.80 pM), and peak at 300 m depth (1.1 pM), similar to previous observations 32,33 . Total methylated Hg (MeHg) concentrations peak at 400 -600 m, (43 % of tHg), where oxygen levels reach their minimum due to microbial remineralization of particulate organic matter 33 . Surface tHg levels in the Bay of Marseille at Endoume pier were higher with 6.1 pM (4.9 to 6.7 pM, median and interquartile range (IQR), n = 8). In four samples from two Atlantic Ocean stations (St21, St38, Extended Data Figure 2), tHg increased with depth from 0.46 to 0.83 pM and represent the mixed layer (5 m, 20 m), intermediate water (650 m), and north-east Atlantic deep water (NEADW, 3345 m) 34 . MeHg in the two Atlantic profiles were similar to Mediterranean station K2 with low levels, 0.04 pM, at the surface and elevated levels, 0.4 pM, at depth (54 % of tHg). pHg at the Mediterranean stations K1, K2 and Julio were low with a median of 0.10 pM (IQR: 0.08 to 0.15 pM, n = 16) for the 5 -800 m depth range. Fram Strait pHg in Atlantic Ocean waters of the West-Spitzbergen current had higher pHg levels of 0.28 pM (0.23 to 0.31 pM, median and IQR, n = 9). tHg isotope depth profiles for δ 202 Hg, Δ 199 Hg and Δ 200 Hg signatures were replicated at station K2 during two sampling cruises in February and May 2019 and show reproducible results (Figure 1bd). δ 202 Hg is uniform with depth, with a median value of -0.09 ‰ (IQR: -0.31 to 0.00 ‰, n = 12). Overall, Δ 199 Hg and Δ 200 Hg are also near-zero, with median values of 0.06 and 0.01 ‰ respectively. The four North-Atlantic Ocean tHg samples show median δ 202 Hg of -0.45 ‰, Δ 199 Hg of 0.09‰, and Δ 200 Hg of 0.06‰, and are therefore similar to Mediterranean waters. pHg isotope data for the Mediterranean Sea (n=19) and Atlantic (n=9) were broadly similar to tHg observations (Figures 1,2, Supporting Information). Mediterranean sediments, had similar δ 202 Hg = -0.75 ‰ (-0.76 to -0.74 ‰), Δ 199 Hg = 0.05 ‰ (0.04 to 0.05 ‰) and Δ 200 Hg = 0.03 ‰ (0.00 to 0.06 ‰) (median and (IQR), n = 4) to mean water column pHg, and were similar to sediment samples taken elsewhere in the Mediterranean Sea 35,36 . Overall, the tHg and pHg Δ 199 Hg/Δ 201 Hg slopes of 0.8 to 1.0 are indicative of photochemical MIF (Figure S2).

Atmospheric Hg(II) and Hg(0) deposition

We use Δ 200 Hg to quantify the combined contribution of gross Hg(II) wet and dry deposition, and gross Hg(0) invasion to marine tHg and pHg (Methods, Eq. 3). It is important to clarify that Hg(0) gas exchange is bi-directional (Extended Data Figure 1), i.e. at any time atmospheric gaseous Hg(0) dissolves into the surface microlayer (invasion), and dissolved aqueous Hg(0) evades to the atmosphere. Although generally surface oceans are supersaturated in Hg(0), and gross Hg(0) evasion exceeds gross invasion, the gross Hg(0) invasion flux is substantial, around 1700 Mg y -1 in models, and an important contributor to marine Hg (Extended Data Figure 1). The Hg(II) dry and wet deposition flux is per definition a gross flux. Hg(II) deposition, after reduction to Hg(0) in ocean waters, does however contribute to the large Hg(0) emission flux. We exclude other marine Hg sources such as hydrothermal or river inputs. At Mediterranean station K2, this is justified by the absence of large rivers draining into the Ligurian Sea, and reflected in the open-ocean type tHg levels around 1 pM. The Rhône River reaches the Mediterranean, 100 km west of K2, at the continental shelf of the Gulf of Lions, and is carried further westward away from K2. Similarly, there is no hydrothermal activity within about 1000 km from the K2 station. At the Atlantic Ocean stations St21 and St38, no influence of river 37 or hydrothermal Hg inputs was found 34 .

Modern, northern hemispheric Hg(II) wet deposition is characterized by a positive Δ 200 Hg of 0.17 ‰ (0.11 ‰ to 0.22 ‰, median and (IQR), n = 106), for background sites with Hg concentrations < 25 ng L -1 ; Extended Data Table 1). We also need to consider the Δ 200 Hg of Hg(II) dry deposition, suggested to represent 40% of total atmospheric Hg(II) deposition to oceans 38 . Aerosol and fog water Hg(II) observations in the marine boundary layer (MBL) and free tropospheric gaseous Hg(II) in Atlantic air masses also have positive but slightly lower Δ 200 Hg of 0.10 ‰ (0.07 to 0.1 ‰; median, IQR, n = 66) 39- 41 . For end-member mixing calculations we estimated the Δ 200 Hg of combined wet and dry Hg(II) deposition to vary between 0.13 and 0.15 ‰ with latitude (Extended Data Figure 6). Atmospheric Hg(0), the largest Hg pool in the atmosphere, exhibits negative Δ 200 Hg of -0.05 ‰ (-0.08 to -0.03 ‰; median, IQR, n = 220, for continental background samples with Hg(0) concentrations < 2 ng m -3 ; Extended Data Table 1). MBL Hg(0) observed at coastal sites and during cruises shows an identical Δ 200 Hg of -0.06 ‰ (-0.08 ‰ to -0.02 ‰, median and IQR, n = 80, two-sided t.test, p = 0.96) [START_REF] Rolison | Isotopic composition of species-specific atmospheric Hg in a coastal environment[END_REF][START_REF] Demers | Coupling atmospheric mercury isotope ratios and meteorology to identify sources of mercury impacting a coastal urban-industrial region near Pensacola, Florida, USA[END_REF][START_REF] Fu | Isotopic Composition of Gaseous Elemental Mercury in the Marine Boundary Layer of East China Sea[END_REF] .

Seawater tHg and pHg samples, including published Pacific Ocean pHg 30 , show Δ 200 Hg values statistically larger than atmospheric Hg(0) (one-sided t.test, p<0.001) and lower than Hg(II) endmembers (one-sided t.test, p<0.001; Figure 2 & Figure 3A). Based on a Δ 200 Hg mixing model (Methods, Eq. 3) we estimate the contribution of Hg(0) uptake, fHg(0), to be 58 % (50 to 76 %, median and IQR, n = 16) to marine tHg and 58 % (39 to 82 %, n = 61) to pHg. This implies that the majority, i.e. approximately 58% of N-Atlantic and Mediterranean Sea tHg and pHg is derived from direct ocean Hg(0) uptake. We apply the same Δ 200 Hg mass balance to the large body of published Hg isotope data in pelagic marine sediments and pelagic biota (n = 735, Extended Data Table 2). Similar to sea water tHg and pHg, global pelagic marine sediments and biota Δ 200 Hg suggest a Hg(0) contribution, fHg(0) of 57 % (49 to 65 %, n = 92) and 40 % (31 to 60 %, n= 643), respectively. The marine sediment and biota Δ 200 Hg data cover a much larger geographical range than the tHg and pHg data, including the southern hemisphere, and indicate that, despite net Hg(0) evasion, gross ocean Hg(0) uptake is a globally important driver of marine pelagic ecosystem Hg levels.

Latitudinal Δ 200 Hg variability

The validity of the Δ 200 Hg mass balance hinges on two important details: 1. the link between aqueous Hg redox transformation rates and the gross or net nature of the Hg(II) deposition and Hg(0) uptake fluxes in the mass balance, and 2. latitudinal variation in marine Δ 200 Hg observations. The current consensus in Hg cycling models is that marine aqueous Hg reduction and oxidation rates are fast 18,[START_REF] Semeniuk | Development of a global ocean mercury model with a methylation cycle: Outstanding issues[END_REF][START_REF] Soerensen | An Improved Global Model for Air-Sea Exchange of Mercury: High Concentrations over the North Atlantic[END_REF] , leading to global surface ocean oxidation and reduction fluxes of 2.6 x 10 6 Mg y -1 45 , which are 1000-fold larger than Hg deposition and air-sea exchange fluxes. This implies that the contrasting Δ 200 Hg signatures of gross Hg(0) invasion (-0.05 ‰) and gross Hg(II) deposition (+0.14 ‰) will be rapidly homogenized in the surface mixed layer before Hg(0) is partially re-emitted to the atmosphere. The Δ 200 Hg derived Hg(0):Hg(II) deposition ratio therefore represents the gross deposition ratio. Secondly, our new seawater tHg and pHg Δ 200 Hg observations are from 43 o -81 o N, where Hg(II) wet deposition is known to be lower than in the northern hemispheric (sub-)tropics (Extended Data Figure 3). We therefore examined current best knowledge on the latitudinal variation of Hg(0) invasion vs Hg(II) deposition by a full latitudinal analysis of marine Δ 200 Hg, combined wet and dry Hg(II) deposition flux, atmospheric and dissolved gaseous Hg(0) concentrations, and climatology (indicated by zonal 'reference model' in Figure 4). Gross Hg(II) deposition, gross Hg(0) invasion, gross Hg(0) evasion and net Hg(0) evasion, all based on a combination of published observations and models, (Figure 4, Extended Data Figure 5) vary as a function of latitude. Hg(0) invasion is primarily driven by observed atmospheric Hg(0) concentrations and wind speed, and is maximal at mid and high latitudes (Figure 4d). Hg(II) deposition is dominated by Hg(II) wet deposition in the sub-tropical northern hemisphere (Figure 4c). We use the Hg(II) deposition and Hg(0) invasion estimates (Figure 4, Extended Data Figure 5), together with Δ 200 Hg end-members (Extended Data Figure 6, Extended Data Table 1) to predict the latitudinal marine Δ 200 Hg distribution for the zonal 'reference model' (Figure 4a). Due to the asymmetric contributions of Hg(II) deposition and Hg(0) invasion to marine Hg, the predicted marine Δ 200 Hg trend shows a maximum of 0.11 ‰ in the northern hemispheric (sub-)tropics and lower values of 0.02‰ at high latitudes. The observed marine Δ 200 Hg distribution in water, sediments and biota is similar in shape but shifted to lower values compared to the predicted Δ 200 Hg distribution, except between 45 -65 o N (Figure 4a). The Δ 200 Hg observations therefore indicate a relatively larger Hg(0) invasion, or alternatively a smaller Hg(II) deposition contribution to pelagic marine Hg. By integrating the marine Δ 200 Hg observations over latitude and weighting by sea surface area, we estimate a global ocean Hg(0) uptake contribution of 50% (IQR: 34% to 67%). Current best model estimates of global gross Hg(0) uptake and gross Hg(II) deposition at the ocean surface are 1700 Mg y -1 and 4600 Mg y -1 respectively. 3 Marine Hg isotope observations therefore suggest that gross Hg(0) uptake is equally important as gross Hg(II) deposition in a 1:1 ratio, compared to the Hg cycling model predicted ratio of 1:3. The latitudinal Δ 200 Hg data are supported by the alternative even-Hg isotope signature Δ 204 Hg, which mirrors Δ 200 Hg (Extended Data Figure 7).

The marine Δ 200 Hg composition suggests that our current understanding of the marine Hg budget is incomplete. We consider the most plausible reason for this to be that Hg(II) deposition to oceans is overestimated, either due to bias in coastal Hg(II) wet deposition observations (Figure 4c) by regional continental anthropogenic Hg emission sources, or due to overestimation of marine Hg(II) dry deposition for which no observations exist (Supporting Information text). Alternatively, current Hg(0) air-sea exchange parameterizations (Equations S1-3) could be incomplete, ignoring effects of the surface micro-layer on the Hg(0) gas exchange velocity. In order to fit observed marine Δ 200 Hg variability, a 2-3x lower marine Hg(II) deposition or 2-3x higher ocean Hg(0) uptake flux would be required (Figures 4c,d, Extended Data Figure 1; Supporting Information text). In either case, a larger relative contribution of Hg(0) to the oceans would have important impacts on the lifetime of anthropogenic Hg in atmosphere and surface ocean, and consequently on the anticipated recovery of ecosystems following aggressive Hg emission policy.

Unfiltered seawater was drawn via acid-cleaned 6 mm FEP tubing into pre-cleaned 20 L Pyrex glass bottles with GL45 PFA Teflon caps. Bottles were filled to the 20 L mark, and not to the brim, in order to preserve a 3 L headspace for purge and trap purposes. Bottles were protected from sunlight and breaking risk in 70 L plastic barrels (Kruizinga.nl Ref#53-WHV70) by using polyurethane expansive foam to fit them in the barrels. We anticipate that future use of 20 L polycarbonate carboys are an alternative option, for safer sampling during rough seas. Unfiltered seawater was drawn from each GOFLO bottle into acid-cleaned and blank-tested 60 mL FEP Teflon bottles (Nalgene) for tHg and 250 mL PFA Teflon bottles (Savillex Purillex) for MeHg, MMHg and dissolved gaseous Hg (DGM = Hg 0 + dimethyl-Hg (DMHg)) analysis. All sampling was compliant with strict GEOTRACES trace metal clean sampling procedures [START_REF] Cutter | Sampling and Sample-handling Protocols for GEOTRACES Cruises[END_REF] . Eight 20 L replicate samples of seawater from the Bay of Marseille were taken every three hours on 12/11/2019 at the Endoume pier. Seawater is continuously pumped at 20 L min -1 into the Mediterranean Institute of Oceanography (MIO) seawater sensing lab (SSL@MM). Samples were transported to MIO and processed within 24 h. Atlantic Ocean tHg samples were collected during the GEOVIDE cruise (GEOTRACES-GA01 transect), on board the RV "Pourquoi Pas?" between 15/05/2014 and 30/06/2014, similar to the MED Sea but using a 24 bottle trace metal clean carousel. tHg values for GEOVIDE have been published elsewhere [START_REF] Cossa | Mercury distribution and transport in the North Atlantic Ocean along the GEOTRACES-GA01 transect[END_REF] .

Particulate Hg. pHg was sampled using in situ pumps (McLane LV08) at stations K1 (43.10 N, 5.49 E, 700 m depth, 10 km off-shore, continental slope), K2, and Julio (43.13 N, 05.36 E, 100 m-depth, 10 km off-shore, shelf) in the Mediterranean Sea on 16/06/2017, and at K2 on 22/05/2019; in Fram Strait Atlantic waters from 21/7/2016 to 1/9/2016 during the FS Polarstern PS100 GRIFF cruise (Geotraces-GN05 transect). Pre-burnt Millipore 142mm QMA, or GF/F were deployed for 1 -3 h to collect particles from 148-792 L of seawater. Filter samples were frozen onboard, shipped frozen to MIO, freeze dried (Christ Gamma 1-16 LSCplus), and stored in the dark until analysis.

Pre-concentration of tHg from seawater for stable isotope analysis

The 20 L Mediterranean tHg samples were acidified and oxidized, within 12 h after sampling, at the MIO laboratory, using 5 mL 0.2 N BrCl (Sigma-Aldrich KBr and KBrO3 salts) in concentrated bi-distilled 9 N HCl, leading to an initial sample HCl concentration of 0.0023 N. BrCl blanks were analyzed before addition, as it potentially constitutes the largest single component of the method blank. The volume of BrCl was optimized by visual inspection of the sample turning slightly yellow, indicating excess BrCl over reduced seawater components such as dissolved and particulate organic matter (DOC, POC, OM).

Samples were let sit for 12 h, after which a 60 mL subsample was taken with an acid cleaned, 60 cm long, burette into pre-combusted 60 mL glass vials with acid-washed Teflon-lined caps for tHg concentration analysis. This tHg subsample is compared to the shipboard 60mL tHg FEP sample and serves to verify that the 20 L bottles are neither contaminated, nor subjected to tHg loss. tHg pre-concentration was started by replacing the GL45 PFA Teflon caps (Savillex) by GL45 two-port PFA Teflon caps (Savillex) to guide 60 cm long 6 mm OD (3 -4 mm ID) Pyrex bubbling post with a 1 cm long P3 porosity frit (VitraPOR Micro Filter-Candle, Robuglas, Germany, custom assembled by Verres Vagner, Toulouse, France). The second port on the GL45 cap hosted a 10 cm long 6 mm OD FEP tube that was connected with a short piece of 10 mm OD, 4 mm ID silicone tubing to a shorter, 25 cm long, elbowed 6mm OD Pyrex bubbling post, with 1 cm long P2 frit (VitraPOR). The P2 bubbler post was then inserted into a 60 mL, 20 cm long glass test tube, filled with 6 mL of oxidizing 40 vol% inverse aqua regia (iAR) solution. The medium P2 bubbler frit inside the 40% iAR trap is critical to avoid over pressure and leaks of Hg(0) from the 20 L bottle. All glassware was pre-combusted at 530°C and Teflonware was cleaned by multiple bi-distilled HCl steps in a class 100 clean room.

Standard protocols for Hg(II) analysis by SnCl2 reduction, such as EPA method 1631 [START_REF]method 1631 Revision EMercury in Water by Oxidation, Purge and Trap, and Cold Vapor Atomic Fluorescence Spectrometry[END_REF] , use a large excess of SnCl2 over Hg(II). While SnCl2 does not pose a blank issue (purging it removes all Hg traces), it generates large volumes of toxic waste in each 20 L bottle after pre-concentration. We therefore tested up to 100x lower levels of anhydrous Sn(II)Cl2 (Sigma-Aldrich). Hg(II) reduction by Sn(II) competes however with excess BrCl and natural oxygen present in seawater, i.e. Sn(II) is oxidized by BrCl and O2 before it can reduce Hg(II). We therefore neutralized excess BrCl by adding 4 mL of NH4.HCl (4.3 M) and verified disappearance of the yellow color. We then pre-purged (before adding SnCl2) the 20 L sample with Hg-free argon at 300 mL min -1 for 3 h to remove > 90 % of dissolved oxygen.

The 40% iAR solution trap was connected during pre-purging to trap any potential, though unlikely, loss of gaseous Hg from the sample. Adding SnCl2 at this point, had however shown abundant precipitation of a fine white solid, presumably SnCl2,s, which we remedied by adding an additional 80 mL volume of HCl to stabilize Sn(II) in the samples. Sn(II) addition was performed in two ways: i) 125 mL of SnCl2 was slowly pumped with a peristaltic pump (Gilson) at 1.25 mL min -1 , and 1/16'' PFA tubing, via the central bubbling post into the bottle over 2 h; ii) the 125 mL was added instantly via the GL45 cap. No differences in Hg recovery were found between the two. Upon addition of SnCl2 by pump or in batch, we purged the 20 L samples for 8 h at 300 mL min -1 , in order to quantitatively collect sample Hg into the oxidizing 40% iAR trap solution. At the end of 6 h of pre-concentration, the argon flow was stopped, and the 40 v% iAR traps removed and diluted with MQ water to 20 v% iAR and stored cold (4 o C) in the dark until analysis.

For the Atlantic Ocean tHg samples, a different pre-concentration technique was applied onboard which is described in detail in the Supporting Information. In brief, 48 L samples, stored in Teflon (Tedlar) bags, were pumped at 5 mL min -1 , through an iodated activated carbon (IAC) cartridge onboard. The IAC sorbent was combusted back on land, at Geosciences Environnement Toulouse (GET), in a dual tube furnace set-up, and sample Hg(0) trapped in 6 mL 40% iAR. We abandoned this method due to higher blanks, challenging Hg recoveries from IAC, and slowness of sea water sample loading (1 week).

Procedural blanks and standards

Procedural Hg blanks, representing all laboratory manipulations, cleaning procedures, reagent additions, and different operators, were determined as follows. Following pre-concentration of a batch of 8 samples for tHg, the residual Hg-free seawater solution, was conserved in the 20 L bottle, and all reagents were newly added to 8 bottles as described above. The solutions were then purged, similar to samples, for 8 hours into newly prepared 6 mL 40% iAR traps. Eight procedural standards were preconcentrated in a similar fashion: following blanks, once more all reagents were added to the remaining 20 L of Hg-free seawater solution, and 4 to 8 ng of NIST SRM 3133 Hg was added as internal standard to each bottle.

Particulate Hg concentration analysis

Total particulate Hg (pHg) concentrations were measured on 25 mm stamp-outs, by combustion -cold vapor atomic absorption spectrometry (CV-AAS, Leco AMA254) equipped with a low level optical cell at MIO. Certified reference material NRC MESS-3 marine sediment (91 ± 9 ng g -1 , 1σ) was used for quality control, with good results in the low, <1 ng Hg, range (88 ± 1 ng g -1 , 1σ). Remaining filter material was combusted whole on the dual tube furnace set-up at GET, following published protocols [START_REF] Sun | A double-stage tube furnace-acidtrapping protocol for the pre-concentration of mercury from solid samples for isotopic analysis[END_REF] . In brief, filters are rolled up, inserted in a 20 mm diameter, 15 cm long quartz tube, which is plugged from both sides with quartz wool. The sample tube is then inserted in a 140 cm long quartz tube, housed in two tube furnaces. The first furnace, hosting the sample tube, was heated from room temperature to 900 o C over 6 h in an 80 mL min -1 flow of high purity oxygen. The released Hg(0) vapor and other volatile compounds passed through the 2 nd pyrolizing oven, maintained at 1000 o C continuously, and purged into a 40 vol% iAR oxidizing solution trap, that uses an elbowed, fritted, P2 porosity, Pyrex post. GF/F and GF/D filters melt at temperatures >530 o C, but remain within the quartz sample tubes, blocked by the quartz wool. Final trapping solutions were diluted to 20%v iAR and stored cold in the dark until Hg concentration analysis by CV-AFS and Hg isotope analysis by MC-ICPMS. Reference material NIST SRM1632d coal was used for weekly quality control. Combustion purge and trapping recovery on samples, assessed by CV-AFS, was 104 ± 28%, 100 ± 28%, and 105 ± 21% (1σ) for the Mediterranean Sea, PS94 and PS100 cruise samples respectively.

tHg and Hg species concentration analysis

We added 40 μL of 0.2N BrCl to the 60 FEP Teflon bottles for ambient tHg analysis. Ambient tHg concentrations in 60 mL FEP Teflon bottle aliquots, in 20 L bottle aliquots before and after preconcentration, and in 20% iAR solution traps were all analyzed in duplicate using a custom-made purge and trap system coupled to a cold vapor atomic fluorescence spectrometry (CV-AFS, Brooks Rand Model III), either at MIO, at GET, or shipboard [START_REF] Semeniuk | Development of a global ocean mercury model with a methylation cycle: Outstanding issues[END_REF] . The purge and trap system consists of 100 mL Teflon batch reactor (VWR), two electromagnetic valves (NResearch), a single gold trap (LECO), all connected by 1/8 inch FEP tubing to the CV-AFS (Brooks Rand Model 3). Seawater aliquots were 35 mL, and 20% iAR aliquots 100 µL. The CV-AFS was calibrated in the 1 -20 pg range using NIST SRM 3133, and the NRC ORMS-5 certified reference material was always found within 10 % of the certified value (26 ± 1.3 ng L -1 , 1σ). MeHg, MMHg, and DGM were analyzed following our published protocols [START_REF] Heimbürger | Shallow methylmercury production in the marginal sea ice zone of the central Arctic Ocean[END_REF] . DMHg was calculated as the difference of MeHg and MMHg, and dissolved Hg(0) as the difference of DGM and DMHg. Details are given in the SI.

Hg isotope analysis

Hg stable isotope ratios of final 20 % iAR trap solutions were measured in duplicate during two sessions by cold vapor multi-collector inductively coupled plasma mass spectrometry (CV MC-ICPMS) at the Observatoire Midi-Pyrénées, Toulouse [START_REF] Jiskra | Insights from mercury stable isotopes on terrestrial-atmosphere exchange of Hg(0) in the Arctic tundra[END_REF][START_REF] Obrist | Tundra uptake of atmospheric elemental mercury drives Arctic mercury pollution[END_REF] . We used a CETAC ASX-520 autosampler and HGX-200 CV system coupled to a Thermo-Scientific Neptune PLUS, equipped with a 10 12 Ω resistor, attributed to the 198 Hg isotope in order to improve isotope ratio precision in the 10-50 mV range. Samples and standard signals at 0.25 ng g -1 tHg levels were generally 180 mV on the 202 Hg isotope, at a sample introduction flow rate of 0.75 mL min -1 . Thallium was not used as an internal standard, and the 203 and 205 masses were monitored to survey Hg-hydride interferences (i.e. 202 Hg 1 H, and 202 Hg 1 H 1 H), which were found to be negligible when using standard H-cones. 196 Hg and 204 Hg were not analyzed due to low abundance, and cup configuration limitations. MDF of Hg stable isotopes is reported in small delta notation (δ) in per mil (‰) deviation from to the reference NIST 3133 Hg standard: δ xxx Hg = (( xxx Hg /198 Hg)sample/( xxx Hg /198 Hg)NIST3133 -1) × 10 3 (1)

where 'xxx' refers to measured isotope masses: 199, 200, 201, and 202. Mass independent fractionation (MIF) is reported in capital delta notation [START_REF] Blum | Reporting of variations in the natural isotopic composition of mercury[END_REF] , which is defined as the difference between the measured δ 199 Hg, δ 200 Hg, and δ 201 Hg values and those predicted for MDF relative to δ 202 Hg using the kinetic MDF law:

Δ xxx Hg = δ xxx Hg -SF xxx × δ 202 Hg (2)
where SF xxx is the mass-dependent scaling factor of 0.2520 for 199 Hg, 0.5024 for 200 respectively, in agreement with previously reported values [START_REF] Bergquist | Mass-Dependent and -Independent Fractionation of Hg Isotopes by Photoreduction in Aquatic Systems[END_REF] .

pHg and tHg isotope method uncertainty

Mean pre-concentration recoveries for tHg isotope analysis were 90 ± 10% (1σ, n

Stable isotope data analysis

The fraction of Hg in marine samples derived from atmospheric Hg(0) (fHg(0)) was calculated using a binary isotope mixing model as follows:

Δ 200 Hgsample = (1-fHg(0) ) × Δ 200 HgHg(II) + fHg(0) × Δ 200 HgHg(0) (3)
where Δ 200 Hgsample represents the measured value of the marine sample (THg, pHg, sediment THg, biota THg) or sample group. Δ 200 HgHg(0) and Δ 200 HgHg(II) end-member compositions are based on 392 published data points (Extended Data Table 1). The Δ 200 HgHg(II) end-member composition varies as a function of latitude, between values of 0.13 and 0.15 ‰ due to variable contributions of Hg(II) dry and wet deposition (Extended Data Figure 6). The uncertainty on calculated fHg(0) and fHg(II) fractions was estimated using a Monte Carlo error propagation approach, taking into account median and IQR in all parameters (Extended Data Table 2).

Figures

Figure 1a- 1), tHg values are from this study, pHg from this study and ref. 30 . Error bars represent the two standard deviation (2SD)

uncertainties of individual samples. from this study and from ref. 30 , data for sediments and biota are from literature (Extended Data Table 1) The small variation is caused by the variable contributions (Extended Data Figure 5) of Hg(II) wet deposition with  200 Hg of 0.16‰, and Hg(II) dry deposition with  200 Hg of 0.10‰ (Extended Data Table 1). The dashed line represents the median and the shaded area the interquartile range (IQR). Quantitative oxidation of Sn(II) by hydrogen peroxide also has the advantage that no traces of Sn(II) remain in the 20 L bottle, which can be acid-cleaned (0.1 vol% commercial HCl) and rinsed with abundant MQ water to receive the next batch of seawater samples. In this study both sampling and pre-concentration were done in the same bottle. We expect however that the use of separate bottles, possibly using plastic 20 L carboys at sea for safety, does not increase blanks.

Extended

Alternative, activated carbon based pre-concentration method for sea water

We have, over the past years, tested an alternative method for low-level Hg pre-concentration in order to measure Hg isotopes in sea water. The method uses small 200 mg iodated activated carbon powder (Brooks Rand) cartridges, over which large volumes (50L) of unfiltered, acidifed (0.4% v/v HCl) sea

water are pumped at a slow flow rate of 5 ml min -1 . Following laboratory recovery and blank testing, we applied the method during the 2014 GEOTRACES Geovides cruise in the North-Atlantic Ocean.

Unfiltered seawater was transferred using clean 6mm FEP tubing from GOFLO bottles into acid washed 50L tedlar bags. A peristaltic pump, with 1.14mm ID (red/red) tygon pump tubing was used to load samples on the IAC traps during 1 week. Traps were dried for 5 min in a dry high purity argon stream, sealed with silicone stoppers and stored and transported dry and in the dark to the GET laboratory.

The IAC powder was combusted using a dual tube furnace combustion method 8 . IAC blanks were 0.5 ng Hg per 200mg of IAC traps, and sample recoveries were 88 ± 31%. In hindsight, it has been difficult to fully recover Hg from IAC traps due to abundant volatile iodine release and transfer to oxidizing solution traps. We recommend that further development of activated carbon based methods use commercial sulfur impregnated activated carbon (Calgon HGR), which does not have this issue 9 .

MMHg and DMHg analysis

MMHg and DMHg were determined by isotope dilution (ID)-gas chromatography -sector field ICP-MS (ID-GC-SF-ICPMS) method at the MIO laboratory, following previously published protocols 10 . First the sum of both species (tMeHg) was quantified on an acidified sample that converts DMHg to MMHg.

A second replicate sample was purged to remove DMHg before acidification, allowing direct measurement of MMHg. DMHg was calculated by difference, as tMeHg -MMHg. In both sample aliquots MMHg and inorganic Hg species were extracted after derivatization. In brief, enriched spikes of 199 iHg and 201 MeHg (ISC Science, Spain) were added to a 115 mL aliquot of the sea water samples.

After 24h of equilibration, pH was adjusted to 3.9 with NH3 (ULTREX® II Ultrapure Reagent, J.T. Baker, USA) and a buffer solution made up with acetic acid (glacial, ULTREX® II Ultrapure Reagent, J.T. Baker, USA) / sodium acetate (J.T. Baker, USA). A solution of 1 % (v:v) sodium tetra propyl borate (Merseburger Spezialchemikalien, Germany) was made up freshly, under cold conditions and avoiding contact with atmospheric oxygen. 1 mL of this solution was then added together with 200 µL hexane (Sigma Aldrich, USA). The glass bottles were hermetically sealed with Teflon-lined caps and vigorously shaken for 15 minutes. The organic phase was recovered and injected in the GC (Thermo Trace Ultra), coupled to a sector field ICPMS (Thermo Element XR). Detection limits were 0.005 pM for MMHg, and 0.01 pM for DMHg.

pHg isotope results

At station K2, pHg Δ 199 Hg and Δ 200 Hg were similar in June 2017 and May 2019 at all depths, while δ 202 Hg was higher in June 2017 by 1.5 ‰ at 100 -400m depth. Only in May 2019 at station K2, tHg and pHg isotopes were determined simultaneously and δ 202 Hg of pHg was depleted by -1.0 ‰ (-0.8 ‰ to -1.3‰; median and (IQR), n = 4) relative to tHg (Figure 1b). Light isotope enriched pHg may be explained by the preferential sorption of light Hg(II) isotopes to particulate organic matter 11 , or by preferential uptake of light isotopes by phytoplankton that is part of the particulate pool. pHg stable isotopes sampled in 2017 at two stations, Julio and K1, closer to the coast were similar to the open sea station (K2) with no clear trends in water depth or distance from the shore (Figure S1). Marine sediments, analyzed for station Julio only (700 m depth), had similar δ 202 Hg = -0.75 ‰ (-0.76 to -0.74 ‰), Δ 199 Hg = 0.05 ‰ (0.04 to 0.05 ‰) and Δ 200 Hg = 0.03 ‰ (0.00 to 0.06 ‰) (median and (IQR), n = 4) to mean water column pHg (K1, K2, Julio), and were similar to sediment samples taken elsewhere in the Mediterranean Sea 12,13 .

Sea water Δ 199 Hg and photochemical reduction of Hg(II) to Hg(0)

During photoreduction of Hg(II)-organic ligand complexes the magnetic isotope effect (MIE) may separate even from odd Hg isotopes 14 . Experimental photomicrobial Hg(II) reduction in simulated sea water medium has been shown to lead to negative Δ 199 Hg in residual aquatic Hg(II) 15 . The sign (positive, negative Δ 199 Hg) and magnitude of the MIE is not fully understood, but has been shown to depend on the nature of the Hg-binding ligand (e.g. O or S), the Hg to ligand concentration ratio, and environmental conditions such as pH 16,17 . Here, we evaluate whether the tHg and pHg data show evidence of in situ marine odd-MIF, in addition to that inherited from atmospheric deposition sources.

We first calculate the excess Δ 199 Hgexc in all seawater samples, defined as the difference between the measured Δ 199 Hg in a marine sample and the expected Δ 199 Hg, based on atmospheric inputs. The expected Δ 199 Hg was calculated by binary mixing of Δ 199 Hg in atmospheric Hg(II) and Hg(0) using the source contributions (fHg(II)) derived from Δ 200 Hg (Methods, equation 3). The excess Δ 199 Hg in the different marine Hg pools (Δ 199 Hgexc), representing the Δ 199 Hg which was produced within the marine system, was calculated as follows:

Δ 199 Hgexc = Δ 199 Hgmeas -(fHg(II) × Δ 199 HgHg(II) + (1-fHg(II)) × Δ 199 HgHg(0)) (Eq. S1)

, where Δ 199 Hgmeas is the measured value. Overall, the Δ 199 Hg pattern in tHg and pHg of seawater and marine sediments is similar to Δ 200 Hg and observed Δ 199 Hg can largely be explained by a conservative mixing of atmospheric Hg(0) and Hg(II) deposition (Figure 2B and3B). Atlantic and Mediterranean Δ 199 Hgexc was 0.03‰ (0.02 to 0.13‰; median, inter quartile range (IQR), n = 17) in tHg and 0.01‰ (-0.07‰ to 0.08‰; median, IQR, n = 61) in pHg, which is not significant. Very low Δ 199 Hgexc were also found in marine sediments of the Mediterranean Sea (0.09‰, 0.03‰ to 0.12‰) and the Atlantic Ocean (0.06‰, 0.02 to 0.10‰). Elevated median Δ 199 Hgexc of 1.64‰ in marine fish (Extended Data Table 2) can therefore be predominantly ascribed to photochemical breakdown of MMHg. The absence of significant odd-MIF in surface seawater does not automatically mean that photoreduction is slow, or that the MIE is absent. Experimental photoreduction observations on seawater, under representative conditions, are needed to examine the issue. are coherent features that belong to a broader latitudinal trend in marine Δ 200 Hg.

Observation

2. We review Hg(II) wet deposition at remote coastal and island monitoring sites globally, and during a S-Atlantic cruise 19 that collected a large number of rainfall events (Extended Data Figure 3, n=12,812). We find a gradual increase from 1.7 ± 0.9 µg m -2 y -1 at high latitudes to 6.7 ± 4.0 at midlatitudes to 15 ± 5 in the (sub-)tropics (mean ± sd), generally attributed to convective cloud formation and upper tropospheric Hg(II) scavenging 20 . Whereas the northern hemisphere (NH) (sub-)tropical rainfall Hg(II) maximum is well defined for Mercury Deposition Network (MDN 21 ) sites along the coastal N-Atlantic Ocean and Caribbean seas, only limited data is available for the NH Southeast Asian seas 22,23 ,

the Pacific Ocean at Hawaii 18 , the equator 19,24,25 and the southern hemisphere (SH) 19,26,27 . Extrapolation where v is the kinematic viscosity (cm 2 s -1 ) = 0.027 x e (-0.025 x T') with T' the SST temperature in degrees Celsius, and D, the diffusivity of Hg(0) in sea water (cm 2 s -1 ) = 0.02293 x e -(17760 J/mol)/RT , where R is the Boltzman's constant (8.314 J K -1 mol -1 ), and T is SST in Kelvin, all based on Kuss et al. 2009 33 .

Hg(II) deposition, gross Hg(0) invasion, gross Hg(0) evasion and net Hg evasion as a function of latitude are summarized in Extended Data Figure 5 top. Hg(0) invasion is driven by observed atmospheric Hg(0)

and wind speed and is maximal at mid and high latitudes. Hg(II) deposition is dominated by Hg(II) wet deposition in the sub-tropical NH. Hg(0) evasion is driven by high DGM concentrations in the (sub-)tropics (Extended Data Figure 3) and by high wind speed at mid and high latitudes. The net Hg evasion trend shows important net deposition in the northern hemisphere, and net evasion in the southern hemisphere, in agreement with 3D Hg cycling models 29 and observations 34 . We use Hg(II) wet deposition, Hg(II) dry deposition and Hg(0) invasion estimates (Extended Data Figure 5 bottom), together with Δ 200 Hg end-members (Extended Data Figure 6, Extended Data Table 1, Equation 3) to calculate an expected latitudinal marine, pelagic Δ 200 Hg distribution (Figure 4a). Expanded to achieve a good fit (Figure 4d, main text). Note that if marine Hg(II) wet deposition is 100% lower, then automatically Hg(II) dry deposition, fixed at 40% of total Hg(II) deposition also becomes 100% lower. With respect to the GEOS-Chem budget, Hg(II) deposition would need to be lowered 2.7x from 4600 to 1700 Mg y -1 in order to achieve a 1:1 Hg(0):Hg(II) gross deposition ratio. We consider that 2-3x times lower Hg(II) deposition is plausible, given the overall uncertainty on observations, and given that the latitudinal coastal Hg(II) wet deposition distribution is asymmetric with higher deposition in NH Hg emission source regions.

We can also keep Hg(II) deposition constant, and increase ocean Hg(0) uptake by increasing the gas-transfer velocity, Kw in equations S1-S3, by a factor of 2.3 to achieve an optimum fit between observed and predicted Δ 200 Hg (Figure 4d, main text). In GEOS-Chem, Kw would have to be increased 270% to increase Hg(0) evasion from 1700 to 4600 Mg y -1 . A 230 -270% increase in Kw exceeds the typical uncertainty on Hg(0) gas-exchange models which is on the order of 30% 36,37 . However, since the Hg(0) gas-exchange parameterizations are extrapolated from CO2, they have not been calibrated against experimental or field observations. In particular the effects of surface ocean micro-layer chemical reactions, for example by consumption of invading Hg(0), could cause underestimation of Kw.

However, there is a caveat in fitting Kw to optimize ocean Hg(0) uptake: gross marine Hg(0) emission and net marine Hg(0) exchange also depend linearly on Kw (equations S2, S3). A 230% increase in Kw would result in large global gross marine Hg(0) emission (10900 Mg/y) and large net air-sea Hg(0) exchange (6500 Mg/y) fluxes. A larger net exchange flux would change the ocean from a net sink in present Hg cycling models, to a net source, which would have to be balanced by an additional terrestrial sink to keep the atmosphere in steady state (as observed).

Non-peer reviewed EarthArXiv preprint

  Hg, and 0.7520 for 201 Hg. The long-term instrumental precision was assessed through repeated analysis of the UM-Almaden and ETH-Fluka Hg standard at 0.25 ng g -1 during the two analysis sessions. ETH-Fluka yielded values of -1.45 ± 0.20 ‰, 0.07 ± 0.11 ‰, 0.01 ± 0.14 ‰, 0.02 ± 0.09 ‰, 0.00 ± 0.18 ‰ (2σ, n = 10) for δ 202 Hg, Δ 199 Hg, Δ 200 Hg, and Δ 201 Hg respectively, in agreement with published values[START_REF] Jiskra | Mercury Deposition and Re-emission Pathways in Boreal Forest Soils Investigated with Hg Isotope Signatures[END_REF] . UM-Almaden standard yielded -0.55 ± 0.16‰, -0.03 ± 0.11‰, -0.01 ± 0.03 ‰, -0.05 ± 0.23 ‰ (2σ, n = 10)

  12) atMediterranean station K2, 93 ± 18% (n=8) at Endoume coastal station, and 88 ± 31% (n = 4) for Atlantic Ocean samples. Procedural blanks were 0.23 ± 0.08 ng Hg (1σ, n = 4) for the SnCl2 pre-concentration method, which is <10% of tHg in 20 L of seawater, e.g. typically 3 -4 ng of tHg in this study. SnCl2 method replication of eight 20L coastal Mediterranean samples (6 pM, analyzed at 1.6 ng g -1 by MC-ICPMS) shows good results with δ 202 Hg, Δ 199 Hg and Δ 200 Hg 2σ uncertainties of 0.23, 0.16, and 0.06 ‰.NIST SRM 3133 procedural standards returned δ 202 Hg, Δ 199 Hg, Δ 200 Hg, and Δ 201 Hg values of 0.07 ± 0.23 ‰, -0.05 ± 0.16 ‰, 0.00 ± 0.06 ‰, -0.01 ± 0.18 ‰, 0.02 ± 0.21 ‰ and a mean recovery of 86 ± 16% (2σ, n = 8), suggesting no bias in the method.pHg quality control results on NIST SRM 1632d yielded values of -1.75 ± 0.24 ‰, -0.04 ± 0.04 ‰, 0.00 ± 0.04 ‰, -0.02 ± 0.08 ‰ (2σ, n = 10) for δ 202 Hg, Δ 199 Hg, Δ 200 Hg and Δ 201 Hg respectively, in agreement with published values[START_REF] Sun | A double-stage tube furnace-acidtrapping protocol for the pre-concentration of mercury from solid samples for isotopic analysis[END_REF] . The 2σ uncertainty on pHg samples was taken to be the larger of either replicate sample analysis, procedural standard NIST SRM1632d, or secondary reference materials UM-Almaden or ETH-Fluka.Most seawater pHg and tHg samples were analyzed in duplicate on different days. The final 2σ uncertainties reported for Mediterranean Sea and Atlantic Ocean pHg and tHg samples are the larger of the duplicate sample analysis, the 2σ on the eight NIST procedural standards (tHg), the 2σ on the ten NIST SRM 1632d standards, or the 2σ of the ETH Fluka or UM-Almaden standards.

  Figure 1a-h. Depth profiles of seawater Hg species concentrations and total and particulate Hg stable isotope composition at station K2 in the Mediterranean Sea (a-d) and the North Atlantic (e-h). a) and e): tHg, pHg, and MeHg concentrations in pmol L -1 (conc. pM). b) and f): mass-dependent fractionation (δ 202 Hg), c) and g): odd mass-independent fractionation (Δ 199 Hg), d) and h): even mass-independent fractionation (Δ 200 Hg). Open symbols represent values for tHg and filled symbols pHg. The lines represent averages of replicate analysis of the same sample. Two standard deviation (2SD) uncertainties on Hg concentrations are 10%. The North Atlantic profile is a composite profile from two stations at 47 o and 59 o N, and the Fram Strait at 79 o to 81 o N.

Figure 2 .

 2 Figure 2. Hg stable isotope composition of atmospheric Hg deposition sources (gaseous Hg(0) and Hg(II) in rainfall), and seawater (total (tHg) and particulate (pHg)). a) even-isotope mass independent fractionation (Δ 200 Hg) vs. mass dependent fractionation (δ 202 Hg), and b) odd-isotope mass independent fractionation (Δ 200 Hg) vs. even-isotope mass independent fractionation (Δ 200 Hg). Values of atmospheric sources are from the literature (see Extended Data Table1), tHg values are from this

Figure 3 .

 3 Figure 3. Hg stable isotope composition in different ocean basins for total Hg (tHg) and particulate Hg (pHg) in seawater, marine sediments and marine fish. a) Even-isotope mass-independent signature (Δ 200 Hg) and b) Odd-isotope mass-independent signature (Δ 199 Hg). tHg values are from this study, pHg

  . The atmospheric deposition sources are shown as vertical bars in red for Hg(0) and blue for reactive and rainfall Hg(II) , the dashed line represents the mean and the shaded area the interquartile range (IQR). Marine samples are shown as horizontal boxes, where the bold line represents the median, the boxes the IQR, the whiskers 1.5 times the IQR and outliers are represented by dots. For biota, Δ 199 Hg are not shown in this Figure as these values are heavily affected by MMHg photo-demethylation.

Figure 4 :Extended Data Figure 2 .Extended Data Figure 3 .

 423 Figure 4: Latitudinal variation in atmospheric Hg sources and deposition fluxes to the global Ocean. Zonal 'Reference model' refers to the combination of zonal model and observation derived fluxes; i.e. the gas-exchange model which assimilates atmospheric and dissolved Hg(0) observations, 3D model global Hg(II) dry deposition 3 , and Hg(II) wet deposition observations (see SI text, Extended Data Figures 3-6). a) Box plot for observed and reference model predicted marine  200 Hg in 5° latitude bins. The bold horizontal line represents the median, the boxes the interquartile range (IQR), the whiskers 1.5 times the IQR and dots are outliers. b) The  200 Hg-derived and reference model derived fraction of ocean Hg(0) uptake relative to total atmospheric Hg deposition. c) The  200 Hg-derived and reference model Hg(II) deposition fluxes. d) The  200 Hg-derived and reference model ocean Hg(0) uptake flux. All fluxes in µg m -2 y -1 . All lines represent medians and the shaded areas IQR. The green  200 Hg-based curves in panels c) and d) represent the gross Hg(II) deposition and gross Hg(0) invasion needed to reconcile marine  200 Hg observations in panel a), i.e. either lower Hg(II) deposition, or higher ocean Hg(0) uptake (see Supporting Information text).

Data Figure 7 : 2 N

 72 Variation of  204 Hg in marine samples. a)  204 Hg vs  200 Hg. The dashed line represents the York regression using IsoplotR 57 for all marine samples (Δ 200 Hg = -0.32(±0.06) Δ 204 Hg + (0.03±0.004), (± se), MSWD = 0.213) b)  204 Hg boxplot for 5° latitudinal intervals. Marine samples are shown in boxes, where the bold horizontal line represents the median, the boxes the interquartile range, the whiskers 1.5 times the IQR and outliers are represented by dots. The solid line represents the predicted  204 Hg based on the observational relationship between  204 Hg and  200 Hg in terrestrial samples by Blum & Johnson, 2017 58 . The dashed line represents the predicted  204 Hg derived from the York regression shown in panel a).  204 Hg data are available for 339 out of 791 marine samples. Note that for pHg and tHg samples presented here,  204 Hg was not measured due to the low abundance of of the method needs to be low, ideally below 10% of the total amount of Hg in the sample. Low blank levels rely on ultra-clean sampling at sea, clean sampling vessels and ultra-low Hg levels of reagents used. Previous studies have successfully developed methods for large volume (1 -20 L) preconcentration of tHg from natural waters, including rain, snow, ice, lake and coastal seawater. Gratz et al. (2010) and Sherman et al. (2010) first used continuous cold vapor generation, with SnCl2 as a reductant, to pre-concentrate 1 -4 L of snow and rainfall samples into small volume (25 mL) 2 % (w/w) oxidizing KMnO4/H2SO4 solution trap 1,2 . This method was later modified to a batch-reactor set-up to pre-concentrate 1 L of rainfall in a 2 L Pyrex bottle, by slow, pumped addition of SnCl2, and identical KMnO4/H2SO4 solution trap 3 and trapping solutions of 40 vol% inverse aqua regia (iAR, 4.2 N HNO3, 1.HCl) 4 . Finally, in Obrist et al. (2017) we scaled up the batch purge and trap method to handle up to 20 L of snow and rain sample 5 . An alternative method was developed by Chen et al. (2016) using the AG-1-X4 anion exchange resin to pre-concentrate >40 ng of tHg from freshwater lakes 6 . HgCl4 2-in the acidified, 0.1 N HCl, sample is pumped at 3.5 mL min -1 over 0.5 mL of AG-1-X4 resin. Sorbed Hg is then eluted with 10 mL of 0.05 % L-cysteine in 0.5 N HNO3, oxidized by BrCl, neutralized with NH4OH and analyzed by MC-ICPMS. Štrok et al. (2015) optimized the anion exchange resin method for seawater and published the first Hg stable isotope data of coastal seawater (1.5-3.1 pM) from the Canadian Arctic Archipelago 7 . The latter two methods by Štrok et al. (2015) and Obrist et al. (2017) are capableof handling sample volumes of 20 L or more that are necessary for background level tHg preconcentration from seawater (0.4 to 1.5 pM). Our objective was therefore to adapt our existing large volume pre-concentration protocol, based on SnCl2 reduction, for rain and snow to seawater. We optimized the protocol for quantitative pre-concentration yields and low blank levels.Pre-concentration troubleshooting, Sn waste disposal and bottle cleaningDuring pre-concentration the 20L sample bottle is under argon over-pressure in order to generate a fine stream of bubbles. It is therefore important at the end of pre-concentration, or during troubleshooting, not to vent the argon supply tube to the 20L sample bottle and release argon pressure. The reason is that with the 20 L bottle under over-pressure, venting the argon supply tube results in a sudden pressure drop, and acidified sample solution with SnCl2 moving from the 20 L bottle into the tall bubbler post, possibly all the way to the argon flow regulator, damaging the latter. Worse, the 40 vol% iAR trap solution is aspirated up into its short bubbler post and into the 20 L bottle, resulting in the loss of the sample. Using our final optimized Sn addition protocol, each 20 L bottle contains at the end of a pre-concentration run, 2.5 g of Sn(II), and should be disposed of following local environmental regulations. If needed, the dissolved Sn(II) concentration can be lowered by hydrogen peroxide addition, which quantitatively precipitates Sn(IV)O2, that can then be filtered or decanted.

  -based estimates of global marine Hg(II) deposition, and air-sea Hg(0) exchange as a function of latitude In order to assess potential latitudinal bias in the global Δ 200 Hg mass balance (main text), which for tHg and pHg is mostly based on northern hemisphere mid-latitude Δ 200 Hg observations (43 o -81 o N), we perform in this section a full 5 degree zonal analysis of marine Δ 200 Hg, rainfall Hg(II), dissolved gaseous Hg(0), climatology and calculated Hg(0) invasion, and evasion fluxes as a function of latitude. The analysis is based on 1. A review of marine aqueous, pelagic biota and pelagic sediment Δ 200 Hg, 2. A review of the latitudinal distribution of Hg(II) wet deposition, 3. A review of gross Hg(0) invasion (i.e. ocean uptake), which allows us to estimate, by mass balance, an expected Δ 200 Hg gradient which we compare to observed marine Δ 200 Hg, and 4. A reversed mass balance where we use the observed marine Δ 200 Hg gradient to estimate the ocean Hg(0) uptake flux, or the Hg(II) deposition that is needed to explain the Δ 200 Hg observations. 1. Figure S3 (and Figure 4, main text) shows the latitudinal distribution of marine pelagic Δ 200 Hg.Δ 200 Hg of marine data at high latitudes (>60 o , 0.01 ‰ (-0.04 ‰ to 0.03‰); median and IQR, n= 69) in both hemispheres are significantly lower (p<0.001, one-sided t test), than mid-latitude (30-60 o , 0.03 ‰ (0.01 ‰ to 0.065‰); median and IQR, n= 428), which are significantly lower (p<0.001, one-sided t test) than the (sub)tropics (0-30 o , 0.07 ‰ (0.04 ‰ to 0.085‰); median and IQR, n= 275). This trend suggests that Hg(II) and Hg(0) deposition contributions to pelagic marine waters are variable. The trend also confirms, to first order, that the observed higher Δ 200 Hg (0.06 ‰) in sub-tropical pHg (Motta et al., 2019)18 and lower pHg Δ 200 Hg in mid-latitude (0.01 ‰) and high latitude (-0.02 ‰) waters (this study)

3 .

 3 of the latitudinal Hg(II) wet deposition trend at marine locations to the global Ocean gives a Hg(II) wet deposition flux of 2561 ± 768 Mg y -1 , assuming the relative standard deviation of 30% observed for individual 5 o latitude intervals applies at the global scale. Seasonal Hg(II) dry deposition observations over oceans are inexistent, and must be estimated from 3D Hg models. Model Hg(II) wet deposition generally is on the order of 60% of total Hg(II) deposition, the remaining 40% being Hg(II) dry deposition28,29 . For the observed global Hg(II) wet deposition budget of 2561 Mg y -1 , Hg(II) dry deposition would then correspond to 1615 ± 485 Mg y -1 . In the absence of observations, we assume Hg(II) dry deposition to be constant as a function of latitude at 5 µg m -2 y -1 , which respects its contribution of 40% to modeled global Hg(II) deposition. The hybrid observational-model estimate (indicated as zonal 'reference model in main text, and Figures 4, Extended Data Figure5) of global Hg(II) deposition to oceans of 4268 ± 1280 Mg y -1 is therefore similar to atmospheric Hg(II) deposition of 4600 Mg y -1 in Hg cycling models29 . Both our zonal 'reference model' and 3D Hg cycling models rely heavily on coastal and continental rainfall observation sites, in particular from the MDN network in N-America. It is therefore possible that the coastal rainfall observations, despite our pre-selection of non-urban remote sites, are biased high by regional anthropogenic Hg(II) emissions. Consequently the marine Hg(II) deposition budget discussed here (Extended Data Figure3) may therefore be biased high, which we argue (in the main text discussion) is a potential reason for the Δ 200 Hg-based underestimation of Hg(0) to the marine Hg budget in 3D Hg cycling models. We review surface Ocean dissolved gaseous Hg (DGM) measurements in order to estimate mean latitudinal DGM distribution (Extended Data Figure4), and a DGM observation-based global marine Hg(0) gross and net emission budget. While DGM technically includes both dissolved gaseous Hg(0) and DMHg, it is thought to represent mostly Hg(0) due to the low surface ocean DMHg concentrations. We estimate marine Hg(0) evasion based on marine boundary layer atmospheric gaseous Hg(0) distribution30 . We use latitudinal mean DGM, mean annual sea surface temperature (SST; 2007-2019; Copernicus product WIND_GLO_PHY_CLIMATE_L4_REP_012_003), wind speed at and marine boundary layer Hg(0), to calculate global gross Hg(0) invasion (Finv, Eq S2), gross evasion (Fev, Eq S3) and net Hg(0) evasion (Fnet, Eq S4) for 5 o latitude bands (all in ng m -2 h -1 ) as follows: Finv = Kw x -Ca/KH (Eq. S2) Fev = Kw x Cw (Eq. S3) Fnet = Kw x (Cw-Ca/KH) (Eq. S4) where Cw is the surface sea water DGM concentration (ng m -3 sea water), Ca is the air Hg(0) concentration (ng m -3 air), KH is the dimensionless Henry's law constant, and Kw is the Hg(0) gas transfer velocity (m h -1 ): ln(KH) = 2403.3/T+6.92 from Andersson et al. 2008 31 , where T is the SST in degrees Kelvin Kw = 0.25 x µ10 2 (ScHg0/ScCO2) -0.5 from Nightingale et al. 2000 32 , where ScHg0 is the Schmidt number for Hg(0): ScHg0 = v/D

4 .

 4 uncertainties on Δ 200 Hg are estimated using a Monte Carlo script in R by randomly varying the stated uncertainties on fluxes and end-member Δ 200 Hg. Due to the asymmetric latitudinal contributions of Hg(II) deposition and Hg(0) invasion to marine Hg, the expected Δ 200 Hg trend (Figure 4a, main text) shows lower values at high latitudes and maximum, positive values in the NH (sub-)tropics. The observed marine Δ 200 Hg distribution is significantly lower than the predicted Δ 200 Hg distribution, except between 45 -65 o N (Figure 4). Our new tHg Δ 200 Hg observations in the Mediterranean Sea and Atlantic Ocean between 43 -59 o N are therefore coherent with predicted Δ 200 Hg. The majority of marine Δ 200 Hg observations, however, are lower than the predicted Δ 200 Hg, which leads us to conclude that the contribution of atmospheric Hg(0) to the oceans and to marine biota is underestimated.Although we were not able to measure the Δ 204 Hg in tHg and pHg, due to instrumental limitations (minor isotope, only one 1013 Ohm amplifier available and attributed to 198 Hg), the large marine biota and sediment data set contains abundant Δ 204 Hg observations. In Extended Data Figure7we show that these data are consistent with Δ 200 Hg observations in the same marine biota data, and with the Δ 200 Hg:Δ 204 Hg relationship observed in terrestrial samples35 . Above we used a hybrid approach combining observations of Hg(II) wet deposition and atmospheric Hg(0), and 3D model-based Hg(II) dry deposition and Hg(0) gas-exchange to predict marine Δ 200 Hg. The predicted Δ 200 Hg trend is shifted to higher values compared to observed marine Δ 200 Hg. Here we discuss why the zonal model, and 3D Hg cycling model predicted Hg(II):Hg(0) gross deposition ratio of 3:1 overestimates Hg(II) deposition to oceans. It is important to understand that Δ 200 Hg does not inform on the absolute magnitude (in µg m-2 y -1 , or in Mg y -1 ) of Hg(II) deposition and Hg(0) uptake fluxes. Rather, it informs on the relative Hg(II) and Hg(0) contributions, and therefore constrains the ratio of the marine Hg(II):Hg(0) gross deposition flux. We therefore need to ask which of the two (or both) absolute flux estimates, either per 5 o latitude band, or on a global basis, is biased.We have indicated above that the marine Hg(II) wet deposition flux is mostly observed at coastal N-American stations, and only rarely over the open Ocean. Using a fitting approach, minimizing the root mean square error (rmse) between observed and predicted Δ 200 Hg, we estimate that Hg(II) wet deposition would need to be approximately half (1252 Mg/y) the current estimate (2561 ± 768, 1SD)

Figure S1 .

 S1 Figure S1. Depth profile of particulate Hg stable isotope composition at three stations in the Mediterranean Sea during the June 2017 campaign. A: mass-dependent fractionation (δ 202 Hg), B: odd mass-independent fractionation (Δ 199 Hg), C: even mass-independent fractionation (Δ 200 Hg).

Figure S2 :

 S2 Figure S2: Scatterplot of odd Hg isotope mass-independent fractionation, Δ 201 Hg vs. Δ 199 Hg of all tHg and pHg seawater data, including the published data by Motta et al. 2019. The dashed line represents the York regression using IsoplotR 38 for tHg (Δ 199 Hg = 0.79(±0.29) Δ 201 Hg + (0.03±0.04), (± se), MSWD = 0.2). The solid line represents the York regression for pHg (Δ 199 Hg = 1.01(±0.0.09) Δ 201 Hg + (0.02±0.02), (± se), MSWD = 1.25). Error bars represent the 2 SD of replicate procedural standards for tHg and pHg.

Hg isotopes, and unavailability of a second 10 13 Ohm amplifier.

Acknowledgements

This work was supported by research grants ANR-17-CE34-0010 MERTOX to DP, FP7-IDEAS-ERC grant No 258537, and H2020 ERA-PLANET grant No 689443 via the iCUPE and iGOSP project to JES, Chantier Arctique Francais funding via the Pollution in the Arctic System Project to JES and LEHB, H2020 Marie Sklodowska-Curie grant No 657195 and Swiss National Science Foundation grant PZ00P2_174101 to MJ, APOG DECOMAR, MISTRALS AT P&C and the AXA RF grants to LEHB, and the French National Research Agency (ANR-13-BS06-0014, ANR-12-PDOC-0025-01), the French National Centre for Scientific Research (CNRS-LEFE-CYBER), the LabexMER (ANR-10-LABX-19), and Ifremer. We are grateful to Géraldine Sarthou and Pascale Lherminier, chief scientists of the 2014 GEOVIDE cruise, and to Hélène Planquette for coordinating clean sampling. We thank Michiel Rutgers van der Loeff, Torsten Kanzow and the Alfred-Wegener-Institute for Polar and Marine Research for organizing the 2016 GRIFF cruise. We thank Emmanuel de Saint-Léger and Fabien Pérault of the technical division of INSU for

support with operation at sea. We thank Laure Laffont for laboratory management, Olivier Grosso and Deny Malengros for technical assistance. We thank Luisa Metral from MARBEC and Frédéric Ménard from the Mediterranean Sea. We thank Joachim Kuss and and FS Polarstern for their support at sea. Thanks also go to the shipboard participants, captain and crew of the N/O l'Atalante for obtaining sediment samples from the 2015 VESPA cruise. VESPA was funded by the French Ministry of Research and Higher Education, with support from the governments of New Zealand and New Caledonia. We thank three anonymous reviewers for critical and constructive comments on our study.

Data availability

Hg stable isotope and Hg speciation data that support the findings of this study are available from https://doi.org/10.5281/zenodo.4740464

Correspondence and requests for materials should be addressed to martin.jiskra@unibas.ch, larseric.heimburger@mio.osupytheas.fr, jeroen.sonke@get.omp.eu

Author contributions

LEHB, JES, MJ and DP conceived the study. LEHB, MJ, DP, MP, MVP, MMD and JES performed sampling. JES, MJ, and LEHB developed and applied the tHg isotope pre-concentration methods. JES, MJ, JM and JC performed isotope measurements. MMD, MVP, AD, LEHB, MJ, JM, DP, and MT performed additional laboratory work. MJ, JES and LEHB analyzed the data. JES and MJ wrote the draft paper, which was improved by contributions from LEHB and DP, and commented by all authors.

Author Information The authors declare no competing financial interests.

Supplementary Information is available for this paper.

Methods

The method for tHg in sea water consists of an ultra-clean shipboard sampling and post-cruise sample processing protocol using a standard stannous chloride (SnCl2) reduction purge-and-trap method, based on the USEPA method 1631 [START_REF]method 1631 Revision EMercury in Water by Oxidation, Purge and Trap, and Cold Vapor Atomic Fluorescence Spectrometry[END_REF] .

Sampling. Repeated, daily cruises were undertaken on the RV Antedon II from Marseille (France) to the nearby (20 km) oligotrophic, off-shore station K2 (42.98 N / 5.41 E / >1500 m depth) between 14/6/2017 and 21/6/2017, on 27/02/2019 and 22/05/2019. We used an epoxy-painted trace metal clean carousel, equipped with a conductivity-temperature-depth unit (CTD, Seabird SBE 911plus), and oxygen sensor (Seabird SBE 43), and 8x 10 L GOFLO trace metal clean bottles (General Oceanics).

Samples were taken at up to 12 depths for Hg species, and at 4 depths for tHg and pHg isotopes, corresponding to surface waters (5 m), the chlorophyll-maximum (20 m), the oxygen minimum zone (400 m) and deep (800 m) waters. See SI for salinity, temperature, oxygen and fluorescence data.

Materials and Methods

Rationale

Total mercury (tHg) concentration in seawater is the sum of several operationally defined species, including dissolved gaseous Hg(0), dissolved gaseous dimethyl-Hg (DMHg), dissolved inorganic Hg(II) compounds, dissolved monomethyl-Hg compounds (MMHg), and particulate-bound Hg(II) and MMHg compounds (pHg). Both concentration and stable isotope analysis of tHg in seawater require the transformation of these compounds to dissolved, labile Hg(II) forms by addition of a strong oxidant such as BrCl, prepared in concentrated HCl. The concomitant oxidation and acidification also inhibits biological activity, stabilizes Hg(II) in solution and minimizes potential losses to sampling container walls or to the atmosphere. Two criteria need to be met for a robust Hg stable isotope analysis of seawater: first, the low-picomolar seawater concentration has to be concentrated to levels suitable for Hg stable isotope analysis (typically 0.2 -1 ng mL -1 or 1 -5 nM). This pre-concentration needs to be quantitative in order to avoid Hg isotope fractionation during transfer. Second, the procedural blank 2 for data sources.


Jean Le Bras

Jacques Muzart
email: jacques.muzart@univ-reims.frwww.univ-reims.fr

Pd-catalyzed domino dehydrogenation/Heck-type reactions of carbonyl compounds

This review covers the domino reactions which involve, at least, both Pd-catalyzed dehydrogenation of carbonyl compounds and Heck-type reactions. While the former occurs under Pd II -catalysis, Pd 0 -or Pd II catalyst is requested for the latter, depending on the nature of the (hetero)arylating agent, ArX or ArH, respectively. The regeneration of Pd II species is assumed by either an oxidant or the aryl halide. Proposed mechanisms are described, with, in some cases, personal comments.

Contents

. 1. Introduction 2. Domino KTR + HR(s) 3. Domino KTR + OHR 4. Domino KTR + DcHR 5. Domino KTR + DHR 6. Domino KTR + PHR 6.1 Using aryl halides 6.2 Using arenes 7. Domino OHR + KTR + PHR 8. Domino HR + KTR + HR 9. Domino KTR + ketonisation + DHR 10. Domino C(sp 3 )-H arylation + KTR + HR (+ DHR) 11. Domino C(sp 3 )-H arylation + KTR (or KTR + HR) + HR + C(sp 2 )-H amidation 12. Conclusion 13. References

Introduction

The synthesis of complex organic molecules via a one-pot reaction corresponds to the sequential addition of the reactants to the reaction flask, possibly under experimental conditions depending of each reactant, followed by work-up and purification. [1] This procedure is more compatible with economic and ecological constraints than the step by step synthesis, which is time-consuming, requires extraction and purification steps leading to large amounts of waste.

The most attractive procedure is however the domino reaction which, according to Tietze, leads to the formation of "several bonds in one sequence without isolating the intermediates, changing the reaction conditions, or adding reagents". [2.3] According to Fogg and dos Santos, [4] the appellation "tandem" could be attributed to some of these reactions but Tietze suggested not to use it, because "Tandem means two at the same time and does not describe a time-resolved transformation". [5] The aim of the present review is to highlight domino reactions which implicate two Pd-catalyzed reactions: dehydrogenation of a carbonyl compound and Heck-type reaction. [START_REF]A few examples are included in other reviews[END_REF] Pd catalyst being used in both reactions, the term "auto-tandem catalysis" has been proposed for such one-pot processes [4.7] but as Tietze, [5] we are not fond of it. The definition of the domino reaction [2] leads to discard procedures involving a modification of the starting conditions in the course of the process. [START_REF] Kim | For such one-pot reactions relevant to the topic of the review[END_REF] α,β-Unsaturated carbonyl compounds are highly useful synthetic blocks in organic synthesis, which can be prepared from Pd II -catalyzed dehydrogenation of the corresponding saturated substrates as depicted in Scheme 1. [6a,9] Sometimes, this reaction (noted below KTR), which has been discovered by Kirschke and Theisen,[10][11][12] is improperly named the Saegusa's reaction. Indeed, Saegusa's reaction [13] concerns the oxidation of silyl enol ethers and related enol derivatives to ,-unsaturated carbonyl compounds. [START_REF] For Reviews | Handbook of Organopalladium Chemistry for Organic Synthesis[END_REF] Over-dehydrogenation of cyclohexanones may afford the corresponding phenols. [6a,9,12,15] Scheme 1. Pd II -catalyzed dehydrogenation of carbonyl compounds (KTR).

Heck-type reactions are involved in a number of domino reactions leading to multiple C-C or C-heteroatom bonds. [16,17] Originally, the Heck reaction (HR), independently discovered by the teams of Mizoroki, [18] Julia [19] and Heck, [20] is the formation of arylalkene from the Pd 0catalyzed coupling of an aryl halide with an alkene (Scheme 1, path a). When a Pd II salt is used as the starting catalyst, its in-situ reduction under the experimental conditions affords the required Pd 0 species. [18,20] Heck's team, which intensively worked in this research area, also discovered the synthesis of arylalkenes via trans-metalation with Pd II catalysts of organometallic reagents used as the aryl source (Scheme 1, path b); [21] such procedure is often called oxidative Heck reaction (OHR). [22] Myers'team proposed the decarboxylative Heck reaction (DcHR), which uses arene carboxylates to form such C(sp 2 )-C(sp 2 ) bonds (Scheme 1, path c). [23] Another procedure, initiated by Fujiwara's team, [24] is the dehydrogenative Heck reaction (DHR), which involves Pd II -catalyzed activation of an arene C-H bond (Scheme 1, path d). [25] Intermediate 2A may suffer either reductive Heck reaction (RHR) [26,27] or protonolysis (PHR) [27][28][29] rather than -H elimination to afford the arylalkyl (Scheme 1, paths e and f, respectively. Heck-type reactions also occur using alkenyl halides instead of aryl halides. [16,20] Scheme 2. Some Heck-type reactions: HR (path a), OHR (path b), DcHR (path c), DHR (path d), RHR (path e), PHR (path f).

Domino KTR + HR(s)

A number of KTR-HR(s) of aldehydes, ketones and esters have been carried out by Cheng's team using Pd(OAc)2 as catalyst, Na2CO3 as the base and an excess of aryl iodides at 120 °C in DMSO under nitrogen. [30] The excess of ArI regenerates Pd II species from Pd 0 , as that occurs for Yoshida's Pd II -catalyzed oxidation procedure of alcohols. [31] 2-Phenylpropanal and -substituted propiophenones reacted with a variety of aryl iodides (2.5 equiv.) leading efficiently to the corresponding -arylated ,-unsaturated aldehydes and ketones [Eqs (1) and ( 2)]. In contrast to the -substituted propiophenones [Eq. ( 2)], the reaction of propiophenone afforded mainly the -diarylation product. Such compounds were then synthetized using a large excess of ArI [Eq. ( 3)]. However, butyraldehyde, pentan-2-one and 1-phenylbutan-1-one, which have a -methyl substituent, did not give the KTR-HR products [Eq. ( 4)]; that is surprising because their reaction could be expected from literature data. [32,[START_REF] Stadler | HR of crotonaldehyde and RHR of hept-3-en-2-one have been reported[END_REF] To give the dehydrogenative coupling products with 2-phenylpropanal and propiophenone, aryl bromides have to react in the presence of 1,4-bis(diphenylphosphino)butane and in DMF instead of DMSO (Eq. 5). [30,[START_REF]The reaction of propiophenone (0.5 mmol) with 4-bromotoluene was carried out in the presence of dppb (0.012 equiv.)[END_REF] The formation of 17% of the 1,1-diarylation product against 26% of the 1,1,5,5-tetraarylation product from the reaction of diethyl ketone with 4-iodotoluene [Eq. ( 6)] suggested to Cheng and co-workers that "the dehydrogenation step is slower than the Heck reaction step". [30] In fact, the same type of species, ArPd II I or ArPd II I(DMSO)n [START_REF] Pd | [END_REF] may mediate the KTR and the HR (Scheme 3), hence the competition between the two reactions.

Scheme 3. The competition between KTR and HR in the domino reaction.

The optimum conditions recently reported by the team of Xie and Shao [36] for the synthesis of ,-diarylacroleins from arylpropanals and aryl iodides, Ag2CO3 as the base [START_REF] Cho | Ag2CO3 can be both base and oxidant. For its use to regenerate Pd II -active species[END_REF] in AcOH under air [Eq. ( 7)], differ from those above. Given the yield decrease with either the amount of the aryl iodide or using nitrogen [Eq. ( 7)], we devise that both ArI and O2 [START_REF] Gligorich | For reviews on the use of O2 to regenerate Pd II -active species[END_REF] participate in the regeneration of the Pd II catalyst. The authors proposed the promotion of the HR by AgI formed in the course of the process.

Domino KTR + OHR

Kim's team reported the synthesis of a range of 3-arylchromones from the KTR-OHR of chromanones with arylboronic acid pinacol esters. [39] Optimum conditions arose at 100 °C in DMSO and oxygen with catalytic amounts of both Pd(OCOCF3)2 and 5-nitro-1,10phenanthroline [Eq. ( 8)]. The cross-coupling was also efficient in DMF but other solvents such as THF, dioxane, PhMe and MeCN, or the absence of the phenanthroline ligand led mainly to the chromone (up to 72%). Under the optimum conditions, traces of 2-arylchroman-4-one, which are produced from the domino KTR-PHR, were possibly produced. Both KTR and OHR require Pd II catalysis. According to the authors, oxygen assumes the catalyst regeneration, [39] but DMSO may also participate to the process. [40] Rather similar conditions were used by Vilela, Lee and co-workers to carry out the KTR-OHR of substituted 1,3-cyclopentadiones. [START_REF] Lamb | [END_REF] The authors however observed that, with Pd(OAc)2 associated to 1,10-phenanthroline in DMF under oxygen, the yields were higher using a non-anhydrous solvent and non-dried glassware instead of anhydrous conditions [Eq. ( 9)]. The authors proposed that residual water promotes the transmetalation. [42]

Domino KTR + DcHR

The KTR-DcHR disclosed by Su and co-workers concerns the Pd II -catalyzed cross-coupling of propiophenones with aryl carboxylic acids. [43] The efficiency of this domino reaction is very sensitive to the structure of the substrates, hence optimum experimental conditions depending on the substitution of the aryl cores. Most reported results were obtained using a mixture of Pd(OAc)2 and PCy3 as the catalyst, Ag2CO3 as the oxidant, n-Bu4NOAc.AcOH as the base in DMF or DME [Eqs (10) to (12)]. Cu(OAc)2 or CuF2 can be more efficient than Ag2CO3 for the DcHR of electron-rich and heterocyclic carboxylic acids with 1phenylpropen-1-one [Eqs (10 ) and (11)]. Most substituted propiophenones leading to poor results, the authors suspected that -H acidity varies with the substituent on the benzene ring, and proposed that adequate acids or bases have to be used, hence the use of subquantities of phenol as additive, or the change of n-Bu4NOAc.AcOH for KOAc [Eq. ( 12)]. In fact, Buchwald and co-workers disclosed that phenol promotes the Pd-catalyzed arylation of ketone enolates with o-halonitroarenes, and suspected its beneficial role in the formation of palladium enolates. [44] Thus, phenol could also promote the KTR, which also occurs via a palladium enolate. [6a,9]

Domino KTR + DHR

The synthesis of 2-arylchromen-4-ones from KTR-DHR of chromanones has been described by Hong's team in 2012, using a large excess of arenes, Pd(OCOCF3)2 as the catalyst and a Cu(OCOCF3)2/AgOAc mixture as the oxidant in pivalic acid [Eq. ( 13)]. [45] In contrast, the same procedure afforded the C3-product from 1-methyl-2,3-dihydroquinolin-4(1H)-one [Eq. ( 14)]. The KTR-DHR of various cyclic -heteroatom-substituted ketones using acrylates instead of arenes was performed under slight different experimental conditions, leading also to C3-products [Eqs ( 15) and ( 16)].

The regioselectivity of the KTR-DHR of -chromanones with arenes [Eq. (13] [46] is consistent with the DHR of chromones with arenes, [47] -of chromanones and dihydroquinolin-4-ones [Eq. ( 15)] with acrylates is consistent with the DHR of chromones [48] dihydropyranones, [49] quinolones [50] and cyclic enaminones [51] with acrylates, -1,3-dimethyldihydropyrimidine-2,4(1H,3H)-dione [Eq. ( 16)] is consistent with the DHR of uracils with acrylates. [52] The C3-arylation of 1-methyl-2,3-dihydroquinolin-4(1H)-one [Eq. ( 14)] was unexpected. [45] In fact, the DHR of 1-methylquinolin-4-one with fluoroarenes also led to such regioselectivity. [53] Besides, modification of the common experimental conditionsforthe Pd IIcatalyzed cross-coupling of coumarins with arenes led to -arylation instead of the usual arylation. [54] The DHRs involve two C(sp 2 )-H. [25] We suspect that the regioselectivity of the above domino reactions could depend on the C-H reacting with palladium. In the presence of acrylates, the heterocyclic substrate reacts first yielding the results depicted in Eqs ( 15) and ( 16). The arylation pathway was more subtle: C2-products as the main compounds [46] when arenes react first [Eq. ( 13)] whereas C3-H of 1-methylquinolin-4(1H)-one is palladated [55] before to react with benzene to afford the C3-product [Eq. ( 14)].

It is usually considered that the elimination of HPdX species requires the syn relationship between the palladium unit and the hydrogen. [16,[START_REF] Tsuji | Palladium Reagents and Catalysts, Innovations in Organic Synthesis[END_REF] The insertion of the C=C bond into Ar-Pd II species being a syn process, [16,[START_REF] Tsuji | Palladium Reagents and Catalysts, Innovations in Organic Synthesis[END_REF][START_REF] Knowles | [END_REF] there is no syn relationship between the palladium unit and the hydrogen geminal to the Ar group in the intermediates formed from above chromones (Scheme 4). Thus, the arylation compound is plausibly produced via an oxo--allylpalladium allowing epimerization of the carbon center, [58] or from base-assisted reductive -H elimination [59] (Scheme 4). [60,[START_REF] Ahmad-Junan | A radical Heck process has been suggested in the case of formal -H antielimination[END_REF] Scheme 4. The -H elimination.

Su's team, who previously performed (KTR-DcHR)s [Eqs (10) to (12)], [43] used again Pd(OAc)2/PCy3 and Ag2CO3 in DME, but with TEMPO as supplementary oxidant [62,[START_REF] Yoo | piperidine-N-oxyl) has been already associated to Ag2CO3 for Pd II -catalyzed reactions of C-H bonds[END_REF] to carry out the KTR-DHR of propiophenones and 1-alkylpropanones with (hetero)arenes. [64] With thiophenes, furans and indoles, optimum results were obtained with LiOAc or NaOAc as additional base [Eqs ( 17) to ( 19)]. The dehydrogenative cross-couplings between fluorobenzenes and propiophenones were effectively carried out with KF as the base and tetramethylene sulfoxide as ligand [Eq. (20)]. The KTR-DHR of 2,3,5,6-tetrafluoropyridine also occurred with a fair yield while that of benzene was disappointing [Eq. (20)]. It seems interesting to note the poor yield also achieved from the KTR-DHR of an unsubstituted heteroarene such as thiophene [Eq. (17)]. According to a set of experiments carried out to ascertain the formation mechanism of the arylation product, the cross-coupling arises effectively from the domino KTR-DHR, that is, successively, ketone dehydrogenation, palladoarylation, across insertion of the C=C bond into the Ar-Pd II bond, and -H elimination.

Bäckvall and Gigant disclosed an aerobic KTR-DHR procedure [65] using an electron-transfer mediator, the iron phthalocyanine (Fe(Pc)), which facilitates the catalyst re-oxidation to its active form by oxygen (Scheme 5). [66] Heated in AcOH containing catalytic amounts of Pd(OAc)2(DMSO)2, benzoquinone and Fe(Pc), a variety of substituted cyclohexanones and arenes led, under oxygen, to the corresponding -arylated cyclohexenones except the 4acetamidocyclohexanone which afforded a 3:2 mixture of the and -arylated isomers [Eq. ( 21)]. Coordinating properties of the acetamido unit could explain the inversion of the regioselectivity. Unsubstituted cyclohexanone and linear aliphatic ketones are decomposed under the reaction conditions, whereas the ,-diarylation product was obtained from indanone [Eq. ( 22)]. In contrast, benzosuberone was monoarylated [Eq. ( 23)].

Scheme 5. Aerobic regeneration of Pd(OAc)2 through low-energy electron transfer involving a catalytic electron-transfer mediator.

Domino KTR + PHR

The PHR reaction can arise using aryl halides as well as arenes since both arylating agents afford the same intermediate as previously depicted in Scheme 2. Thus, (KTR-PHR)s using either one or the other have been reported.

Using aryl halides

In 2002, Hartwig's team reported that the Pd-catalyzed reaction of lithium enolate of methyl isobutyrate with thirty nine bromo(hetero)arenes afforded selectively the -(hetero)arylation compound except with 2-bromothiophene which reacted to the  and  positions [Eq. ( 24)].

The authors suspected the formation of the -compound through a "-hydrogen elimination and reinsertion of the olefin into the metal hydride". [67] In 2010, Clot, Baudoin and co-workers disclosed experimental conditions leading, in most cases, to the selective -(hetero)arylation of various ester enolates [Eq. ( 25)]. [68] Subsequently, the same team related the strong dependence of both conversion and / selectivity on the nature of the ligand. [69] For an example, the / ratio of the cross-coupling between t-butyl isobutyrate and 2-fluorobromobenzene was 85:15 with Pt-Bu3, and <2:98 with 2-dicyclohexylphosphanyl-2'-(N,N-dimethylamino)biphenyl [Eq. ( 25)]. Use of a chiral ligand led to cross-coupling products in fair yields and with enantioselectivities which remain to improve [Eq. ( 26)]. [68] Analysis of the reactivity of deuterated esters led the Clot and Baudoin team to exclude a direct -C(sp 3 )-H activation and to propose a mechanism supported by computational studies. [69] Trans-metalation of the lithium enolate with the arylpalladium complex affords palladium enolate 6A (Scheme 6). The agnostic Pd-H liaison may favor the formation of olefin complex 6B rather than the reductive elimination leading to the -arylated product. Bond rotation gives isomeric complex 6C. Subsequent insertion of the C=C bond into the H-Pd bond provides palladium homoenolate 6D which undergoes reductive elimination to provide the -arylated product. According to this catalytic cycle and despite the absence of free ,-unsaturated ester, this -arylation corresponds to a domino KTR-PHR. That led us to suspect that some other Pd-catalyzed -C(sp 3 )-H functionalizations of carbonyl compounds could also involve an intermediate dehydrogenation reaction. [START_REF] Jazzar | For reviews highlighting some metal-catalyzed remote C(sp 3 )-H functionalizations[END_REF] RO Dong and Huang disclosed the -arylation of cyclic and linear ketones as well as chromanone, with aryl iodides [Eq. ( 27) to ( 31)]. [28] Catalyzed by the Pd(OCOCF3)2/P(i-Pr)3 association, this KTR-PHR occurred at 80 °C in a hexafluoro-2-propanol/dioxane mixture containing Ag(OCOCF3)2 or Cu(OCOCF3)2 to regenerate Pd II species. No arylation was observed in the absence of the oxidant, while the main product was the self-coupling of the aryl iodide in the absence of the phosphine [Eq. ( 27)]. The formation of the diarylated compound from propiophenone [Eq. ( 31)] was attributed to a domino process involving four successive reactions: KTR, PHR, KTR and PHR. [28] Preliminary studies using 1-bromo-3,5dimethoxybenzene indicated that aryl bromides would be suitable for the above (KTR-PHR)s.

Using arenes

In treating a 3:2 mixture of ethyl 2-oxocyclopentanecarboxylate and 1,3,5-trimethoxybenzene with Pd(OAc)2 catalyst in AcOH/dichloroethane at 50 °C under oxygen, Pihko and coworkers isolated a 1.5:1 mixture of the KTR-PHR and KTR-DHR products. [71] A survey of different Brönsted acids as additives revealed the strong promotion of the PHR by diphenyl phosphate which, consequently, was used for a number of cross-couplings between dicarbonyl compounds and trialkoxybenzenes [Eq. (32)]. The domino reaction was inefficient with arenes bearing two donor groups such as 1,3-dimethoxybenzene but, under modified conditions, occurred with unprotected phenols [Eq. ( 33)].

From a set of experiments, the authors proposed that the -arylation of 1,3-dicarbonyl compounds with trialkoxybenzenes occurs via an "early-arylation" pathway (b) rather than the usually admitted "late-arylation" pathway (a) (Scheme 7). [71] Diphenyl phosphate would promote the formation of cationic arylpalladium complex 7A, which would mediate the dehydrogenation leading to 7B. The latter would evolve via either arene or hydride insertion to afford 7C or 7D, respectively. Subsequent reductive elimination of Pd 0 would afford the product (7E). Note that the delivery of 7E is accompanied by the formation of either Pd 0 or Pd II , depending on the reaction pathway. The authors mention a plausible "interceptedarylation" pathway (c) mediated by diphenyl phosphate, leading to 7B from 7F. Scheme 7. -Arylation of 1,3-dicarbonyl compounds: "late-arylation" pathway (a) versus "early-arylation" pathway (b) or "intercepted-arylation" pathway (c).

Pihko's team also studied the KTR-PHR of -dicarbonyl compounds with indoles. [29,72] The optimum conditions differ from those disclosed in Eqs ( 32) and ( 33), t-butyl perbenzoate being the best oxidant [Eq. (34)]. Diastereoselective cross-couplings were effectively performed using 8-phenylmenthyl 2-oxocyclopentanecarboxylate, even with a bromine substituent in the indole nucleus [Eq. (35)]. [29] Pd(OCOCF 3 ) 2 (0.1 equiv.) PhCO 3 t-Bu (1.3 equiv.)

i-PrOH/AcOH (4:1), 25 °C R 1 R 2 O R 3 O (1.5 equiv.) (34) R 1 -R 2 = (CH 2 ) 2 , R 4 = Me, R 5 = H, R 3 = OMe (78%), OEt (79% a ), OCH 2 CF 3 (55%), OBn (74%), Ot-Bu (80%) R 1 -R 2 = (CH 2 ) 3 , R 3 = OEt, R 4 = Me, R 5 = 2-Me (70%) R 1 -R 2 = (CH 2 ) 4 , R 3 = OMe, R 4 = Me, R 5 = 2-Me (61%) R 1 -R 2 = OCH 2 , R 3 = Me, R 4 = Me, R 5 = H (63%) R 1 -R 2 = OCH 2 , R 4 = Me, R 5 = 2-Me, R 3 = i-Pr (53%), CH 2 allyl (53%) R 1 = Me, R 2 = H, R 3 = OEt, R 4 = Me, R 5 = H (54% b ), Me (55%) R 1 -R 2 = (CH 2 ) 2 , R 3 = OEt, R 4 = Me, R 5 = 2-Me (84%), 5-Br (86%), 6-CO 2 Me (67%), 6-Cl (81%) R 1 -R 2 = (CH 2 ) 2 , R 3 = OEt, R 4 = H, R 5 = H (94%), 5-Me (74%), 5-OMe (87%), 2-Ph (96%) R 1 -R 2 = (CH 2 ) 2 , R 3 = OEt, R 4 = Bn, R 5 = H (83%) a Other oxidants: O 2 (1atm., 64%), H 2 O 2 (46%), t-BuOOH (67%), t-BuOOt-Bu (26%), t-BuOOAc (72%), PhCMe 2 OOH (57%), BzOOBz (37%), AgOAc (42%), Oxone (35%), K 2 S 2 O 8 (59%), MnO 2 (58%). b Using 4.5 equiv. of ethyl 2-methyl-3-oxobutanoate. R 1 R 2 O R 3 O N R 4 R 5 + N R 4 R 5
Kinetic experiments, isotope effects, deuterated starting materials, 1 H NMR monitoring and DFT calculations led the authors to assume the mechanism depicted in Scheme 8 for the cross-coupling between ethyl 2-oxocyclopentanonecarboxylate and N-methylindole (8A). [29,72] The proposal highlights the unexpected role of the indole, particularly in the assistance of the dehydrogenation reaction. Indeed, 8A is involved in the early stage of the reaction as ligand leading to complex 8B, which mediates the KTR. Trifluoroacetic acid and t-butyl perbenzoate jointly assumed the regeneration of 8B, which also mediates the PHR. Scheme 8. A KTR-PHR using N-methylindole as both ligand and reagent.

Domino OHR + KTR + PHR

Piko's team performed three-component domino reactions between -ketoesters, indoles and aryl boronates under experimental conditions [Eq. (36)] close to those used in the absence of the third component [see Eqs (34) and (35)]. [73] Studies of two-component coupling experiments led to favor a domino reaction involving firstly the coupling between the indole and the arylboronate [START_REF] Yang | Oxidative couplings between indoles at the 2-position and arylboronates or aryltrifluoroborates were previously reported: a)[END_REF] and subsequent reaction of the resulting OHR product with the dehydrogenated -ketoester, as depicted in Scheme 9. Control experiments have nevertheless shown that the KTR-PHR product independently obtained from -ketoester/indole coupling (see Subchapter 6.2) reacts with the aryboronate to also afford the three-component product, but that would be, at the best, a minor reaction pathway under the three-component domino reactions conditions. Scheme 9. Successive steps of Pihko's three-component domino reactions.

Domino HR + KTR (+ HR)

While Heck reaction between phenyl iodide and allyl alcohol led, in most cases, to a mixture of 3-and 2-phenylpropanal, the linear isomer being the major product, [75] Wang, Li and coworkers, in 2010, succeeded domino (HR-KTR)s leading to cinnamaldehydes with high selectivities from such substrates [Eq. (37)]. [76] The reactions were carried out in the presence of catalytic Pd(OAc)2, Bu4NCl and NaHCO3 in DMSO/DMF with oxygen to regenerate the Pd II species required for the dehydrogenation (Scheme 10). [START_REF] Gligorich | For reviews on the use of O2 to regenerate Pd II -active species[END_REF] The HR leads to arylated enolic species 10A, which coordinates to Pd(OAc)2 to finally afford the product.

Scheme 10. Synthesis of enals from aryl iodides and allyl alcohol.

While the above (HR-KTR)s were carried out with an excess of allyl alcohol versus ArI, Huang and co-workers used an excess of the latter. Thus, they synthetized 3,3-diaryl propenals by triple palladium catalysis. [77] The cross-coupling product issued of the HR-KTR undergoes, in-situ, a Heck reaction leading to the HR-KTR-HR compound [Eq. (38)]. Subjecting 3-iodothiophene to similar experimental conditions afforded 3,3-di(thiophen-3yl)acrylaldehyde in a modest yield [Eq. ( 39)].

Domino KTR + ketonisation + DHR

Tetracyclic compounds have been prepared by Hong's team from the domino reaction of 2benzylchroman-4-ones and 2-benzyl-2,3-dihydroquinolin-4(1H)-ones [Eq. ( 40)]. [55] These syntheses involve three steps: i) the KTR, ii) the benzylic oxidation and iii) the DHR. Control experiments showed that the benzylic oxidation is mediated by Cu(OAc)2/O2. The procedure allowed the synthesis of Wrightiadione (Z = O, R 1 = R 2 = H), which is a natural product exhibiting a broad range of biological activities.

Pd(OAc) 2 (0.2 equiv.) Cu(OAc) 2 (3 equiv.) , Ag 2 O (1.5 equiv.) AcONa (0.5 equiv.), O 2 (1 atm)

t-BuCO 2 H, 120 °C, 8-24 h Z O R 2 Z O R 2 O ( 40
)
Z = NMe, R 1 = H, R 2 = H (67% a , 74% b ), 7-OH (33%), 9-Me (63%), 9-(t-Bu) (59%), 9-OMe (63%), 8-Me + 10-Me (57%, 4.7:1), 8-OMe + 10-OMe (62%, 5:1) Z = NMe, R 2 = H, R 1 = 2-Me (71%), 3-CF 3 (67%), 3-OMe (62%), 3-Cl (63%) R 1 = H, R 2 = H, Z = NPh (55% c ), NBn (66% c ), NCO 2 Et (60%) Z = O, R 1 = H, R 2 = H (52%), 7-Me (34%), 9-OMe (42%), 8-Me + 10-Me (37%, 5.3:1) Z = O, R 2 = H, R 1 = 2-F (40%) a 2-benzoyl-1-methylquinolin-4(1H)-one (11%) as by-product. b t-BuCO 2 H/t-BuOAc (10:1) as the solvent, 2-benzoyl-1-methylquinolin-4(1H)-one (9%) as by-product. c t-BuCO 2 H/t-BuOAc (10:1) as the solvent. In 2001, Miura and co-workers reported the first domino reaction related to the topic of the review. Three Pd-catalyzed reactions of propiophenone were involved, -phenylation, dehydrogenation and Heck reaction, which successively arose in a basic media at 160 °C with Pd(OAc)2/PPh3 as the catalytic system [Eq. (41)]. [78] The first step of the process is well known with reports from the Miura, Buchwald and Hartwig teams. [79,80] Mechanistically, the -phenylation occurs through a phenylpalladium enolate, which provides the -phenylated product upon reductive elimination.

An extensive domino reaction arose from butyrophenone leading to the formation of up to five C-C bonds [Eq. (42)]. [78] The successive steps, which require either Pd 0 or Pd II catalyst, are proposed in Scheme 11. Under the reaction conditions, triphenylphosphine may mediate the reduction of Pd(OAc)2, [81] while PhBr forms active Pd II species from Pd 0 . [31] The first reaction of butyrophenone would be either the dehydrogenation or the -phenylation leading to [11A] or 11B, respectively. The triphenylation product 11C is issued either from [11A] or via the dehydrogenation product [11D] of 11B. Both pathways involve double bond isomerization and multiple Heck reactions, the isomerization being probably Pd II -catalyzed [82] but, given the reaction temperature, Pd 0 species could also be involved. [83] HR of 11C affords 11E, which may suffer Pd 0 -catalyzed ortho-phenylation of the benzoyl group [84] to deliver 11F. Another plausible pathway for the latter is ortho-phenylation of 11C leading to [11G], followed by HR. Triphenylnaphthalenone 11H could be obtained from intramolecular DHR of 11C. [85] The process was extended to other substrates but only the main products were characterized [Eq. ( 43)].

Scheme 11. Domino reaction of butyrophenone. The numbers in square brackets correspond to suspected intermediates.

Domino C(sp 3 )-H arylation + KTR (or KTR + HR) + HR + C(sp 2 )-H amidation

Preparation of 4-aryl-2-quinolinones from the treatment in t-amyl alcohol of N-(2,3,5,6tetrafluoro-4-(trifluoromethyl)phenyl)propionamides with aryl iodides, silver carbonate and catalytic amounts of both PdCl2 and 2.5-lutidine was discovered by Yu's team [Eq. (44)]. [86] The efficiency highly depends on both ligand and N-aryl group. Indeed, the process stopped at the level of the first arylation in the absence of lutidine, or led to lower yields with other Naryl groups [Eq. (44)].

The authors considered that these domino reactions involve a triple C-H activation, and proposed the C(sp 3 )-H arylation of the amide followed by a KTR leading to intermediate 12A (Scheme 12, path a). This arylation regioselectivity contrasts with that of propiophenone [Eq. (41)]. The amide group could favor the -C(sp 3 )-H activation, but the mechanism studies of the arylation of ester enolates summarized in Sub-chapter 6.1 (Scheme 6) [69] leads us to suspect a KTR-HR as another plausible pathway (Scheme 12, path b). HR of 12A affords 12B via syn insertion of C=C bond into the Ar 2 -PdI bond, rotation around the C-C bond and syn -H elimination. [87] Subsequent intramolecular C-N bond formation by Pd II -catalyzed dehydrogenative coupling gives 12C. [88,89] The proposed 12A to 12B pathway is consistent with the arylation of -substituted propionamides depicted in Eq. (45). Indeed, this stereospecific domino reaction would occur via KTR-HR and then dehydrogenative cyclization rather than C(sp 3 )-H arylation followed by KTR and subsequent dehydrogenative cyclization.

Scheme 12. Plausible catalytic pathways leading to 2-quinolinones from propionamides.

Conclusion

The Pd-catalyzed domino dehydrogenation/enone functionalization are often included in domino multi-reactions, thus in processes with increased values. Indeed, the green and economic interests of a domino reaction is correlated with the number of bonds efficiently created during the process. Most domino reactions above highlighted occur under routine laboratory conditions and are not limited to a few examples. Moreover, some of them are carried out under enantio-or diasteroselective conditions, or afford products with structural complexity. Thus, these domino reactions belong to the toolbox of synthetic organic chemists. The mechanism of the different steps is often attributed with good confidence but a few remain matter of debate. It is plausible that other functionalizations ascribed, in the literature, to a -C(sp 3 )-H activation could, in fact, arise through a dehydrogenation pathway.

References (1)

For recent one-pot Pd-catalyzed reactions, see: a) N.

Scheme 6 .

 6 Scheme 6. Mechanism of the and -arylation of alkyl isobutyrate.

  C(sp 3 )-H arylation + KTR + HR (+ DHR)

  Rana, P. Niharika, D. R. Kishore, G. Satyanarayana, ChemistrySelect 2017, 2, 10809-10813; b) K. M. Saini, R. K. Saunthwala, A. K.Verma, Org. Biomol. Chem. 15, 10289-10298; d) A.- D. Manick, F. Berhal, G. Prestat, Org. Lett. 2018, 20, 194-197; e) A. Soozani, A. Keivanloo, M. Bakherad, Tetrahedron 2018, 74, 150-156; f) S. Basuli, G. Satyanarayana, Eur. J. Org. Chem. 2018 In press. (2) L. F. Tietze, Chem. Rev. 1996, 96, 115-136. (3) According to Tietze, 2 the expression cascade is less appropriated than domino for these reactions. (4) D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004, 248, 2365-2379. (81) a) C. Amatore, A. Jutand, M. A. M'Barki, Organomet. 1992, 11, 3009-3013; b) C. Amatore, A. Jutand, Acc. Chem. Res. 2000, 33, 314-321; c) A. Bottoni, M. A. Carvajal, G. P. Miscione, J. J. Novoa, Molecular Physics 2010, 108, 1619-1640. (82) A. Sen, T.-W. Lai, Inorg. Chem. 1984, 33, 3257-3258. (83) a) H. A. J. Carless, D. J. Haywood, J. Chem. Soc., Chem. Commun 1980, 980-981; b) Y. Hoshino, N. Takeno, Bull. Chem. Soc. Jpn 1994, 67, 2873-2875. (84) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174-238. (85) Miura's team proposed different pathways for the production of 9E, 9F and 9I. 78 (86) Y. Deng, W. Gong, J. He, J.-Q. Yu, Angew. Chem. Int. Ed. 2014, 53, 6692-6695. R. Bernini, S. Cacchi, I. D. Salve, G. Fabrizi, Synlett 2006, 2947-2952. (88) W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 14560-14561. (89) M.-L. Louillat, F. W. Patureau, Chem. Soc. Rev. 2014, 43, 901-910. Domino Reaction: start with all reagents and then, laisser-faire.

	Graphical abstract.
	Pd 0 or Pd II ArX or ArH additives	R	O	R'	R	O	R'	R	Ar R	O O	R'	product
	solvent, t °C							Ar			R'