Dr Etienne Allart
email: etienne.allart@chru-lille.fr

Arnaud Delval

Alexandre Caux-Dedeystere

Julien Labreuche

Romain Viard

Renaud Lopes

Hervé Devanne

Parietomotor connectivity in the contralesional hemisphere after stroke: a paired-pulse TMS study

Keywords: posterior parietal cortex PMC: premotor cortex M1: motor cortex aIPS: anterior part of the intraparietal sulcus pIPS stroke, parietal cortex, transcranial magnetic stimulation, connectivity, spatial neglect, motor impairment

Highlights

 PPC-M1 connectivity from posterior part of the PPC is disrupted in patients with spatial neglect  aIPS-M1 connectivity in the contralesional hemisphere is unaffected in stroke patients  The severity of motor impairment is not correlated with contralesional PPC-M1 connectivity

Introduction

Stroke is the main cause of acquired disability in adults. Upper limb paresis is one of the most frequent symptoms after stroke; the recovery of upper limb function is often problematic but constitutes a key factor in personal autonomy. Spatial neglect (defined as a failure to acknowledge or explore stimuli towards the contralesional side) [START_REF] Heilman | Neglect and related disorders[END_REF] is another challenging consequence of stroke, since it slows recovery and impairs activities of daily living (Di [START_REF] Monaco | Severity of unilateral spatial neglect is an independent predictor of functional outcome after acute inpatient rehabilitation in individuals with right hemispheric stroke[END_REF]. In fact, spatial neglect is a frequent consequence of lesions in the right hemisphere -especially those affecting the inferior parietal, temporoparietal and superior parietal territories [START_REF] Mort | The anatomy of visual neglect[END_REF]Verdon et al. 2010;[START_REF] Molenberghs | Is there a critical lesion site for unilateral spatial neglect? A meta-analysis using activation likelihood estimation[END_REF][START_REF] Rousseaux | Neuroanatomy of space, body, and posture perception in patients with right hemisphere stroke[END_REF]). As a sensory-motor interface and a key structure in movement planning and control, the posterior parietal cortex (PPC) may play a role in post-stroke cerebral plasticity and recovery from both upper limb paresis and spatial neglect [START_REF] Buneo | The posterior parietal cortex: Sensorimotor interface for the planning and online control of visually guided movements[END_REF],.

Parietofrontal networks (comprising the PPC, the premotor cortex (PMC) and the primary motor cortex (M1)) are significantly involved in the planning and online control of visually guided movements [START_REF] Buneo | The posterior parietal cortex: Sensorimotor interface for the planning and online control of visually guided movements[END_REF][START_REF] Filimon | Human cortical control of hand movements: parietofrontal networks for reaching, grasping, and pointing[END_REF][START_REF] Davare | Interactions between areas of the cortical grasping network[END_REF]Vesia et al. 2013). More specifically, the most anterior structures of the PPC (i.e. the anterior part of the intraparietal sulcus (aIPS) and the supramarginal gyrus) are connected to the ventral PMC and control the grasping phase of movements [START_REF] Davare | Temporal Dissociation between Hand Shaping and Grip Force Scaling in the Anterior Intraparietal Area[END_REF][START_REF] Koch | Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex[END_REF]Koch et al. , 2008a;;[START_REF] Cavina-Pratesi | Functional Magnetic Resonance Imaging Reveals the Neural Substrates of Arm Transport and Grip Formation in Reach-to-Grasp Actions in Humans[END_REF][START_REF] Koch | In vivo definition of parieto-motor connections involved in planning of grasping movements[END_REF]Vesia et al. 2013). In contrast, the most posterior structures in the PPC (i.e. the posterior part of the intraparietal sulcus (pIPS) and the adjacent cortical structures in the superior and inferior parietal lobule (the superior parieto-occipital cortex (SPOC) and the angular gyrus) are connected to the dorsal PMC and control the reaching phase [START_REF] Makris | Segmentation of Subcomponents within the Superior Longitudinal Fascicle in Humans: A Quantitative, In Vivo, DT-MRI Study[END_REF][START_REF] Koch | Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex[END_REF]Koch et al. , 2008a;;[START_REF] Busan | Effect of Transcranial Magnetic Stimulation (TMS) on Parietal and Premotor Cortex during Planning of Reaching Movements[END_REF][START_REF] Cavina-Pratesi | Functional Magnetic Resonance Imaging Reveals the Neural Substrates of Arm Transport and Grip Formation in Reach-to-Grasp Actions in Humans[END_REF][START_REF] Karabanov | Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS[END_REF]Vesia et al. 2013). Most of these findings on PPC-M1 functional connectivity come from paired-pulse transcranial magnetic stimulation (ppTMS) studies (for a review, see [START_REF] Rothwell | Using transcranial magnetic stimulation methods to probe connectivity between motor areas of the brain[END_REF]. At rest or just before movement initiation, a test stimulus (TS) is delivered to M1 a few milliseconds after a conditioning stimulus (CS) has been delivered to the PPC. Various studies of PPC-M1 connectivity in the left hemisphere have been performed in righthanded, healthy controls at rest. Depending on the intensity of CS and the length of the interstimulus interval (ISI, between the CS and the TS), one can variously observe an inhibitory influence of the CS when the latter is applied over the aIPS with an ISI of 4 ms [START_REF] Koch | Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex[END_REF][START_REF] Karabanov | Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS[END_REF]Vesia et al. 2013), a potentiating influence when the CS was applied over the pIPS [START_REF] Koch | Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex[END_REF][START_REF] Karabanov | Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS[END_REF], and the lack of an effect when the CS was applied over the SPOC (Vesia et al. 2013). However, SPOC-M1 connectivity may become functional during arm movements toward a target (Vesia et al, 2013). Furthermore, transcallosal interparietal functional connections are asymmetric in right-handed healthy controls; the right PPC inhibits contralateral parietofrontal connections more strongly than the left PPC does [START_REF] Koch | Asymmetry of Parietal Interhemispheric Connections in Humans[END_REF]. As a consequence, post-stroke neglect might result from the loss of interhemispheric balance between the right and left PPCs; this hypothesis is supported by the results of imaging studies in stroke patients [START_REF] Rode | Representation and disconnection in imaginal neglect[END_REF][START_REF] Bozzali | Microstructural damage of the posterior corpus callosum contributes to the clinical severity of neglect[END_REF][START_REF] Lunven | White matter lesional predictors of chronic visual neglect: a longitudinal study[END_REF] and ppTMS studies in which contralesional (left) PPC-M1 connectivity was greater in right-handed patients with left spatial neglect than in patients without neglect or in healthy controls (Koch et al. 2008b[START_REF] Koch | θ-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect[END_REF]. Subsequently, the application of repetitive TMS to the left PPC gave encouraging results in terms of recovery from peripersonal and behavioral neglect (for a review, see [START_REF] Jacquin-Courtois | Hemi-spatial neglect rehabilitation using non-invasive brain stimulation: Or how to modulate the disconnection syndrome?[END_REF]. In these ppTMS studies, however, the CS was applied over the pIPS with a broad figure-of-eight coil; this probably activated posterior structures in the superior and inferior parietal lobules. Finally, a growing body of literature data suggests that parietofrontal networks are involved in post-stroke recovery from motor impairment [START_REF] Inman | Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke[END_REF][START_REF] Schulz | Parietofrontal motor pathways and their association with motor function after stroke[END_REF][START_REF] Schulz | Enhanced Effective Connectivity Between Primary Motor Cortex and Intraparietal Sulcus in Well-Recovered Stroke Patients[END_REF].

In summary, the PPC and the associated parietomotor networks are key structures not only for gesture planning and control but also for spatial representations. Parietofrontal networks seems to be involved in the genesis of spatial neglect and may be related to motor recovery -making the PPC a possible target for therapeutic modulation by non-invasive brain stimulation techniques. However, functional specialization has been evidenced for subregions of the PPC in humans, and little is known about this aspect in stroke patients. Indeed, to the best of our knowledge, contralesional connections between subregions of the PPC (the aIPS, pIPS and SPOC) and M1 have not previously been studied in stroke patients.

Hence, the primary objective of the present study was to compare left PPC-M1 connectivity in right hemispheric stroke patients and in healthy controls by using a ppTMS protocol to assess the effect of a CS (applied over the aIPS, pIPS and SPOC) on M1 excitability. The secondary objective was to assess the relationship between spatial neglect and motor impairment on one hand and left (contralesional) PPC-M1 connectivity on the other.

Methods

Study participants

Patients were recruited from among in-and outpatients in the Neurorehabilitation Unit at Lille University Medical Center (Lille, France) between August 2014 and February 2016. We included 12 stroke patients who had suffered a single right ischemic or hemorrhagic hemispheric stroke (diagnosed by MRI) and had displayed left hemiparesis for at least 6 months before inclusion. The presence of spatial neglect was not an inclusion criterion but was assessed in all included patients (see 2.5). We also included 12 healthy age-matched healthy controls. We excluded patients with bilateral lesions, those who were unable to consent to or understand the study protocol due to language, cognitive or psychiatric disorders, and those presenting contraindications to TMS or MRI. All participants were right-handed, according to the Edinburgh Handedness Inventory [START_REF] Oldfield | The assessment and analysis of handedness: the Edinburgh inventory[END_REF], and gave their informed written consent to participation. The study was approved by the local investigational review board (Comité de protection des personnes Nord Ouest IV, Lille, France; reference 2013-A01766-39), and was conducted in accordance with the tenets of the Declaration of Helsinki.

Experimental procedures

The participants were seated in a comfortable chair, with their right forearm resting on a second chair (the height of which could be adjusted). They were told to keep their arm still throughout the experimental session. As the first dorsal interosseous (FDI) muscle is activated during both phases of prehension movements (Koch et al. 2008a;[START_REF] Davare | Ventral premotor to primary motor cortical interactions during object-driven grasp in humans[END_REF], motor evoked potentials (MEPs) were recorded at this site. Electromyographic (EMG) activity was recorded with Ag-AgCl surface electrodes in a belly-tendon montage. The electrodes were positioned over the body of the muscle and the first metacarpophalangeal joint. A ground electrode was attached to the wrist. The EMG signals were amplified (×1000), high-pass filtered at 10 Hz, low-pass filtered at 1000 Hz (Digitimer, Hertfordshire, UK) and then sampling at 2 kHz (1401 MicroMKII device; Cambridge Electronic Design, Cambridge, UK). Data were stored for subsequent off-line analysis using SIGNAL software (Cambridge Electronic Design, Cambridge, UK).

Transcranial magnetic stimulation

We used a previously described ppTMS technique to study PPC-M1 interactions in the left hemisphere (for a review, see [START_REF] Rothwell | Using transcranial magnetic stimulation methods to probe connectivity between motor areas of the brain[END_REF]. The CS was delivered at 90% of the resting motor threshold (RMT) using a figure-of-eight coil (PMD 25 decentral, Mag&More, Münich, Germany; inner diameter 25mm) connected to a PowerMag100 stimulator (Mag&More). The RMT was defined as the lowest possible stimulus intensity required to elicit MEPs with a >50 V peak-to-peak in at least 5 out of 10 trials when participants kept the FDI relaxed in both hands [START_REF] Rossini | Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee[END_REF]. The coil was held tangentially to the scalp surface and was turned slightly anticlockwise (by 15°) to induce a posterior-anterior-directed current in the underlying cortical tissue (Fig. 1a). The TS was delivered over M1 of the left hemisphere using a Magstim 200 stimulator (The Magstim Company Ltd, Whitland, UK), at an intensity that evoked MEPs with a ~1 mV peak-to-peak amplitude in the control condition. We placed a figure-of-eight coil (Magstim Alpha Branding Iron, The Magstim Company Ltd; external diameter: 50mm) tangentially to the scalp at an angle of 45° to the mid-sagittal line, in order to induce a posterior-anterior-directed current across the central sulcus (Fig. 1a). The coils were held on to the scalp surface by articulated arms. The ISI was set to 4 ms or 6 ms. At each site over the PPC, three conditions were tested in pseudorandom order: the TS alone (the control condition) and the combined CS-TS condition with the two ISIs. Eight responses were recorded for each condition, giving a total of 24 responses for each PPC site. The inter-trial interval was set to 51s.

Localization of brain sites

The scalp location for M1 was defined as the point at which stimulation evoked the largest MEP in the right FDI. We used a stereotaxic neuronavigation system (eXimia ® TMS, Nexstim, Helsinki, Finland) to accurately identify each PPC stimulation site and monitor the TMS coil position.

Before the TMS session, participants underwent MRI on a 3T machine (Achieva, Philips Medical Imaging, Best, The Netherlands) equipped with an eight-channel head coil. Volumetric T1-weighted images were acquired with a magnetization-prepared gradient echo sequence (voxel size: 0.750 x 0.727 x 0.727 mm 3 ; repetition time 10.4 ms; echo time 4.76 ms; matrix size: 214 x 352 x 352 voxels).

With regard to individual anatomical landmarks, we selected the three regions of interest within the PPC (the aIPS, pIPS and SPOC; Fig. 1b). The aIPS was defined as the region located over the intersection between the postcentral sulcus and intraparietal sulcus [START_REF] Frey | Cortical topography of human anterior intraparietal cortex active during visually guided grasping[END_REF]. The pIPS was situated over the intraparietal sulcus [START_REF] Karabanov | Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS[END_REF]. The SPOC was defined as the region along the medial surface of the parietal lobe, anterior to the parieto-occipital sulcus, posterior to the subparietal sulcus and medial to the intraparietal sulcus (Vesia et al. 2013).

Clinical assessment

Patients were classified as suffering from spatial neglect ("N+") or not ("N-") with regard to their performance in the three tests described hereafter. Peripersonal neglect was first assessed using the bells test [START_REF] Gauthier | The Bells Test: A quantitative and qualitative test for visual neglect[END_REF]. In this test, participants have to identify 35 bell symbols distributed throughout a field of other symbols. Patients were considered to display peripersonal spatial neglect if they omitted at least 6 bells [START_REF] Gauthier | The Bells Test: A quantitative and qualitative test for visual neglect[END_REF][START_REF] Rousseaux | Presenting a battery for assessing spatial neglect. Norms and effects of age, educational level, sex, hand and laterality[END_REF]. Personal (body) neglect was assessed with the fluff test (cut-off score: 13), which consists in removing targets attached to the front of the participant's clothes [START_REF] Cocchini | The Fluff Test: A simple task to assess body representation neglect[END_REF]. Lastly, behavioral neglect was assessed via the examiner's part of the Catherine Bergego Scale (cut-off score: > 10) [START_REF] Azouvi | Behavioral assessment of unilateral neglect: study of the psychometric properties of the Catherine Bergego Scale[END_REF].

Motor impairment was assessed via the upper extremity subsection of the Fugl-Meyer Assessment (FMA-UE), which comprises the motor function of the upper arm, wrist and hand, and overall coordination [START_REF] Fugl-Meyer | The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance[END_REF]. The 14-item Motor Activity Log questionnaire (MAL-14) was used to measure upper limb function in daily life; participants have to rate the amount and quality of movement of the paretic arm when completing 14 activities of daily living [START_REF] Uswatte | Reliability and validity of the upperextremity Motor Activity Log-14 for measuring real-world arm use[END_REF].

Statistical analysis

Peak-to-peak MEP amplitude was analyzed as the raw data for each condition (TS and CS-TS at each ISI) and (after normalization) as a proportion of the MEP recorded under control conditions (delivery of the TS alone) during the same block of trials. The normality of the data distribution was checked with a Shapiro-Wilk test and Q-Q plots. Intergroup comparisons of demographic and strokerelated variables were performed using Student's t test (or the Mann-Whitney U test, for non-normally distributed data) for quantitative variables and Fisher's exact test for qualitative variables.

To study inter-and intragroup differences, we used linear mixed models for repeated measures (using an unstructured covariance pattern model, with restricted maximum likelihood approach as the estimation method) to take account of the correlation between repeated measures within the same subjects. For each linear mixed model, we checked the normality and homoscedasticity of the residuals.

To study intergroup differences in PPC-M1 connectivity, we first compared the normalized MEP amplitude at each PPC site in healthy controls vs. the whole stroke patient population (i.e. the study's primary objective). In these models, the dependent variable was the normalized MEP amplitude and the fixed effects were the group (healthy controls vs. patients), the ISI (4 ms vs. 6 ms) and the group x ISI interaction. We next compared the normalized MEP amplitude at each PPC site among stroke patients (as a function of N+ vs. N-status), using the same linear mixed model approach. In both analyses, post-hoc comparisons at each ISI were performed (using linear contrasts with Bonferroni correction) whenever the group x ISI interaction was statistically significant.

To study intragroup differences in PPC-M1 connectivity (i.e. to determine whether the MEP in the CS-TS conditions differed from the TS condition in each group: healthy controls, the whole stroke patient population, N+ patients, and N-patients) for the three different PPC sites, we also computed separate linear mixed models in which the raw MEP amplitude was the dependent variable, and the condition (TS, and CS-TS at ISIs of 4 and 6 ms) was the fixed effect. Whenever the effect of condition was significant, post-hoc comparisons of TS vs. each CS-TS condition were performed (using linear contrasts with Bonferroni correction).

Spearman's rank correlation coefficient was used to evaluate the respective associations between the severity of spatial neglect, upper limb function and motor impairment on one hand and contralesional PPC-M1 connectivity on the other.

The threshold for statistical significance was set to p<0.05. All tests were two-tailed. All statistical analyses were performed with SAS software (version 9.3, SAS Institute, Cary, NC).

Results

Patients

The characteristics of the study population are summarized in Table 1. Six of the 12 patients presented symptoms of spatial neglect. There were no significant differences between patients and healthy controls in terms of the mean age and the gender ratio. Even though N+ patients had slightly higher FMA-UE scores and were slightly older than N-patients, the intergroup differences were not statistically significant (FMA-UE score: p=0.199; age: p=0.108; also disease duration: p=0.378).

As seen on overlap maps (Fig. 2), the lesions were more widespread in the neglect group (mean  standard error of the mean (SEM) volume = 134888  52085 voxels in the N+ group and 29444  25349 in the N-group; p=0.015) and were more likely to involve the parietal lobe. There was less lesion overlap in the N-group.

The ppTMS protocol was not performed for the aIPS in 2 patients (one in each group) and 4 healthy controls because this structure was too close to M1 (due to skull size) and so the coils could not be placed properly.

The RMT and the M1 stimulation intensity

The RMT for the left M1 (used to calibrate the intensity of the CS) was 65.3  12.7% of the maximum stimulator output in the patients (70  14.5% in N+ and 60.7  9.7% in N-) and 63.1  10.3% of the maximum stimulator output in healthy controls (Fig. 3a); the intergroup difference was not statistically significant. Likewise, there was no significant intergroup difference in the TS intensity needed to elicit a 1 mV MEP in the control condition (Fig. 3b) or the MEP amplitude elicited in the control condition (TS) at any PPC site.

Intergroup differences in PPC-M1 connectivity

In the linear mixed models comparing all stroke patients with healthy controls, we did not observe any significant intergroup differences (group effect: p=0.53; ISI x group interaction: p=0.98).

Only a significant effect of the ISI on aIPS-M1 connectivity was observed (p=0.005) (Fig 4a). This indicated that MEP suppression was greater at an ISI of 4 ms than at 6 ms in all subjects, regardless of their group. Furthermore, we did not find any differences between the N+ and N-groups (group effect: p=0.47; ISI x group interaction: p=0.51); only a non-significant difference between the two ISIs was observed (p=0.066) (Fig 4b).

When comparing SPOC-M1 connectivity in the stroke patient population vs. healthy controls, the effects of group and ISI were not significant (group effect: p=0.51; ISI effect: p=0.083; ISI x group interaction: p=0.56) (Fig 4e). Interestingly, when comparing N+ and N-patients, the ISI x group interaction was significant (p=0.005). Post-hoc comparisons showed that when the CS was applied over the SPOC after an ISI of 6 ms, N+ patients showed stronger facilitation than N-patients (Bonferroni-adjusted p=0.016) (Fig. 4f).

For pIPS-M1 connectivity, we did not find any group or ISI effects when comparing either the whole stroke patient population with healthy controls (group effect: p=0.15; ISI effect: p=0.81; ISI x group interaction: p=0.67) or when comparing N+ patients with N-patients (group effect: p=0.20; ISI effect: p=0.65; ISI x group interaction: p=0.55). (Fig 4c,d).

Intragroup differences in PPC-M1 connectivity

When comparing the non-normalized MEP amplitudes under the three conditions (TS alone vs. CS-TS at each ISI), a significant difference in aIPS-M1 connectivity was observed for healthy controls (p=0.05), the whole stroke patient population (p=0.028) and N+ patients (p=0.015) but not for N-patients (p=0.22). Post-hoc comparisons revealed significant MEP suppression at an ISI of 4ms for healthy controls, the whole stroke patient population, and the N+ group (Bonferroni-adjusted p<0.05, Fig 4a,b). A main effect of condition on SPOC-M1 connectivity was only found in N+ patients (p=0.028), in whom connectivity was significantly facilitated at an ISI of 6 ms (Bonferroni-adjusted p=0.037) (Fig 4f). As with the intergroup comparisons, we did not find any difference between TS and CS-TS modalities after applying the CS over the pIPS (p>0.30 for all comparisons) (Fig 4c,d).

Relationships between PPC-M1 connectivity and clinical assessments

As SPOC-M1 connectivity at an ISI of 6 ms discriminated between N+ and N-patients, we chose this interval to study the association between the severity of neglect and PPC-M1 connectivity.

Interestingly, patients who presented with more severe peripersonal neglect tended to show stronger MEP facilitation; indeed, the number of omissions in the bells test was significantly correlated with the degree of facilitation induced by PPC conditioning (r=0.841; p=0.036) (Fig 5). No such association was found for personal neglect (i.e. performance in the fluff test) and behavioral neglect (i.e. with the Catherine Bergego Scale).

Lastly, neither the degree of motor impairment (as assessed by the total FMA-UE score) nor upper limb function (as assessed by the MAL-14 score) was associated with contralesional PPC-M1 connectivity when analyzing either the whole patient group or the N+ and N-subgroups separately.

Likewise, the FMA-UE subscores for proximal motor function (volitional movements) and distal motor function (wrist and hand movements) were not correlated with PPC-M1 connectivity when the CS was applied to the posterior sites (the pIPS and the SPOC) and the anterior site (the aIPS), respectively.

Discussion

The present study is the first to have evaluated contralesional (left-side) PPC-M1 connectivity at rest in stroke patients by precisely targeting three subparts of the PPC, i.e. an anterior region (the aIPS) and two posterior regions (the SPOC and the pIPS). Although there were no intergroup differences when comparing the patients as a whole (regardless of their neglect status) with healthy controls, we demonstrated that applying CS over the SPOC at an ISI of 6 ms facilitated MEP responses in the N+ group but not in the N-group or healthy controls -especially when peripersonal neglect was severe. Furthermore, ppTMS of the aIPS exerted an inhibitory influence on M1 in both patients and healthy controls. Lastly, the severity of motor impairment was not associated with PPC-M1 connectivity.

Functional connectivity between posterior regions of the PPC and M1

Our results highlighted the fact that neglect status must be taken into account when assessing contralesional PPC-M1 connectivity at posterior PPC sites (the pIPS and the SPOC). Previous work has already shown that connectivity between the posterior part of the PPC and M1 is modified not only in the contralesional hemisphere of stroke patients with neglect (Koch et al. 2008b[START_REF] Koch | θ-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect[END_REF] but also in healthy controls (relative to a control condition) as a result of asymmetric interparietal functional connections [START_REF] Koch | Asymmetry of Parietal Interhemispheric Connections in Humans[END_REF]. However, Koch et al. only studied the pIPS as the target for the CS. In the present study (and in contrast to previous works (Koch et al. 2008b[START_REF] Koch | θ-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect[END_REF])), we did not observe hyperexcitability in pIPS-M1 networks in either patients or healthy controls but did evidence hyperexcitability of parietomotor connections in the N+ group when the CS was applied over the SPOC after an ISI of 6 ms. Koch et al. applied the CS over the pIPS (either located by the EEG coordinates or by neuronavigation) using a broad TMS coil; this would have modulated cortical regions over the angular gyrus and the posterior part of the superior parietal lobule. In the present study, we used a much smaller coil and thus produced a much narrower stimulation field. Furthermore, we placed the coil over the sulcus [START_REF] Karabanov | Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS[END_REF] and not over the superior part of the angular gyrusin contrast to previous studies (Koch et al. 2008b[START_REF] Koch | Asymmetry of Parietal Interhemispheric Connections in Humans[END_REF][START_REF] Koch | θ-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect[END_REF]. Accordingly, the regions bordering the sulcus (the angular gyrus and superior parietal lobule) would have been less modulated; this may be why we did not observe any effect when stimulating the pIPS. Moreover, the SPOC is close to the pIPS, and both regions are involved in planning and controlling visually-guided reaching movementsalbeit with their own specific features (the encoding of reach goals for the SPOC, and reach vectors for the pIPS (Vesia et al. 2010)). Both regions produced the same facilitation pattern in ppTMS protocols when the CS was applied during movement planning (Koch et al. 2008a[START_REF] Koch | In vivo definition of parieto-motor connections involved in planning of grasping movements[END_REF]Vesia et al. 2013). In a more integrated analysis, both the SPOC and the pIPS are posterior nodes in the dorsal attentional network. This network is known to mediate the top-down, guided, voluntary allocation of attention to location or features [START_REF] Corbetta | Control of goal-directed and stimulus-driven attention in the brain[END_REF][START_REF] Szczepanski | Functional and structural architecture of the human dorsal frontoparietal attention network[END_REF]Vossel et al. 2014). Dysfunction to the dorsal attentional networkwhether caused either directly (Ptak andSchnider 2010, 2011) or indirectly (by damage to the ventral attentional network;

Corbetta and Shulman 2011) -is thought to be one of the mechanisms underlying spatial neglect.

Finally, if lesions in the inferior parietal lobule or the superior temporal gyrus tend to lead to neglect whereas damage to the superior parietal lobule leads to optic ataxia [START_REF] Vallar | The anatomy of unilateral neglect after right-hemisphere stroke lesions. A clinical/CT-scan correlation study in man[END_REF], lesions to the IPS and superior parietal lobule lesions can be also involved in neglect [START_REF] Molenberghs | Is there a critical lesion site for unilateral spatial neglect? A meta-analysis using activation likelihood estimation[END_REF]. Taken as a whole, these arguments strengthen the hypothesis whereby SPOC hyperexcitability in N+ patients is related to neglect (as pIPS-M1 hyperexcitability was seen to be related to neglect in earlier studies).

Interestingly (and even though this result should be interpreted with caution, in view of the small number of patients with neglect), the amount of facilitation induced by the conditioning of SPOC at an ISI of 6 ms was correlated with the severity of peripersonal spatial neglect but not with personal or behavioral neglect. Koch et al. reported an association with peripersonal neglect when the CS was applied over the pIPS (Koch et al. 2008b), whereas fMRI studies have extended these links to behavioral neglect [START_REF] Baldassarre | Large-scale changes in network interactions as a physiological signature of spatial neglect[END_REF][START_REF] Ramsey | Normalization of network connectivity in hemispatial neglect recovery[END_REF]. With regard to the specific function of the posterior regions of PPC, it would be interesting to study the motor component of neglect (directional hypokinesia), i.e. an impairment in initiating or completing movements in the leftward direction [START_REF] Heilman | Directional hypokinesia: prolonged reaction times for leftward movements in patients with right hemisphere lesions and neglect[END_REF][START_REF] Kim | Directional and spatial motor intentional disorders in patients with right versus left hemisphere strokes[END_REF]. The lack of correlation between PPC-M1 connectivity and personal neglect is not surprising, as they represent two different entities that are sometimes but not always associated. Spatial attention is less involved in body perception, and the neuroanatomical correlates of personal neglect are different from those of peripersonal neglect [START_REF] Baas | Personal neglect-a disorder of body representation?[END_REF][START_REF] Rousseaux | Anatomical and psychometric relationships of behavioral neglect in daily living[END_REF]. Hence, in addition to the lesion site (as discussed above) and as already suggested in the lietrature (Koch et al. 2008b), the neglect subtype is another important factor to be taken into account when seeking to interpret abnormal PPC-M1 connectivity in patients with neglect. On the clinical level, the SPOC may be an alternative to the pIPS as a target for non-invasive brain stimulation protocols aimed at reducing left parietal hyperexcitability in patients with spatial neglect. Nevertheless, the results of the present pilot study must first be confirmed and extended.

Functional connectivity between aIPS and M1

Our data indicated that contralesional aIPS-M1 connectivity was maintained after stroke and was not influenced by spatial neglect. This result is not surprising, since anterior regions of the PPC are brought into play in the grasping phase of upper limb movements but are not involved in encoding and controlling reaching movements and thus the integration of the contralateral workspace. Furthermore, lesions in the anterior part of PPC are not a cause of neglect in stroke patients. PPC-M1 connectivity was not correlated (whatever the target for the CS) with the severity of motor impairment and upper limb function. We hypothesize that contralesional PPC-M1 connectivity may be indirectly modified (via interhemispheric connections) in the lesioned hemisphere in paretic patients. Indeed, recent imaging studies have highlighted a potential association between resting state connectivity in the parietofrontal networks of the lesioned hemisphere (especially the connectivity from the aIPS) and residual motor function in stroke patients, together with the involvement of these networks in motor recovery [START_REF] Inman | Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke[END_REF][START_REF] Schulz | Parietofrontal motor pathways and their association with motor function after stroke[END_REF][START_REF] Schulz | Enhanced Effective Connectivity Between Primary Motor Cortex and Intraparietal Sulcus in Well-Recovered Stroke Patients[END_REF]. In the future, the analysis of ipsilesional aIPS-M1 connectivity using a ppTMS protocol might be of greater relevance to the link between parietomotor connectivity and motor recovery.

Possible mechanisms underlying changes in PPC-M1 connectivity

The most widely accepted explanation for contralesional PPC-M1 hyperexcitability in neglect patients is based on the notion of interhemispheric rivalry; the imbalance concerns homotopic regions of the two hemispheres, rather than the whole lesioned hemisphere. Unsurprisingly, we found that lesions of the parietal lobe were more frequent in N+ patients, since these lesions often cause neglect and directly affect the interhemispheric balance. However, one must also bear in mind that remote lesions in the downstream structures of parietofrontal networks might also alter the PPC's interhemispheric balanceespecially in cases of damage to the ventral attentional network [START_REF] Corbetta | Spatial neglect and attention networks[END_REF][START_REF] Lunven | White matter lesional predictors of chronic visual neglect: a longitudinal study[END_REF]. The influence of the lesion site on the amount of interhemispheric imbalance (and thus on the hyperexcitability of PPC-M1 connectivity in the contralesional hemisphere) has not yet been explored. The small number of patients in the N+ group prevented us from performing this analysis in the present study. In the future, this question could be addressed by measuring PPC-M1 connectivity as a function of whether the neglect patient's lesion includes parietal areas. Moreover, ppTMS protocols can only study connections from parietal areas to motor areas; it might be interesting to use functional imaging or TMS-EEG to study the connectivity of other parietofrontal networks in general and direct connections to premotor areas (i.e. the ventral and dorsal PMC) in particular.

One can also speculate as to whether M1 excitability has a role in changes in PPC-M1 connectivity. As already reported in acute and chronic stroke patients, we found that the RMT for the contralesional hemisphere was similar when comparing the stroke group with healthy controls and when comparing N+ patients with N-patients [START_REF] Liepert | Motor cortex disinhibition of the unaffected hemisphere after acute stroke[END_REF][START_REF] Manganotti | Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke[END_REF]; this indicated that PPC-M1 abnormalities in patients were probably not due to changes in the excitability of the corticomotoneural cells located in the primary motor cortex. Although the PPC neurons' mechanisms of action on M1 are poorly understood, it has been suggested that (i) there are direct, functional connections between several PPC regions and M1 [START_REF] Koch | Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex[END_REF] and (ii) MEP facilitation would arise from interaction with late I-wave circuits. Other researchers have shown that local inhibitory and excitatory interneurons may be dysfunctional in the contralesional hemisphere following stroke (Edwards et al, 2013;Mello et al, 2015). It is therefore conceivable that the changes in the posterior PPC's influence on M1 excitability observed after stroke could also be due to dysfunction in M1 interneuron circuits.

Study limitations

The present study suffered from several limitations. Firstly, the sample size was small (particularly in the N+ subgroup); this may have led to a lack of statistical power when studying the influence of spatial neglect and may possibly have biased the correlations. Secondly, it should be borne in mind that the number of LMMs was high, and so we cannot rule out false positives. Thirdly, the patient population was quite heterogeneous with regard to disease characteristics. To reduce this heterogeneity, we included only chronic stroke patients. However, this choice complicated the inclusion of patients with neglect because this impairment often disappears in the months following stroke. Moreover, despite our use of small coils, a lack of space prevented proper coil placement over the aIPS in 6 participants (2 stroke patients and 4 healthy controls); surprisingly, only one previous study has reported this type of problem [START_REF] Karabanov | Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS[END_REF]. Lastly, we decided to study connectivity at 2 ISIs (4 and 6 ms) only; this was done to reduce the numbers of comparisons and because PPC-M1 connectivity at these intervals was modified at rest in both stroke patients and healthy controls (depending on the PPC site). However, we cannot rule out the possible occurrence of PPC-M1 connectivity at longer ISIs. Even though these limitations emphasize that our present findings are hypothesis-generating and need to be replicated in larger studies, our present results open up new perspectives in the assessment of parietomotor connectivity after stroke.

Conclusions

Contralesional aIPS-M1 connectivity seems to be unaffected in stroke patients, whereas connectivity from the most caudal sites in the PPC was disrupted in patients with spatial neglect. In particular, SPOC-M1 connectivity in the contralesional hemisphere was higher in post-stroke neglect patients (and particularly those presenting with peripersonal neglect). This finding provides potentially important insight into the contribution of interhemispheric rivalry to the physiopathology of neglect, which may be correlated with the functional status of connections between the most caudal sites in the PPC and motor areas. In the contrary, motor impairment did not seem to depend on PPC-M1 (c, d) or SPOC (e,f). Graphs in the left-hand column display data from all patients vs. healthy controls, whereas graphs in the right-hand column display data from patients with neglect (N+) vs. those without neglect (N-). For each condition, the MEP amplitude was normalized against TS alone (the dotted line represents the TS condition). The protocol was not performed for the aIPS in 2 patients (one in each group) and in 4 healthy controls. Intergroup differences: § p<0.05 vs. the N-group Intragroup differences: £ p<0.05 vs. the control condition (TS alone) in patients; ° p<0.05 vs. the control condition in healthy controls * p<0.05 vs. control condition in the N+ group; Error bars correspond to the SEM.

Fig. 2 Fig. 3 .Fig. 4

 234 Fig 1. (a) Schematic illustration of the coil positioning in our ppTMS experiment. The red ellipses represent the coil delivering the CS over each of the 3 PPC regions, and the white ellipses represent the coil delivering the TS over M1. (b) Stimulation sites over the aIPS (blue), pIPS (red) and SPOC (green) in the left hemisphere.

Fig 5 .

 5 Fig 5. MEP facilitation as a function of the severity of peripersonal spatial neglect, as assessed by the total number of Bells test omissions in the 6 patients in the N+ group.

Table 1

 1 Bolton DA, Mochizuki G, Staines WR. Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions. Neuropsychologia. 2013;51:410-7. Vesia M, Prime SL, Yan X, Sergio LE, Crawford JD. Specificity of human parietal saccade and reach regions during transcranial magnetic stimulation. J Neurosci 2010;30:13053-65. Vossel S, Geng JJ, Fink GR. Dorsal and Ventral Attention Systems. The Neuroscientist. 2014;20:150-9. Characteristics of stroke patients and healthy controls

	connectivity at rest.

the authors thank David Fraser for editorial support.

Funding: this work was funded by the 2013 "hospital fund to assist emergence and structuring of activities and research teams" from the Lille University Medical Center, Lille, France; and the


Miguel Baya

Pavel A Dub

Jennifer Houghton

Jean-Claude Daran

Natalia V Belkova

Elena S Shubina

Lina M Epstein

Agusti Lledos

Rinaldo Poli
email: poli@lcc-toulouse.fr

Agustí Lledós

Investigation of the [Cp*Mo(PMe 3 ) 3 H] n + ( n = 0, 1) Redox Pair: Dynamic Processes on Very Different Time Scales

Keywords: Molybdenum, Phosphine ligands, Cyclopentadienyl ligands, Paramagnetic hydride complex, Dihydrogen bonding, DFT calculations

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Hydride complexes generally feature a closed shell configuration. They are implicated in a variety of catalytic cycles and are also intermediates of C-H oxidative addition processes.

Open-shell, paramagnetic versions, on the other hand, have not so far demonstrated broad utility, mainly because of their instability and multitude of decomposition pathways, including deprotonation, 1 disproportionation, 2 dihydrogen reductive elimination (for complexes containing at least two hydride ligands), 3 atom transfer, etc. [START_REF] Poli | Paramagnetic mono-and polyhydrides of the transition metals[END_REF] Yet, fundamental processes such as dihydrogen evolution in Nature appear to take place via open-shell hydride complexes. [START_REF] Foerster | [END_REF][6][7][8] It is also possible to imagine potential implication in electrocatalytic hydrocarbon oxidation. Therefore, paramagnetic hydride complexes are attracting renewed interest. It has long been known that one-electron oxidation of hydride complexes increases the M-H bond acidity. 1 However, this property highly depends on the medium. [START_REF] Kristjánsdóttir | Acidity of Hydrido Transition Metal Complexes in Solution[END_REF][START_REF] Jacobsen | Hydridicity of Transition Metal Hydrides and its Implications for Reactivity[END_REF] For instance, hydride complexes with hydridic character may be strong acids in water. [START_REF] Jacobsen | Hydridicity of Transition Metal Hydrides and its Implications for Reactivity[END_REF] Many oxidized hydride complexes spontaneously decompose by transferring a proton to a base, which may be the 18-electron hydride precursor itself. [START_REF] Poli | Paramagnetic mono-and polyhydrides of the transition metals[END_REF] Suppression of this reactivity has been achieved by the use of strong donating ligands possessing, at the same time, a significant steric bulk. [START_REF] Baya | [END_REF]12 We have previously shown that the electron-rich hydride complex [CpMo(PMe3)3H] is reversibly oxidized to yield unstable 17-electron [CpMo(PMe3)3H] + , 13 which decomposes by deprotonation and disproportionation at room temperature. We have therefore turned our attention to the bulkier and electron-richer Cp* analogue, [Cp*MoH(PMe3)3], 1. 14 In this contribution, we will show that this is indeed leading to a more stable one-electron oxidation product, [Cp*MoH(PMe3)3] + , 2. We present here the synthesis and characterization of this material, including detailed spectroscopic studies, and a computational investigation designed to elucidate the nature of a second product that has been detected in solution for both 1 and 2. A cyclic voltammetric study of 1 shows a reversible oxidation process (Ep = 64 mV; cf. 67 mV for ferrocene under the same conditions) at E1/2 = -1.40 V vs. ferrocene in MeCN (-1.35 V in THF). This should be compared with the reversible oxidation of the analogous Cp compound at E1/2 = -1.46 V vs. ferrocene in MeCN. These low potentials make these complexes stronger reductant than Cp2Co (for which E1/2 = -1.33 V vs. ferrocene in CH2Cl2), although not as strong as Cp*2Co (E1/2 = -1.94 V). 15 We are not aware of other hydride complexes with such low E1/2 values. Note that the oxidation of 1 is slightly less facile than that of the Cp analogue. This is an unexpected result, because replacement of Cp with the electron-richer Cp* ligand usually causes a considerable negative shift in the oxidation potential. The reason of this trend reversal is unclear and is still under investigation. In line with our expectations (see Introduction), however, the 1-electron oxidation product 2, generated by oxidation of [Cp*Mo(PMe3)3H] with 1 equiv. of Cp2FePF6 in THF (see equation 1), is thermally more stable than the Cp analogue. It is moderately stable in MeCN at room temperature, decomposing slowly over a period of 24 h and could be crystallized by slow diffusion of either diethyl ether or pentane into a THF solution at -40°C to yield suitable single crystals for an X-ray analysis. In the solid state, the compound does not significantly deteriorate upon standing in air at room temperature, in contrast to the extreme air sensitivity of its precursor 1. A view of the molecule is shown in Figure 1. Relevant bonding parameters are collected in Table 1. The coordination geometry around the Mo atom is that of a typical 4-legged piano stool. The hydride H atom was directly located from difference Fourier maps and freely refined. Although the Mo-H distance of 1.72(6) Å is not very accurately determined, it corresponds closely to the Mo-H distances determined by neutron diffraction for other Mo hydride compounds: 1.685(3) Å for Cp2MoH2, 16 1.69(5) Å for Mo(H)( 2 -Me2C=NAr)[NiPr(3,5-C6H3Me2)]2, 17 1.712(8), 1.719(9) and 1.719(9) Å for (1,2,4-C5H2iBu3)Mo(PMe3)2H3, 12 and 1.789 (7) for Cp*Mo(CO)3H. 18 One interesting structural feature is the relative location of the two ions, with the PF6 - ion facing the cation on the same side as the hydride ligand. Since the oxidation of hydride complexes is known to often induce decomposition by deprotonation, [START_REF] Poli | Paramagnetic mono-and polyhydrides of the transition metals[END_REF] this observation suggests that the hydride ligand has become polarized + and that it establishes a Coulombic interaction with the PF6 -anion. The H [START_REF] Baya | [END_REF] no significant contacts were observed between the anion and the hydride ligand(s). The question of the charge on the hydride ligand in this compound has been addressed by computational methods (vide infra).

Results and Discussion

Table 1. Selected bond distances (Å) and angles (°) for compound 2 and comparison with the DFT-optimized parameters for the cation in the gas phase. a a The subscripts in Pc and Pt refer to the position cisoid and transoid to the hydride ligand.

In agreement with the presence of a single unpaired electron, solutions of complex [Cp*Mo(PMe3)3H] + in THF are EPR active. However, the isotropic spectrum is rather broad (width = 274 G at 273 K) and does not reveal any hyperfine structure, in contrast to the sharp EPR spectrum of the Cp analogue. 13 Cooling the sample does not result in any significant sharpening down to the freezing point. A frozen glass spectrum exhibits an essentially cubic tensor and is much sharper (width = 21.3 G at 110K) than the isotropic spectrum, but insufficiently so to reveal any hyperfine coupling. Cp*Mo(PMe3)3Cl, 19 the oxidized complex is stable under the same conditions. This is in line with the expected hydridicity reduction upon oxidation.

(b) Infrared characterization of complexes 1 and 2.

The ground state properties of the Mo-H bond for the neutral and cationic complexes were probed by infrared spectroscopy in solution (Figure 2). An immediately striking observation is the presence of two bands in each case, whereas only one band is expected for a monohydride complex. A major band around 1794 cm -1 and a minor one at ca. 1730 cm -1 are observed in both n-hexane and THF for 1, whereas two bands of approximately equal intensity at ca. 1800 and 1770 cm -1 are observed in both THF and CH2Cl2 for the cationic complex 2. The observed blue shift upon oxidation parallels that reported for other redox couples, for instance [CpFeH(dippe)] 0/+• (M-H = +28 cm -1 ) and [Cp*FeH(dippe)] 0/+• (M-H = +14 cm -1 ). 20 The parallel magnetic resonance investigations (NMR for 1 and EPR for 2)

did not show any evidence for the presence of more than one species in solution. However, the timescale of the magnetic resonance techniques is longer than that of infrared Contrary to the solution infrared spectra, the solid state spectra of 1 and 2 do not clearly reveal a second component. In the spectrum of 1 (Figure 2 The two bands have a smaller intensity difference in 2. Under the assumption of similar extinction coefficients for the Mo-H vibration in the two species, this means that the two species are more equally populated (smaller free energy difference) in 2. The solution IR spectra recorded at different temperatures (supporting Figures S4 andS5) showed a change of the band intensity ratio, this being more evident for 1 where the Boltzmann population difference is greater. For the neutral complex, an estimation of ca. 0.2 kcal/mol as G (Gminor-Gmajor) can be derived from the I(1800)/I(1730) ratios at the two extreme temperatures: 2.95 at 290 K and 3.5 at 200 K.

The two possibilities envisaged for such equilibrating species are (i) a phosphine ligand dissociation and (ii) a geometric isomerism. In order to probe for the ligand dissociation hypothesis, spectroscopic studies were carried out in the presence of deliberately added PMe3.

The measurement of the intensity ratio of the two IR bands (conditions as in Figure 2, with 10 equiv of PMe3) was prevented by the strong absorption of free PMe3 in the Mo-H stretching region. Useful information, however, could be obtained by NMR and EPR spectroscopy. For the neutral complex, the 1 H and 31 P NMR spectra of 1/PMe3 mixtures showed the superposition of the distinct free ligand and hydride complex resonances, demonstrating that ligand exchange between coordinated and free PMe3 is slow in the NMR timescale. Together with the absence of the 1 H and 31 P NMR resonances of free PMe3 for a solution of pure 1, this observation rules out the presence of a dissociation equilibrium. Concerning the 2/PMe3 solutions, the 1 H and 31 P NMR spectra showed sharp resonances at the usual diamagnetic position for the free PMe3, unaffected by the presence of the paramagnetic complex. Thus, ligand exchange is slow on the NMR timescale also for the cationic complex. The parallel EPR investigation shows that the presence of free PMe3 does not alter the linewidth of the observed resonance. Therefore, no significant PMe3 dissociation is suggested. Hence, we remain with the option of a dynamic process interconverting two different stereoisomers.

This possibility was addressed in more detail by DFT calculations (see section d below).

(c) Low-temperature NMR study of compound 1.

Compound 1 has already been described, 14,21 but its NMR investigation was limited to room temperature, showing a single 31 P resonance and a binomial quartet 1 H resonance for the hydride signal. This shows that either the three PMe3 ligands occupy symmetry-equivalent positions or that a rapid dynamic exchange process is occurring. The peculiar IR spectrum observed for compound 1 has encouraged us to carry out a new NMR investigation at variable temperatures.

The shape of the hydride resonance in the 1 H NMR spectrum changes upon cooling to ultimately yield a doublet of triplets (Figure 3), demonstrating the presence of a dynamic behaviour and two types of inequivalent PMe3 ligands (in a 2:1 ratio) in the ground state structure. The hydride nucleus has a stronger coupling (J = 77 Hz) with the two equivalent P nuclei and a smaller one (J = 13 Hz) with the unique P nucleus. The two different types of P nuclei are coupled to each other in the low-T 31 P{ 1 H} spectrum with a J of 54 Hz.

Simulations with SpinWorks 22 provided an excellent fit, at each temperature, of both 1 H and 31 P{ 1 H} spectra with the same mutual exchange rate constant (data in the Supporting Information). The Eyring analysis of the temperature dependent rate constants provided the activation parameters for the mutual exchange: H ‡ = 11.7(3) kcal mol -1 ; S ‡ = -3(1) e.u.

The most obvious structure of 1 that fits these data is the four-legged piano stool, identical to that observed by X-ray diffraction for the corresponding cation 2. We were not successful in growing single crystals of compound 1, but assuming that the geometry, particularly the bond angles, is not significantly different than that observed for 2, it is interesting to note that the pseudo-trans P nucleus shows the weaker coupling and the pseudo-cis P nuclei the stronger one, contrary to the typical situation for trans and cis arrangements in square planar and octahedral complexes. Stronger coupling in four-legged piano stool geometries between pseudo-cis ligands relative to pseudo-trans ligands have also been observed in other compounds, notably CpMo(CO)2(PR3)H (R = Me, Ph, Cy) [23][24][25] and CpOs(PiPr3)H3. 26 The most interesting observation is the absence of any other hydride resonance in the low-temperature spectra. According to the low-temperature IR study (vide supra) a significant amount of the minor isomer (20%) remains present at 200 K, under the assumption that the extinction coefficient for the Mo-H vibration is the same in both species. Since no separate NMR resonance is observed for this isomer, we conclude that the dynamic process that exchanges the major and minor species observed in the IR spectrum is faster than the dynamic process that exchanges the inequivalent PMe3 ligands in the ground state structure.

Furthermore, this dynamic process must maintain the chemical inequivalence of the PMe3 ligands.

The PMe3 exchange process must take place through a more symmetric, higher energy intermediate or transition state. In the case of an intermediate, this is not significantly populated in the temperature range used in our study and is therefore unobserved by IR spectroscopy. The most likely candidate is a pseudo-trigonal bipyramidal structure, characterized by trans Cp* and H ligands in the axial positions and equivalent PMe3 ligands in the pseudo-trigonal plane. As will be shown later in the DFT section, a higher energy local minimum is indeed observed for this geometry. Examples of pseudo-trigonal bipyramidal structures for CpML4 complexes are known, 27,28 and the interconversion mechanism between these two geometries has been addressed. 29 In conclusion, the combined IR and NMR investigation of compound Mo-H distances show a smaller dependence on the metal oxidation state, which is generally in the opposite direction (shorter in the higher oxidation state). These trends cannot be verified experimentally in the absence of an X-ray structure of compound 1, but were noted recently in the related pair of structurally characterized [( 5 -1,2,4-C5H2tBu3)Mo(PMe3)2H3] n+ (n = 0, 1) complexes. 12 Calculations were also run for the ion pair, [Cp*Mo(PMe3)3H] + PF6 -, in the gas phase, in order to probe the nature of the cation-anion interaction. The optimized geometric parameters are shown in Table 1. The geometry of the cation is relatively close to that calculated for the isolated cation. The optimization was conducted starting from the relative cation-anion orientation as found in the crystal structure, but the PF6 anion rearranges itself during the optimization procedure to yield two shorter contacts with the hydride ion (Figure 4). These are significantly shorter than in the crystal, suggesting the presence of an attractive force between the hydride ligand and the fluorine atoms of the PF6 -ion. Indeed, the Mulliken charge calculated for the hydride ligand in 2 is slightly positive (+0.017), whereas it is negative in 1 (-0.106) and also, although to a lesser extent, in the isolated cation of 2 (-0.066).

This Mulliken charge changes confirm the effect of oxidation on the metal-hydride bond polarization and underline the importance of the cation-anion interaction for this polarization.

In further support of an attractive force between the hydride ligand and the PF6 -ion, the related optimization of the adduct of PF6 -and diamagnetic 1 features much longer H In search for a third isomer for 1 and 2, the energy of which is closer to that of the PS isomer, we have considered the following possibilities: a second minimum along the Berry pseudo-rotation coordinate (BPR), an agostic cyclopentadiene derivative (AC), a -complex with a C-H bond of a dissociated phosphine ligand (AP), and a Cp rotamer (ROT), as illustrated in Scheme 1. A different minimum in the Berry pseudo-rotation pathway might be allowed by the presence of two competitive preferred distortions of the ideal PS geometry. 30, where the dissociated PMe3 ligand must necessarily be transoid to the hydride in order to maintain the P inequivalence in the low-temperature NMR, may be made energetically favourable by the metal electron richness. Finally, two distinct minima around the Mo-Cp* axis are justified by the symmetry mismatch of the Cp* ring (five fold) and ML4 moiety (pseudo four fold).

Mo PR 3 R 3 P R 3 P Mo H PR 3 R 3 P R 3 P H n+ R' R' R' R' R' n+ R' R' R' R' R' Mo R 3 P R 3 P H n+ R' R' R' R' R'

Scheme 1

The calculations on the BPR, AC and AP hypotheses show that these cannot rationalize the experimental observation, because either no second minimum could be found or this occurred at a prohibitively high energy (details in the Supporting Information). The hypothesis of a Cp* rotamer, on the other hand, is supported by the computational results.

These calculations were carried out only on the full molecule (C model). A scan of the energy as a function of the rotation angle is illustrated in Figure 6. The calculations show two minima around the C-CNT-Mo-H dihedral angle, with the second rotamer being located 0.56 kcal mol -1 higher in energy (3.08 kcal mol -1 in free energy) for 1C-ROT and 0.36 kcal mol -1 higher in energy (but 0.04 kcal mol -1 lower in free energy) for 2C-ROT. The highest energy corresponds, for both 1C and 2C, to the eclipsed geometry (C-CNT-Mo-H dihedral angle around zero). Note that the calculations reproduce, at least at a qualitative level, the lower energy difference for the two conformers in the cationic complex. Views of the optimized minima emphasizing the Cp* dihedral angle (the PMe3 methyl groups have been removed for clarity) and their calculated Mo-H distances, Mo-H vibrational frequencies, and relative energies and free energies, are also shown.

The calculated Mo-H distances and vibrational frequencies are also reported in Figure 6.

Notably, the calculated (Mo-H) of the global minimum of 1C-PS is at higher frequency than that of the higher energy minimum, in agreement with the experiment. The calculated frequencies (1794 and 1745 cm -1 ) are also in excellent agreement with the experimental values (1794 and 1730 cm -1 ). For system 2C-PS, the calculated frequencies of the nearly isoenergetic rotamers (1836 and 1787 cm -1 ) also compare rather well with the experimentally observed ones (ca. 1800 and 1770 cm -1 ), being blue shifted relative to the frequencies of the neutral species.

Once likely candidates for the observed species have been found, validation of their independent observation by the IR spectroscopic technique is necessary. First of all, the calculated rotational barriers shown in Figure 6 are much too low for the individual observation of the rotamers by NMR spectrometry (for the diamagnetic compound 1). More typical barriers for processes that can be frozen on the NMR timescale are in the order of 10 kcal mol -1 , as found above for the P exchange process in 1. The EPR spectroscopic technique operates on a faster timescale than NMR and fluxional processes with lower activation barriers have been investigated, 33,34 including a substituted cyclopentadienyl ring rotation in compound (C5Ph4H)Mo(CO)2(L2) (L2 = 2,3-bis(diphenylphosphino)maleic anhydride) (H ‡ = 2.2 kcal mol -1 ). 35 However, the broadness of the EPR resonance of 2 does not permit to reveal any coalescence phenomenon. Thus, the energy profiles shown in Figure 6 are entirely consistent with the observation of only one species in solution for both 1 and 2 even at low temperatures.

Concerning the IR experiments, in order to observe separate bands for exchanging species with a frequency difference of ca. 60 cm -1 (as observed in 1) or ca. 30 cm -1 (as observed in 2), the exchange rate must be slower than 1.8•10 12 s -1 or 9•10 11 s -1 , respectively, corresponding to activation barriers above 0.7 or 1.1 kcal mol -1 according to the Eyring equation. The calculated free energy barriers for the Cp* ring rotation (Figure 6) are indeed higher than these values (3.3 kcal mol -1 for 1C and 1.51 kcal mol -1 for 2C). The smaller frequency difference and the smaller calculated activation barrier for the two rotamers of 2 suggests that the spectrum of this compound is closer to the coalescence region. However, warming up this sample to 350 K in dichloroethane shows no clear evidence for the beginning of a coalescence phenomenon (Figure S5). It should be recalled that the coalescence of IR bands caused by molecular dynamics, though not as familiar as the same phenomenon in NMR spectroscopy, is well established and appreciated. [36][37][38][39][40][41] The separate observation of different rotamers for these two redox-related compounds is worth a brief discussion because it is unusual. This is apparently the first reported case of the simultaneous IR observation of metal-hydrogen stretching vibrations in different rotamers of a cyclopentadienyl hydride complex. We attribute this observation to the concurrence of a few favourable circumstances. The first one is the highly crowded nature of the molecule, with the PMe3 and Cp* methyl groups imposing relatively large barriers to go past each other through the Cp* ring rotation. The second one is the relatively high frequency difference for the two rotamers, created by a sufficiently different transmission of electronic and steric effects from the Cp* conformation to the Mo-H bond in the two separate minima. In addition to the above factors, we point out that metal-hydrogen stretching vibrations typically have relatively low extinction coefficients, requiring high concentrations (thus high solubility) and long optical paths for measurement of the absorption bands at reasonably high signal/noise ratio. Thus, this phenomenon may have been missed in previously investigated complexes of this type. Other hydride complexes containing the Cp* ring that have been investigated in our laboratories, for instance Cp*M(dppe)H (M = Fe, 42 Ru, 43 Os 44 ) for which high quality (high S/N) spectra were obtained, only show a single band, either because there is only a single minimum around the M-Cp* rotational coordinate, or because the different minima are related by a lower rotational barrier, or because the two structures have much closer vibrational frequencies.

Even though the experimental evidence is against the occurrence of PMe3 dissociation, the bis-phosphine complexes resulting from the dissociation of one phosphine ligand were also optimized. These are open-shell systems and may adopt two different spin states 45 (singlet and triplet for the 16-electron neutral system, doublet and quartet for the 15-electron cationic one). They will be described by codes 16-1, 16-3, 15-2 and 15-4, respectively. The relative energies for each system are also shown in Figure 5. Strictly on the basis of energy, the phosphine dissociation is less favourable than isomerization to the TBP structure for both oxidation state levels. If we keep into account the entropic contribution, the phosphine dissociation process becomes less disfavoured and indeed becomes the preferred process in the gas phase. However, the free energy lowering caused by the entropic contribution in a condensed phase cannot be precisely estimated, because of the partial quenching of the translational and rotational degrees of freedom.

Note that, independent on the model used for the calculation and contrary to the isomerization to TBP, ligand dissociation is more favourable for the neutral system. It should be noted that the phosphine bond dissociation energy is more strongly dependent on the steric bulk than on the oxidation state: it is lowered by 10 kcal mol -1 on going from system A to system C for 1 and by 15 kcal mol -1 for 2, but only by ca. 5 kcal mol -1 on going from 1C to 2C. Therefore, phosphine dissociation becomes possible for bulkier systems. In this respect, we point out our recent isolation and crystallographic characterization of a salt of [(1,2,4-C5H2tBu3)MoH(PMe3)2] + , though this was obtained by another route (H2 reductive elimination from [(1,2,4-C5H2tBu3)MoH3(PMe3)2] + ). [START_REF] Baya | [END_REF]12 Another point of interest is the relatively similar energy for the two possible spin configurations for the dissociation product, both for the neutral and for the cationic systems, independent on the chosen model, the difference being less than 3 kcal mol -1 . Given the empirical and imprecise handling of electron pairing by density functional methods, [46][47][48][49][50] it is not possible to make reliable predictions as to the spin state adopted by these unsaturated species. The above mentioned cationic 15-electron system containing the bulkier (1,2,4-C5H2tBu3) ligand was found to adopt a spin quartet ground state. [START_REF] Baya | [END_REF]12 (e) Protonation of [Cp*Mo(PMe3)3H]

Protonation of compound 1 with HBF4 in THF affords the cationic dihydride complex [Cp*Mo(PMe3)3H2] + , 3 (equation 2). An IR study shows that both MoH bands of 1 disappear, to give rise to only one new high frequency band at 1818 cm -1 (Figure 7). 2). On the other hand, the hydride at  -6.53 is significantly coupled only to the two equivalent P nuclei (JHP = 45 Hz), whereas the coupling to the unique P nucleus is not clearly discernible in the 1 H{sel. 31 P: 7.6} spectrum and is estimated as ca. 10 Hz. These data are in agreement with a pseudo-octahedral geometry for 3 in which one of the hydride ligands is trans to Cp* ring, but do not allow to unambiguously tell which resonance belongs to which hydride ligand. However, a comparison of the observed coupling constants of 3 with those found for 1 (where the assignment is unambiguous) and considering the similarity of the bond angles in the optimized structures of the two compounds (vide infra for compound 3), strongly suggests that the signal at  -3.30 should correspond to the axial hydride ligand and that at -6.53 to the equatorial one. A similar structure was reported for the isoelectronic [CpW(CO)2(PMe3)(H)2] + [OTf] -compound 51 and later proposed for the related [CpMoH2(CO)(dppe)] + [OTf] -compound. 52 It has also been observed for the isoelectronic molybdenum complex [CpMo(PMe3)3(MeCN)H] 2+ in its BF4 -salt, where the pseudoequatorial hydride position is replaced by the neutral MeCN molecule. 13 -6.00 -5.00 -4.00 -3.00 The 1 H hydride resonance and the 31 P resonances broaden with the loss of observable coupling upon temperature increase, showing coalescence at ca. 250 K. Knowledge of the full coupling pattern allowed simulation (Figure 9) and an Eyring analysis of the rate constant for the exchange process (supplemental figure S8). The rate constants for the H and P exchange processes that best fit the experimental data are essentially identical at each temperature, suggesting that the same pathway simultaneously exchanges the two types of nuclei. A least-squares Eyring fit to the data yields H ‡ = 9.3 ± 0.1 kcal/mol and S ‡ = -4.1 ± 0.4 e.u. for the hydride exchange process and H ‡ = 9.2 ± 0.1 kcal/mol and S ‡ = -4.9 ± 0.5 e.u for the P exchange process. the third PMe3 ligands sits on the mirror plane. The third minimum is a dihydrogen complex with a four-legged piano stool geometry (3c), at much higher energy (13 kcal mol -1 ). Four transition states (TS) interconnecting these minima could be located. As shown in Figure 10, the lowest energy TS is that leading from the global minimum to the symmetric classical isomer, TS-3a/b. This rearrangements makes the two H ligands equivalent and at the same time two previously inequivalent P atoms (one trans to the equatorial H atoms and the other one trans to the third P atom) become equivalent. Continuation of this process along the opposite and symmetry related direction exchanges the two H ligands and another pair of P ligands. Thus, this process is in full agreement with the experimental observation of the same activation parameters for the H and P exchange processes. A second exchange mechanism involving the migration of the equatorial hydride to the axial position, thus pushing the axial hydride to the opposite side of the equatorial plane (TS-3a/a), is energetically disfavored compared to the previous one. An additional exchange mechanism, whereby the two H ligands exchange their position via rotation of the H2 ligand in a nonclassical isomer, is also not operative in this case whereas it is rather common for dihydride compounds. 53,54 Not only is the corresponding transition state (TS-3a/c) located higher in energy, this mechanism is also excluded because it would not lead to the simultaneous exchange of the P nuclei. This

( a )

 a Synthesis and characterization of [Cp*Mo(PMe3)3H] + PF6 -, 2.

[ 1 )Figure 1 .

 11 Figure 1. An ORTEP view of compound 2 (ellipsoids are drawn at the 30 % probability level). All hydrogen atoms except the hydride are not shown for clarity.

Figure 2 .

 2 Figure 2. Infrared spectra of: (a) complex Cp*Mo(PMe3)3H (0.08 M, 0.4 mm pathlength) at room temperature (thinner line: in hexane; thicker line: in THF); (b) complex [Cp*Mo(PMe3)3H]PF6 (0.042 M, 1.2 mm pathlength) in CH2Cl2 at 200 K. The band labelled with an asterisk in Figure 2a is due to an oxidation impurity (see text).

Figure 3 .

 3 Figure 3. Variable temperature 1 H (a) and 31 P{ 1 H} (b) NMR properties of compound Cp*Mo(PMe3)3H in toluene-d8. Spectra were taken at 10 K intervals, between 200 and 300 K.

[

  Cp*Mo(PMe3)3H] demonstrates that there must be at least three structures in solution: the ground state structure with inequivalent PMe3 ligands in a 2:1 ratio (presumably a 4-legged piano stool), a symmetric intermediate responsible for the mutual PMe3 exchange process (presumably a trigonal bipyramid) that is not thermally populated, and a second asymmetric, thermally populated structure (at ca. 0.2 kcal/mol in enthalpy from the ground state) that exchanges rapidly with the ground state structure on the NMR time scale, but not on the IR time scale. The nature of these structures has been explored by the DFT calculations.(d) DFT study of the ground state structures of 1 and 2 and exchange barriersGeometry optimizations were run for both neutral and cationic complexes, using systems [(C5R5)Mo(PR'3)3H] n+ (n = 0, 1), with R = R' = H (A), R = H, R' = Me (B), and R = R' = Me (C, real systems). All optimized geometries, as well as tables of optimized distances and angles, Mo-H stretching frequencies, and a discussion of the structural changes as a function of the chosen model (A, B or C), are provided as supporting information.The most stable structure was in all cases the typical 4-legged piano stool (PS), independent of the model and of the oxidation state. This agrees with our assignment of the observed major (Mo-H) band of 1 to the PS isomer. The calculated Mo-H stretching frequencies of 1C-PS and 2C-PS (1794 and 1836 cm -1 respectively) qualitatively reproduce the experimental trend of a blue shift upon oxidation. The optimized distances and angles for 2C-PS compare quite well with those experimentally determined by X-ray diffraction (see Table1), attesting to the suitable level of theory used for the calculations. Comparison of the optimized structures of each redox pair shows interesting trends. The Mo-P distances are longer (by 0.06 -0.15 Å) for the oxidized species, whereas the Mo-CNT (ring centroid) and

Figure 4 .

 4 Figure 4. Gas-phase optimized geometry of [Cp*Mo(PMe3)3H]PF6. Hydrogen atoms on the Cp* and PMe3 ligands have been omitted for clarity.

Figure 5 .

 5 Figure 5. Relative energies and gas-phase free energies (in parentheses), in kcal mol -1 , for the isomerization and phosphine dissociation process for models of Cp*Mo(PMe3)3H (below) and its one-electron oxidation product (above). The energy values are used to represent the states on the vertical scale. For the definition of the labels (A, B, C, 1, 2, TBP, TS, 16-1, 16-3, 15-2 and 15-4, see text).

1 Figure 6 .

 16 Figure 6. Energy of molecules 1C and 2C as a function of the C-CNT-Mo-H dihedral angle.Views of the optimized minima emphasizing the Cp* dihedral angle (the PMe3 methyl groups have been removed for clarity) and their calculated Mo-H distances, Mo-H vibrational frequencies, and relative energies and free energies, are also shown.

[Figure 7 .

 7 Figure 7. Change of the IR spectrum upon protonation in THF at 200 K. (a) Cp*Mo(PMe3)3H. (b) Cp*Mo(PMe3)3H in the presence of 1 equiv HBF4.

Figure 8 .

 8 Figure 8. Low temperature (200 K) 1 H NMR spectra of compound 3 in CD2Cl2 with various P decoupling modes.

Figure 9 . 3 Compound 3

 933 Figure 9. Experimental and simulated NMR spectra for compound 3 at various temperatures. (a) 1 H NMR. (b) 31 P{ 1 H} NMR.

Figure 10 .

 10 Figure 10. Energies (in kcal mol -1 ) and geometries of optimized minima and transition states for system [Cp*Mo(PMe3)3H2] + .

The AC geometry has previously been proposed and optimized for an intermediate of the isomerization process of the isoelectronic [Cp*Fe(dppe)H2] + complex.

The AP geometry,

Acknowledgement

We thank bilateral grants (PICS and GDRE "CH2D", France-Russia; LEA, France-Spain) and National support from the Institut Universitaire de France and CNRS (France), the RFBR (08-03-00464) and the Division of Chemistry and Material Sciences of RAS (Russia) and the Spanish MEC (Project CTQ2005-09000-C02-01 and Consolider Ingenio 2010 CDS2007-00006). MB thanks the Spanish Ministerio de Educación y Ciencia for a postdoctoral fellowship and the Spanish MEC/Universidad de Zaragoza for funding through the "Ramón y Cajal" program.

mol -1 (millisecond timescale) for compound 1. The ligand mobility in compound 2 cannot be probed experimentally, because of the broadness of the EPR resonance.

Experimental section

General. All preparations and manipulations were carried out with rigorous exclusion of oxygen and moisture using Schlenk-tube techniques. Solvents were dried by conventional methods and distilled under argon prior to use. The starting material Cp*Mo(PMe3)3H (1) was prepared by the published method. 21 Room temperature (293K) NMR investigations were carried out on a Bruker DPX300 and a Bruker AV300LiQ spectrometers operating at 300.1 MHz ( 1 H), 121.49 MHz ( 31 P { 1 H}) and 75.47 MHz ( 13 C{ 1 H}). Low-temperature 1 H and 31 P data were collected with a Bruker AV500 spectrometer, operating at 500.3 MHz and 202.5 MHz, respectively. The temperature was calibrated using a methanol chemical shift thermometer; the accuracy and stability was ±1 K. All samples were allowed to equilibrate at every temperature for at least 3 min. The spectra were calibrated with the residual solvent resonance relative to TMS ( 1 H, 13 C), and with external 85% H3PO4 ( 31 P). The conventional inversion-recovery-pulse method (180-τ-90) was used to determine the variable-temperature longitudinal relaxation time T1, the calculations being done with standard Bruker software. Coupling constants, J, are given in hertz. All NMR simulations were performed with SpinWorks software. VT-EPR spectra were measured on a Elexsys E500 BRUKER spectrometer (X-band) equipped with both a frequencemeter and gaussmeter. Cyclic voltammograms were recorded with an EG&G362 potentiostat connected to a Macintosh computer through MacLab hardware/sofware. The electrochemical cell was fitted with an Ag/AgCl reference electrode, a 1 mm-diameter Pt-disk working electrode, and a platinum-wire counter electrode. [Bu4N]PF6 (ca. 0.15 M) was used as the supporting electrolyte. All potentials are reported relative to the ferrocene/ferrocenium couple. Ferrocene was added and measured as an internal standard at the end of each experiment. The solution IR measurements were performed on ''Infralum 801'' and "Specord M-82" FT-IR spectrometers. Solid state spectra were measured with a Perkin-Elmer Spectrum 100 FTIR spectrometer (2 cm -1 resolution) on the neat solid sample which was pressed inside a quarz crystal. Solution spectra were measured using CaF2 cells of 0.04-0.22 cm path length. All variable temperature IR measurements in the 190-350 K temperature range were carried out by use of a home-modified cryostat (Carl Zeiss Jena). The cryostat modification allows operating under an inert atmosphere and transferring the reagents (premixed either at low or room temperature) directly into the cell which is pre-cooled or warmed to the required temperature. The accuracy of the temperature adjustment was ±1 K. (8 mL). Immediate formation of a whitish solid was monitored. The suspension was left to stir for 10 min and then it was decanted. The resulting solid was washed with diethyl ether (3 x 10 mL) and dried in vacuo. A white solid was obtained. Yield: 96 mg (82 %). Anal. Calcd. for C19H44BF4MoP3: C, 41.63; H, 8.09. Found: C, 41.41; H, 7.94. 31 P{ 1 H} NMR (CDCl3):  4.7 (s). 1 H NMR (CDCl3):  -4.52 (q, J = 49.0 Hz, 2 H, Mo-H), 1.55 (pseudo q, J = 2.6 Hz, 27 H, P(CH3)3), 1.96 (s, 15 H, C5(CH3)5). 1

Preparation of [Cp

NMR and EPR tube monitoring experiments. For all NMR and EPR tube

experiments, the sample (ca. 10 mg) was charged as a solid in the glovebox under argon and the tube was sealed with a rubber septum and further wrapped with parafilm. The solvents and/or other solutions were added to the NMR tube by cannula transfer on a Schlenk line. All solvents were degassed by three freeze-pump-thaw cycles prior to use.

Computational details.

Quantum mechanical calculations were performed with the Gaussian03 package 55 at the DFT/B3LYP level. [56][START_REF] Perdew | Electronic Structure of Solids[END_REF][START_REF] Perdew | [END_REF] Core electrons of the Mo and P atoms were described using the effective core pseudopotentials of Hay-Wadt 59,60 and valence electrons were described with the standard LANL2DZ basis set. 55 In the case of the P atoms, a set of d type functions was added. 61 Carbon and hydrogen atoms non-bonded to the metal were described with a 6-31G basis set, carbon atoms linked to the metal were described with a 6-31g* basis set, and the hydride hydrogen atom was described with a 6-31g** basis set. [62][63][64][65][66][67][68][69][70][71] All minima and transition states were characterized by analytically computing the Hessian matrix and no scaling factors were used for frequencies. Information on atom coordinates (xyz files) for all optimized structures is collected in the supplementary material.

X-ray Structure Determination.

A single crystal of [Cp*Mo(PMe3)3H]PF6 was mounted under inert perfluoropolyether at the tip of glass fibre and cooled in the cryostream of an Oxford-Diffraction XCALIBUR CCD diffractometer and data were collected using the monochromatic MoK radiation (= 0.71073). The structure was solved by direct methods (SIR97) 72 and refined by least-squares procedures on F 2 using SHELXL-97. [START_REF] Sheldrick | Program for Crystal Structure refinement[END_REF] All H atoms attached to carbon were introduced in calculation in idealised positions and treated as riding models. The hydride H atom was located in difference Fourier syntheses and was freely refined with isotropic thermal parameter. The drawing of the molecule was realised with the help of ORTEP32. [START_REF] Farrugia | [END_REF] Crystal data and refinement parameters are shown in Table 2.

Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 603848. Copies of the data can be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).