Preparation of Protected β2‐ and β3‐Homocysteine, β2‐ and β3‐Homohistidine,and β2‐Homoserine for Solid‐Phase Syntheses

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³‐homoamino acid derivatives were obtained by Arndt–Eistert methodology from Boc‐His(Ts)‐OH and Fmoc‐Cys(PMB)‐OH (Schemes 2–4), with the side‐chain functional groups' reactivities requiring special precautions. The β²‐homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti‐enolates to formaldehyde (generated in situ from trioxane) and subsequent functional‐group manipulations. These include OH→O^tBu etherification (for β²hSer; Schemes 5 and 6), OH→STrt replacement (for β²hCys; Scheme 7), and CH₂OH→CH₂N₃→CH₂NH₂ transformations (for β²hHis; Schemes 9–11). Including protection/deprotection/re‐protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.     

Preparation of β2‐Homotryptophan Derivatives for β‐Peptide Synthesis

In view of the prominent role of the 1H‐indol‐3‐yl side chain of tryptophan in peptides and proteins, it is important to have the appropriately protected homologs H‐β² HTrp OH and H‐β³ HTrp OH (Fig.) available for incorporation in β‐peptides. The β²‐HTrp building block is especially important, because β²‐amino acid residues cause β‐peptide chains to fold to the unusual 12/10 helix or to a hairpin turn. The preparation of Fmoc and Z β²‐HTrp(Boc) OH by Curtius degradation (Scheme 1) of a succinic acid derivative is described (Schemes 2–4). To this end, the (S)‐4‐isopropyl‐3‐[(N‐Boc‐indol‐3‐yl)propionyl]‐1,3‐oxazolidin‐2‐one enolate is alkylated with Br CH₂CO₂Bn (Scheme 3). Subsequent hydrogenolysis, Curtius degradation, and removal of the Evans auxiliary group gives the desired derivatives of (R)‐H β²‐HTrp OH (Scheme 4). Since the (R)‐form of the auxiliary is also available, access to (S)‐β²‐HTrp‐containing β‐peptides is provided as well.     

2‐Cyano‐2‐isocyanoalkanoates in Multicomponent Reactions

The reactivity of 2‐cyano‐2‐isocyanoalkanoates 2 in multi‐component reactions was investigated, i.e., in the Passerini reaction and the Ugi‐four‐component condensation (see Schemes 2 and 3, resp.). Interestingly, the structure of the 2‐cyano‐2‐isocyanoalkanoates 2 strictly limited the possible starting materials. Only the combination of aliphatic aldehydes, halogenated acetic acid derivatives, and nonaromatic amines gave satisfactory results, i.e., provided depsidipeptides 5 (Tables 3 and 4) and depsitripeptides 9 (Tables 6), respectively. Some of the products of the multicomponent reactions were transformed into crystalline compounds by decarboxylation (see Scheme 4). After fractional crystallization, the molecular structure of one of the decarboxylated depsitripeptides, i.e., of 10 , was established by X‐ray crystallography.     

Specific heat on Sr<Subscript>2</Subscript>Nb<Subscript>2</Subscript>O<Subscript>7</Subscript> and Sr<Subscript>2</Subscript>Ta<Subscript>2</Subscript>O<Subscript>7</Subscript>

Summary Specific heats on the single crystals of Sr₂Nb₂O₇, Sr₂Ta₂O₇ and (Sr_1-xBa_x)₂Nb₂O₇ were measured in a wide temperature range of 2-600 K. Heat anomalies of a λ-type were observed at the incommensurate phase transition of T_INC (=495 K) on Sr₂Nb₂O₇ and at the super-lattice phase transition of T_SL (=443 K) on Sr₂Ta₂O₇; the transition enthalpies and the transition entropies were estimated. Furthermore, a small heat anomaly was observed at the low temperature ferroelectric phase transition of T_LOW (=95 K) on Sr₂Nb₂O₇. The transition temperature T_LOW decreases with increasing Ba content x and it vanishes for samples of x>2%.     

MAO‐free polymerization of propylene by rac‐ Me2Si(1‐C5H2‐2‐Me‐4‐tBu)2Zr(NMe2)2 compound

Ansa‐zirconocene diamide complex rac‐Me₂Si(CMB)₂Zr(NMe₂)₂ (rac‐1, CMB = 1‐C₅H₂‐2‐Me‐4‐^tBu) reacts with AlR₃ (R = Me, Et, i‐Bu) and then with [CPh₃]⁺[B(C₆F₅)₄]⁻ (2) in toluene in order to in situ generate cationic alkylzirconium species. In the sequential NMR‐scale reactions of rac‐1 with various amount of AlMe₃ and 2, rac‐1 transforms first to rac‐Me₂Si(CMB)₂Zr(Me)(NMe₂) (rac‐3) and rac‐Me₂Si(CMB)₂ZrMe₂ (rac‐4) by the reaction with AlMe₃, and then to [rac‐Me₂Si(CMB)₂ZrMe]⁺ (5⁺) cation by the reaction of the resulting mixtures with 2. The activities of propylene polymerizations by rac‐1/Al(i‐Bu)₃/2 system are dependent on the type and concentration of AlR₃, resulting in the order of activity: rac‐1/Al(i‐Bu)₃/2 > rac‐1/AlEt₃/2 > rac‐1/MAO ≫ rac‐1/AlMe₃/2 system. The bulkier isobutyl substituents make inactive catalytic species sterically unfavorable and give rise to more separated ion pairs so that the monomers can easily access to the active sites. The dependence of the maximum rate (R_{p, max}) on polymerization temperature (T_p) obtained by rac‐1/Al(i‐Bu)₃/2 system follows Arrhenius relation, and the overall activation energy corresponds to 0.34 kcal/mol. The molecular weight (MW) of the resulting isotactic polypropylene (iPP) is not sensitive to Al(i‐Bu)₃ concentration. The analysis of regiochemical errors of iPP shows that the chain transfer to Al(i‐Bu)₃ is a minor chain termination. The 1,3‐addition of propylene monomer is the main source of regiochemical sequence and the [mr] sequence is negligible, as a result the meso pentad ([mmmm]) values of iPPs are very high ([mmmm] > 94%). These results can explain the fact that rac‐1/Al(i‐Bu)₃/2 system keeps high activity over a wide range of [Al(i‐Bu)₃]/[Zr] ratio between 32 and 3,260. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1071–1082, 1999     

Methyl 2‐acetamido‐2‐deoxy‐β‐d‐glucopyranoside dihydrate and methyl 2‐formamido‐2‐deoxy‐β‐d‐glucopyranoside

Methyl 2‐acetamido‐2‐deoxy‐β‐d ‐glucopyranoside (β‐GlcNAcOCH₃), (I), crystallizes from water as a dihydrate, C₉H₁₇NO₆·H₂O, containing two independent molecules [denoted (IA) and (IB)] in the asymmetric unit, whereas the crystal structure of methyl 2‐formamido‐2‐deoxy‐β‐d ‐glucopyranoside (β‐GlcNFmOCH₃), (II), C₈H₁₅NO₆, also obtained from water, is devoid of solvent water molecules. The two molecules of (I) assume distorted ⁴C₁ chair conformations. Values of ϕ for (IA) and (IB) indicate ring distortions towards B_C2,C5 and ^C3,O5B, respectively. By comparison, (II) shows considerably more ring distortion than molecules (IA) and (IB), despite the less bulky N‐acyl side chain. Distortion towards B_C2,C5 was observed for (II), similar to the findings for (IA). The amide bond conformation in each of (IA), (IB) and (II) is trans, and the conformation about the C—N bond is anti (C—H is approximately anti to N—H), although the conformation about the latter bond within this group varies by ∼16°. The conformation of the exocyclic hydroxymethyl group was found to be gt in each of (IA), (IB) and (II). Comparison of the X‐ray structures of (I) and (II) with those of other GlcNAc mono‐ and disaccharides shows that GlcNAc aldohexopyranosyl rings can be distorted over a wide range of geometries in the solid state.     

2′‐De­oxy‐2‐fluoro­tubercidin

In the title compound [systematic name: 7‐(2‐de­oxy‐β‐d ‐erythro‐pentofuranos­yl)‐2‐fluoro‐7H‐pyrrolo[2,3‐d]pyrimidin‐2‐amine], C₁₁H₁₃FN₄O₃, the conformation of the N‐glycosylic bond is between anti and high‐anti [χ = −110.2 (3)°]. The 2′‐deoxy­ribofuranosyl unit adopts the N‐type sugar pucker (₄T³), with P = 40.3° and τ_m = 39.2°. The orientation of the exocyclic C4′—C5′ bond is −ap (trans), with a torsion angle γ = −168.39 (18)°. The nucleobases are arranged head‐to‐head. The crystal structure is stabilized by four inter­molecular hydrogen bonds of types N—H⋯N, N—H⋯O and O—H⋯O.     

Substitutional disorder in Sr2−yEuyB2−2xSi2+3xAl2−xN8+x (x≃ 0.12, y≃ 0.10)

A novel nitride, Sr_2−yEu_yB_2−2xSi_2+3xAl_2−xN_8+x (x≃ 0.12, y≃ 0.10) (distrontium europium diboron disilicon dialuminium octanitride), with the space group P2c, was synthesized from Sr₃N₂, EuN, Si₃N₄, AlN and BN under nitrogen gas pressure. The structure consists of a host framework with Sr/Eu atoms accommodated in the cavities. The host framework is constructed by the linkage of MN₄ tetrahedra (M = Si, Al) and BN₃ triangles, and contains substitutional disorder described by the alternative occupation of B₂ or Si₂N on the (0, 0, z) axis. The B₂:Si₂N ratio contained in an entire crystal is about 9:1.     

2‐Diazo‐2H‐indoles

2‐Diazo‐2H‐indoles were prepared by diazotization of the corresponding 1H‐indol‐2‐amines and subsequent neutralization. On the basis of NMR data and ab initio and semiempirical calculations, we suggest that the zwitterionic form A is the most representative structure for 2‐diazo‐2H‐indoles. In fact, spectral data are compatible with a 1H‐indole structure, and the fully optimized molecules gave distances in agreement with those reported for the anion obtained from 1H‐indole. The calculated charges are compatible with a zwitterionic structure in which the negative charge is mainly located at the ring N‐atom at variance with the case of diazopyrroles and 3‐diazo‐3H‐indoles where the negative charge is essentially located on the ipso C‐atom.     

On the Reactivity of the Platina‐β‐diketone [Pt2{(COMe)2H}2(μ‐Cl)2] Towards Ph2PCH2CH2CH2SOxPh (x = 0, 2)

The reaction of the electronically unsaturated platina‐β‐diketone [Pt₂{(COMe)₂H}₂(μ‐Cl)₂] ( 1 ) with Ph₂PCH₂CH₂CH₂SPh ( 2 ) leads selectively to the formation of the acetyl(chlorido) platinum(II) complex (SP‐4‐3)‐[Pt(COMe)Cl(Ph₂PCH₂CH₂CH₂SPh‐κP,κS)] ( 4 ) having the γ‐phosphinofunctionalized propyl phenyl sulfide coordinated in a bidentate fashion (κP,κS). In boiling benzene complex 4 undergoes decarbonylation yielding the methyl(chlorido) platinum(II) complex (SP‐4‐3)‐[PtMeCl(Ph₂PCH₂CH₂CH₂SPh‐κP,κS)] ( 6 ). However, the reaction of 1 with the analogous γ‐diphenylphosphinofunctionalized propyl phenyl sulfone Ph₂PCH₂CH₂CH₂SO₂Ph ( 3 ) affords the acetyl(chlorido) platinum(II) complex (SP‐4‐4)‐[Pt(COMe)Cl(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)₂] ( 5 ). In boiling benzene complex 5 undergoes a CO extrusion yielding (SP‐4‐4)‐[PtMeCl(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)₂] ( 8 ) whereas in presence of 1 the formation of the carbonyl complex (SP‐4‐3)‐[PtMeCl(CO)(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)] ( 7 ) is observed. Addition of Ag[BF₄] to complex 5 leads to the formation of the cationic methyl(carbonyl) platinum(II) complex (SP‐4‐1)‐[PtMe(CO)(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)₂][BF₄] ( 9 ). All complexes were characterized by microanalysis and NMR spectroscopy (¹H, ¹³C, ³¹P) and complexes 4 and 6 additionally by single‐crystal X‐ray diffraction analyses.     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

Kristallstruktur,Schwingungsspektren und Normalkoordinatenanalyse von (n‐Bu4N)2[{Ru(NO)ClI2}2(μ‐I2)] · 2 I2

Crystal Structure, Vibrational Spectra, and Normal Coordinate Analysis of ( n ‐Bu₄N)₂[{Ru(NO)ClI₂}₂(μ‐I₂)] · 2 I₂ By treatment of (n‐Bu₄N)₂[Ru(NO)I₅] with (n‐Bu₄N)Cl in dichloromethane (n‐Bu₄N)₂[{Ru(NO)ClI₂}₂(μ‐I₂)] is formed. The X‐Ray structure determination on a single crystal of (n‐Bu₄N)₂[{Ru(NO)ClI₂}₂(μ‐I₂)] · 2 I₂ (monoclinic, space group I 2/a, a = 20.446(6), b = 11.482(8), c = 27.225(3) Å, β = 107.51(4)°, Z = 4) reveals a dinuclear iodine bridged structure, in which the chlorine atoms are trans positioned to the nitrosyl groups. The low temperature IR and Raman spectra have been recorded of (n‐Bu₄N)₂[{Ru(NO)ClI₂}₂(μ‐I₂)] · 2 I₂ and are assigned by normal coordinate analysis. A good agreement between observed and calculated frequencies is achieved. The valence force constants are f_d(NO) = 14.08, f_d(RuN) = 5.58, f_d(RuCl) = 1.52, f_d(RuI_t) = 0.90 and f_d(RuI_b) = 0.76 mdyn/Å.     

Mixed β2/β3‐Hexapeptides and β2/β3‐Nonapeptides Folding to (P)‐Helices with Alternating Twelve‐ and Ten‐Membered Hydrogen‐Bonded Rings

The structural properties of four mixed β‐peptides with alternating β²/β³‐ or β³/β²‐sequences have been analyzed by two‐dimensional homonuclear ¹H‐NMR‐ and CD spectroscopic measurements. All four β‐peptides fold into (P)‐helices with twelve‐ and ten‐membered H‐bonded rings (Figs. 3–6). CD Spectra (Fig. 2) of the mixed β³/β²‐hexapeptide 4a and β³/β²‐nonapeptide 5a , indicating that peptides of this type also adopt the 12/10‐helical conformation, were confirmed by NMR structural analysis. For the deprotected β³/β²‐nonapeptide 5d , NOEs not consistent with the 10/12 helix have been observed, showing that the stability of the helix decreases upon N‐terminal deprotection. From the NMR structures obtained, an idealized helical‐wheel representation was generated (Fig. 7), which will be used for the design of further 12/10 or 10/12 helices.     

Synthesis of (2′S)‐2′‐Deoxy‐2′‐C‐methylpurine Nucleosides and Their Phosphoramidites

We describe the stereoselective synthesis of (2′S)‐2′‐deoxy‐2′‐C‐methyladenosine ( 12 ) and (2′S)‐2′‐deoxy‐2′‐C‐methylinosine ( 14 ) as well as their corresponding cyanoethyl phosphoramidites 16 and 19 from 6‐O‐(2,6‐dichlorophenyl)inosine as starting material. The methyl group at the 2′‐position was introduced via a Wittig reaction (→ 3 , Scheme 1) followed by a stereoselective oxidation with OsO₄ (→ 4 , Scheme 2). The primary‐alcohol moiety of 4 was tosylated (→ 5 ) and regioselectively reduced with NaBH₄ (→ 6 ). Subsequent reduction of the 2′‐alcohol moiety with Bu₃SnH yielded stereoselectively the corresponding (2′S)‐2′‐deoxy‐2′‐C‐methylnucleoside (→ 8a ).     

Bis­[bis(N,N‐diethyl‐1,1‐di­seleno­car­bam­ato)copper(II)], [Cu(Se2CNEt2)2]2

The title centrosymmetric Cu^II binuclear complex, bis(μ‐N,N‐diethyl‐1,1‐di­seleno­carbamato‐Se,Se′:Se)­bis­[(N,N‐diethyl‐1,1‐di­seleno­carbamato‐Se,Se′)copper(II)], [Cu(Se₂CNEt₂)₂]₂ or [Cu₂(C₅H₁₀NSe₂)₄], is built from two symmetry‐related [Cu{Se₂CN(Et)₂}₂] units by pairs of Cu—Se bonds. The coordination geometry at the unique Cu atom is distorted square pyramidal, with Cu—Se distances in the range 2.4091 (11)—2.9095 (10) Å.     

Preparation of (S,S)‐Fmoc‐β2hIle‐OH, (S)‐Fmoc‐β2hMet‐OH,and (S)‐Fmoc‐β2hTyr(tBu)‐OH for Solid‐Phase Syntheses of β2‐ and β2/β3‐Peptides

The preparation of three new N‐Fmoc‐protected (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) β²‐homoamino acids with proteinogenic side chains (from Ile, Tyr, and Met) is described, the key step being a diastereoselective amidomethylation of the corresponding Ti‐enolates of 3‐acyl‐4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐ones with CbzNHCH₂OMe/TiCl₄ (Cbz=(benzyloxy)carbonyl) in yields of 60–70% and with diastereoselectivities of >90%. Removal of the chiral auxiliary with LiOH or NaOH gives the N‐Cbz‐protected β‐amino acids, which were subjected to an N‐Cbz/N‐Fmoc (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) protective‐group exchange. The method is suitable for large‐scale preparation of Fmoc‐β²hXaa‐OH for solid‐phase syntheses of β‐peptides. The Fmoc‐amino acids and all compounds leading to them have been fully characterized by melting points, optical rotations, IR, ¹H‐ and ¹³C‐NMR, and mass spectra, as well as by elemental analyses.     

β‐Tl2SO4

The ambient‐temperature form of dithallium sulfate, β‐Tl₂SO₄, is similar to β‐K₂SO₄ and is characterized by isolated sulfate tetrahedra and two different thallium sites with coordination numbers 9 and 11. All the atoms, except one O atom, lie on mirror planes. In spite of there being a high concentration of Tl⁺ cations, the stereochemical activity of the 6s² pairs is low, similar to that of isotypic Tl₂XO₄ compounds (X = Cr and Se). This behaviour is the consequence of both weak Tl—O bonds and strong X—O bonds, because in a Tl—O—X linkage the electronic cloud of the O²⁻ anion is strongly distorted and displaced towards X, resulting in a low negative charge in the face of the Tl atom. Consequently, the Coulombic repulsions between the lone pair and the O²⁻ anions are weak. All of the Tl₂XO₄ compounds exhibit the same open packing of A⁺ cations and [XO₄]²⁻ anions as their isotypic alkali counterparts.     

Double‐Oxygen‐Atom Transfer in Reactions of CemO2m+ (m=2–6) with C2H2

Cerium oxide cluster cations (Ce_mO_n⁺, m=2–16; n=2m, 2m±1 and 2m±2) are prepared by laser ablation and reacted with acetylene (C₂H₂) in a fast‐flow reactor. A time‐of‐flight mass spectrometer is used to detect the cluster distribution before and after the reactions. Reactions of stoichiometric Ce_mO_2m⁺ (m=2–6) with C₂H₂ produce Ce_mO_2m?2⁺ clusters, which indicates a “double‐oxygen‐atom transfer” reaction Ce_mO_2m⁺+C₂H₂→Ce_mO_2m?2⁺+(CHO)₂ (ethanedial). A single‐oxygen‐atom transfer reaction channel is also identified as Ce_mO_2m⁺+C₂H₂→Ce_mO_2m?1⁺+C₂H₂O (at least for m=2 and 3). Density functional theory calculations are performed to study reaction mechanisms of Ce₂O₄⁺+C₂H₂, and the calculated results confirm that both the single‐ and double‐oxygen‐atom transfer channels are thermodynamically and kinetically favourable.     

Kristallstrukturen aus CaBe2Ge2‐ und CeMg2Si2‐analogen Blöcken: Die Phosphide LnPt2P2−x (Ln: La,Sm)

Crystal Structures of CaBe₂Ge₂ and CeMg₂Si₂ analogous Units: The Phosphides LnPt₂P_2?x (Ln: La, Sm) Single crystals of LaPt₂P_1.44 (a = 4.174(1), c = 19.212(5) Å) were grown by reaction of vaporous phosphorus with LaPt₂ at 1050 °C during two weeks, whereas SmPt₂P_1.50 (a = 4.131(1), c = 19.086(4) Å) was synthesized by heating mixtures of the elements at 900 and 1100 °C (60 h) and annealing at 1050 °C (300 h). Both phosphides were investigated by single crystal X‐ray methods. Their crystal structures (I4/mmm; Z = 4) consist of CaBe₂Ge₂ and CeMg₂Si₂ analogous units alternating with each other along [001]. The positions of the P1 atoms are occupied incompletely causing the deviation to the 1:2:2 stoichiometry. Another compounds LnPt₂P_2?x were studied by X‐ray powder diffraction resulting in the following lattice constants: a = 4.150(1), c = 19.132(5) Å for CePt₂P_2–x, a = 4.137(1), c = 19.085(4) Å for PrPt₂P_2?x, and a = 4.127(1), c = 19.040(2) Å for NdPt₂P_2?x.     

Study on the non-isothermal kinetics of decomposition of 4Na<Subscript>2</Subscript>SO<Subscript>4</Subscript>·2H<Subscript>2</Subscript>O<Subscript>2</Subscript>·NaCl

The non-isothermal decomposition kinetics of 4Na₂SO₄·2H₂O₂·NaCl have been investigated by simultaneous TG-DSC in nitrogen atmosphere and in air. The decomposition processes undergo a single step reaction. The multivariate nonlinear regression technique is used to distinguish kinetic model of 4Na₂SO₄·2H₂O₂·NaCl. Results indicate that the reaction type Cn can well describe the decomposition process, the decomposition mechanism is n-dimensional autocatalysis. The kinetic parameters, n, A and E are obtained via multivariate nonlinear regression. The n ^th-order with autocatalysis model is used to simulate the thermal decomposition of 4Na₂SO₄·2H₂O₂·NaCl under isothermal conditions at various temperatures. The flow rate of gas has little effect on the decomposition of 4Na₂SO₄·2H₂O₂·NaCl.