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Química Inorgânica · Coordination chemistry

Substituição de ligantes

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O que você vai aprender

  • Distinguish dissociative, associative and interchange substitution from intermediates, rate laws and activation parameters.
  • Use the trans effect to plan the syntheses of cisplatin and transplatin and to predict substitution products of square-planar Pt(II).
  • Predict whether an octahedral complex is labile or inert from its d-electron configuration, and separate inertness from thermodynamic stability.
  • Explain the chelate and macrocyclic effects in terms of entropy and effective concentration, and apply them to drugs and sequestering agents.

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Three ways to swap a ligand

In a dissociative (D) mechanism the leaving ligand departs first, giving an intermediate with one fewer ligand; the rate does not depend on the entering ligand. In an associative (A) mechanism the entering ligand binds first, giving an intermediate with one more ligand; the rate is proportional to its concentration. Interchange (I) mechanisms are concerted, with no detectable intermediate: I_d when bond breaking dominates the transition state, Iₐ when bond making does. Activation parameters help: ΔS‡ and ΔV‡ are negative for associative activation and positive for dissociative activation. The electron count usually decides: 16-electron square-planar d⁸ complexes (Pt(II), Pd(II), Ni(II), Au(III)) react associatively, while 18-electron octahedral complexes react dissociatively. In the arrow-pushing drawings each metal is shown bare with its donor atoms bonded to it; the minus charges on the metal and the plus charges on neutral donors (H₃N⁺–, H₂O⁺–) are Lewis formal charges of the dative bonds, and the text always gives the real oxidation state.

Square-planar d⁸: associative substitution

The incoming ligand approaches perpendicular to the square plane and uses the empty metal p orbital, giving a five-coordinate, 18-electron trigonal bipyramid. The leaving group departs from the trigonal plane, so the entering ligand takes its place and the geometry is retained. With excess entering ligand Y the rate law has two terms: rate = (k₁ + k₂[Y])[complex]. The k₂ term is direct attack by Y; the k₁ term is rate-determining attack by solvent, followed by fast replacement of the solvent by Y. A plot of k_obs against [Y] is a straight line with slope k₂ and intercept k₁. Bulky groups cis to the reaction site, such as the ortho-methyls of a mesityl ligand, block the axial approach and slow the reaction sharply, which is further evidence for associative activation. Pd(II) reacts about 10⁵ times faster than Pt(II).

The trans effect: cisplatin and transplatin

A ligand speeds up substitution of the ligand trans to it. Approximate series: CO, CN⁻, C₂H₄ > PR₃, H⁻ > CH₃⁻ > SC(NH₂)₂ > I⁻ > Br⁻ > Cl⁻ > NH₃, py, H₂O. Strong σ donors weaken the trans bond in the ground state (the trans influence, seen in bond lengths); π acceptors such as C₂H₄ and CO also stabilise the five-coordinate transition state, so their kinetic trans effect is large even when their trans influence is modest. Because Cl⁻ > NH₃, treating [PtCl₄]²⁻ with two NH₃ gives cisplatin: after the first NH₃ enters, the two mutually trans chlorides are the labile ones. Treating [Pt(NH₃)₄]²⁺ with two Cl⁻ gives transplatin: the first chloride labilises the ammonia trans to it. The Dhara route goes through [PtI₄]²⁻, because iodide's stronger trans effect gives purer cis product. In the Kurnakow test, thiourea converts the cis isomer to [Pt(tu)₄]²⁺ but the trans isomer only to trans-[Pt(NH₃)₂(tu)₂]²⁺.

Cisplatin in the cell

Blood plasma contains about 100 mM chloride, which suppresses aquation, so cisplatin travels as the neutral dichloride; cisplatin is infused in saline for the same reason. Inside the cell chloride is only about 4–20 mM, so a chloride is replaced by water. The aqua complex binds the N7 atom of guanine (9-methylguanine shown), which is nucleophilic, exposed in the major groove and not used in Watson–Crick pairing. A second aquation then lets platinum bind a neighbouring guanine, forming the 1,2-intrastrand crosslink that kinks DNA. Transplatin cannot form this crosslink because its two labile sites are opposite each other. Soft Pt(II) also binds sulfur donors such as glutathione strongly and almost irreversibly, a route to drug resistance. Carboplatin carries a chelating cyclobutane-1,1-dicarboxylate leaving group and is activated much more slowly.

Labile and inert octahedral complexes

A complex is called inert if its substitution half-life exceeds about one minute at 25 °C, and labile if it is faster. Water exchange spans more than 15 powers of ten: [Cu(H₂O)₆]²⁺ about 10⁹ s⁻¹ (Jahn–Teller distortion leaves weak axial bonds), [Mn(H₂O)₆]²⁺ about 10⁷ s⁻¹, [Ni(H₂O)₆]²⁺ about 3 × 10⁴ s⁻¹, [Cr(H₂O)₆]³⁺ about 2.4 × 10⁻⁶ s⁻¹. The inert configurations are d³ (Cr(III)) and low-spin d⁶ (Co(III), Rh(III), Ir(III), Pt(IV)), which have large crystal-field stabilisation energies (−1.2 Δo and −2.4 Δo) that are partly lost in a five- or seven-coordinate transition state. Co(III) substitution is dissociatively activated: the rate depends strongly on the leaving group and little on the entering group. In base, Co(III) ammine complexes react much faster by the conjugate-base mechanism: hydroxide removes an N–H proton and the amido complex loses chloride quickly, so complexes without N–H lack this path. Inert (a statement about rate) is not the same as stable (a statement about equilibrium): [Co(NH₃)₆]³⁺ survives for days in acid although its decomposition is strongly favoured, and oxygen-18 labelling shows that acid decomposition of a carbonato complex breaks the O–C bond, not the Co–O bond.

The chelate effect

A ligand with several donor atoms binds far more strongly than the same number of separate donors. For Ni²⁺, log β₆ for [Ni(NH₃)₆]²⁺ is about 8.6, but log β₃ for [Ni(en)₃]²⁺ is about 18.3, although both have six Ni–N bonds. Replacing six NH₃ by three en releases more particles than it consumes, so ΔS° is positive. Kinetically, once one end of a chelate is bound, the other donor is held next to the metal at a high effective concentration, so ring closure is fast and ring opening is usually reversed. Five-membered chelate rings, as formed by ethane-1,2-diamine, are the most stable for first-row transition-metal ions such as Ni²⁺ and Cu²⁺. Hexadentate EDTA⁴⁻ (shown) displaces about six waters at once and binds even hard Ca²⁺ strongly. A preorganised macrocycle such as cyclam binds more strongly still: the macrocyclic effect.

What to carry forward

Count electrons first: 16-electron square-planar d⁸ complexes substitute associatively, and 18-electron octahedral complexes dissociatively. In square-planar chemistry the trans effect decides which ligand leaves, which is how cisplatin and transplatin are made selectively. In octahedral chemistry the d count decides the speed: d³ and low-spin d⁶ are inert, while Jahn–Teller d⁹ and high-spin d⁵ are labile. Do not confuse inertness (rate) with stability (K). Chelating and macrocyclic ligands win on entropy and on effective concentration.

Problemas de prática (40)

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Desenhe o mecanismo 10

Cisplatin in the cell

  • Aquation activates cisplatinDraw the associative replacement of one chloride of cisplatin by water, the step that activates the drug inside cells.
  • Activated cisplatin binds guanine N7Draw the substitution of the aqua ligand of activated cisplatin by guanine N7 and explain why N7 is the binding site.

Trans effect and platinum synthesis

  • The trans effect directs the second ammonia: cisplatinDraw the substitution of [PtCl₃(NH₃)]⁻ by ammonia and use the trans effect to decide which chloride leaves, giving cisplatin.
  • Ammonia replaces chloride on tetrachloroplatinate(II)Draw associative substitution of one chloride of [PtCl₄]²⁻ by ammonia through a five-coordinate intermediate.
  • Transplatin from tetraammineplatinum(II)Draw the two associative substitutions that convert [Pt(NH₃)₄]²⁺ into transplatin and explain with the trans effect why the second chloride enters trans to the first.

Octahedral lability and inertness

  • Base hydrolysis of [Co(NH₃)₅Cl]²⁺: the conjugate-base mechanismDraw the conjugate-base (SN1CB) mechanism for base hydrolysis of [Co(NH₃)₅Cl]²⁺ and explain why the rate is first order in hydroxide.
  • Acid decomposition of a carbonato cobalt(III) complexDraw the acid-promoted loss of CO₂ from [Co(NH₃)₅(OCO₂)]⁺ and explain why the Co–O bond is retained, so the reaction is not a substitution at cobalt.
  • Aquation of pentaamminechlorocobalt(III)Draw the dissociatively activated replacement of chloride by water in [Co(NH₃)₅Cl]²⁺.

The chelate effect

  • Ethylenediamine chelates hexaaquanickel(II)Draw the stepwise binding of ethylenediamine to [Ni(H₂O)₆]²⁺, including the ring-closing step that forms the five-membered chelate ring.

Mechanisms and rate laws

  • The solvent pathway in square-planar substitutionDraw the solvent-assisted (k₁) pathway by which pyridine replaces chloride in [Pd(dien)Cl]⁺: associative aquation, then fast replacement of water.

Preveja o produto 4

Trans effect and platinum synthesis

  • The thiourea test for cis and trans isomersPredict the products of the Kurnakow test from the trans effect of thiourea.
  • Which ligand labilises the trans chloride most?Pick the ligand that most accelerates substitution of a trans chloride in [PtCl₃L]⁻.

Cisplatin in the cell

  • Which leaving group activates most slowly?Predict which leaving group gives the slowest-activating cis-diammineplatinum(II) drug, using the chelate effect.

Octahedral lability and inertness

  • Which complex resists base hydrolysis?Predict which cobalt(III) complex lacks the hydroxide-accelerated conjugate-base pathway.

Classificar 2

Mechanisms and rate laws

  • Name the mechanism from its intermediateClassify a substitution as D, A or I from the coordination number of its intermediate.

Octahedral lability and inertness

  • Spot the inert complexClassify octahedral complexes as labile or inert from their d-electron configuration.

Comparar 5

The chelate effect

  • Which diamine chelates best?Compare ligands by the chelate ring they form and choose the one giving the most stable Ni²⁺ complex.
  • Chelate and macrocyclic effectsRank Cu²⁺ complexes with four amine nitrogen donors by stability to show the chelate and macrocyclic effects.

Mechanisms and rate laws

  • Ortho-methyl groups and associative attackCompare substitution rates of square-planar complexes whose cis aryl ligand carries increasing ortho substitution.

Trans effect and platinum synthesis

  • Rank ligands by trans effectOrder common ligands by their kinetic trans effect in square-planar Pt(II) substitution.

Octahedral lability and inertness

  • Rank aqua ions by water-exchange rateOrder hexaaqua ions by water-exchange rate using d-electron configuration, charge and the Jahn–Teller effect.

Calcular 5

Octahedral lability and inertness

  • Crystal-field stabilisation of Co(III)Calculate the octahedral crystal-field stabilisation energy of a low-spin d⁶ ion in units of Δo.
  • Half-life for water exchange on Cr(III)Calculate the half-life of a first-order ligand-exchange reaction from its rate constant.

The chelate effect

  • Free energy of the chelate effectCalculate ΔG° for replacing six ammonia ligands by three ethylenediamine ligands from overall stability constants.
  • Counting particles in EDTA bindingCount the change in the number of free solution particles when a hexadentate ligand replaces six waters.

Mechanisms and rate laws

  • Second-order rate constant from two runsExtract the direct-attack rate constant k₂ from pseudo-first-order rate constants measured at two nucleophile concentrations.

Encontre o erro 1

  • Find the flaw in a seven-coordinate pathwayDiagnose why an associative pathway is wrong for water exchange on an 18-electron low-spin d⁶ complex.

Interprete as evidências 2

Mechanisms and rate laws

  • Read the activation parametersUse the signs of the activation entropy and activation volume to assign associative or dissociative activation.
  • What the intercept meansInterpret the slope and intercept of a k_obs versus [Y] plot for square-planar substitution.

Planeje uma síntese 2

Trans effect and platinum synthesis

  • Choose the route to cisplatinChoose the order of ligand addition that gives cisplatin rather than transplatin.

Cisplatin in the cell

  • Choosing the infusion solutionChoose an infusion medium for cisplatin that keeps the drug in its unactivated dichloride form.

Explique por quê 9

Cisplatin in the cell

  • Where does cisplatin become active?Explain how the chloride concentration difference between blood and cytoplasm controls cisplatin activation.
  • Why cis and not trans?Explain the anticancer activity of cisplatin, and the inactivity of transplatin, from the geometry of their labile sites.
  • What intercepts cisplatin before DNA?Identify the cellular molecule that binds and deactivates Pt(II) using hard–soft reasoning.

Octahedral lability and inertness

  • Why Cu²⁺ swaps water so fastExplain the extreme lability of hexaaquacopper(II) with the Jahn–Teller effect.
  • Inert is not the same as stableDistinguish kinetic inertness from thermodynamic stability using [Co(NH₃)₆]³⁺ in acid.

Trans effect and platinum synthesis

  • Why go through the tetraiodide?Explain why converting [PtCl₄]²⁻ to [PtI₄]²⁻ before adding ammonia improves the cisplatin synthesis.
  • Ethylene: big trans effect, modest trans influenceDistinguish the kinetic trans effect from the thermodynamic trans influence using a π-acceptor ligand.

The chelate effect

  • Which ligand grips Ca²⁺ tightest?Explain why a hexadentate ligand binds a hard metal ion far more strongly than monodentate or bidentate ligands with similar donors.

Mechanisms and rate laws

  • Why ligands enter Ni²⁺ at nearly the same rateExplain the near independence of complex-formation rate constants from the entering ligand with the Eigen–Wilkins mechanism.

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