教学课件学术资源大全高等有机化学lecture 17

1、Lecture 17: Organolithium AggregatesE. KwanChem 106Key Questions:Organolithium AggregatesEugene E. KwanOctober 14, 2011.(1) What do organolithium reagents look like in solution?(2) How are aggregation equilibria affected by solvation?(3) What effect do aggregates have on reactivity?MeMeMeMeMeMeOOOLi

2、HMDSScope of Lecturedimer : monomer3:11:3550:1aggregates of LiHMDS and LDAenthalpy and entropy of solvation and aggregationvariables to optimizeConventional Wisdom?organolithiums form aggregates (dimers and higher oligomers)enolization and the Ireland modelorganolithium aggregatesaggregation and rea

3、ctivitykinetics: order in reagentsHelpful Referencesmethod of continuous variation vs. DOSY1. Structure and Reactivity of Lithium Enolates. Seebach, D. ACIEE1988, 27, 1624-1654.2. Is TMEDA a Good Ligand for Lithium? Collum, D.B. Acc. Chem.Res.1992, 25, 448-454.3. Solution Strcture of Lithium Dialkyl

4、amides. Collum, D.B. Acc. Chem. Res. 1993, 26, 227-234.As we will see, this cyclic logic is seriously flawed.4. LiHMDS: A View of Lithium Ion Solvation. Collum, D.B. Acc. Chem. Res. 1999, 32, 1035-1042.5. Characterization of Reactive Intermediates by.DOSY Williard, P.G. et al. Acc. Chem. Res. 2009,

5、42, 270-280.6. LDA: Solution Kinetics and Implications for Organic Synthesis. Collum, D.B.; McNeil, A.J.; Ramirez, A. ACIE 2007, 46, 3002-3017.Acknowledgement:I thank Professor David Collum (Cornell) for helpful discussions and feedback in the preparation of this lecture.strongly coordinating ligand

6、s like TMEDA and HMPA will outcompete aggregationobserve higher reactivity in the presence of donor ligandsaggregates are less reactive and are to be avoidedSMe3Si N Li N SiMe3+ 2 S2Me3Si N Li SMe3SiLiSiMe3Me3SiSSLecture 17: Organolithium AggregatesE. KwanChem 106Lithium Hexamethyldisilazide (LiHMDS

7、)LiHMDS is a very important base in organic synthesis. How would you draw LiHMDS? Naively, one could draw:For example, it is commonly held thatTMEDA deaggregates organolithiums(?)(We will soon see if this is true.) Often, X-ray structures of organolithiums with TMEDA are in a lower aggregation state

8、 than the organolithiums on their own. However, all this means is that TMEDA chelates are accessible, insoluble, and nicely crystalline (D. Collum). So I will ignore crystal structures in this lecture.Aggregation vs. SolvationA reasonable assumption is that lithium has a coordination number of three

9、. If so, then:SMe3SiN LiMe Si3A key theme in this lecture is that such a representation isentirely inadequate to describe structure and reactivity.In fact, NMR spectroscopy tells us that in hydrocarbons, LiHMDS is a mixture of tetramer and dimer, while in etheral solutions,it is a mixture of dimer a

10、nd monomer:hydrocarbon solutionsMe3SiMe3SiLiSiMe3SiMe3Me3SiMe3SiSSetheral solutionsSNN+ 2 S2N LiLi SdimerSiMe3Me3SiNLiLiSiMe3 SiMe3Me SiLiLi SSiMeMe SiSSNLi3Me3Si33Me3SimonomerNNN LiSiMe3Me3SiNLiNMe3SiThese things are a bit tedious to draw out, so I will follow the convention in ref. (5), and abbrev

11、iate:SiMe3Me3SitetramerdimermonomerA: base (LiHMDS fragment)S: solventThese are called aggregates. (Usually, S = THF or Et2O.)Thus, here we have:A2S2 + 2 SAlthough I have drawn some solvents explicitly, the number of solvents on lithium can vary, even within aggregates of the same order. There may a

12、lso be more loosely associated solvents in a secondary solvation sphere.2 AS2Q1: Is solvent SA a better ligand for lithium than solvent SB?There are many X-ray crystal structures of Li aggregates. However, they do not necessarily say anything about what the aggegrates in solution look like.Q2: Given

13、 a particular solvent, what is the preferred dimer/monomer ratio?Lecture 17: Organolithium AggregatesE. KwanChem 106Lithium Hexamethyldisilazide (LiHMDS)Comparing SolventsIt is often mentioned that THF is a good ligand for lithium. That may be true, but good relative to what? The reference is:DG0sol

14、vA2SASB+SAA2(SA)2 + SBIf SB is a better ligand than SA, it will displace some SA from Li, pushing the equilibrium to the right. This is associated with a free energy, DG0solv.Here are some numbers, relative to THF.DG0solv (kcal/mol)Solvent (S)3.5Omore hindered ligands are not as good (more positiven

15、umbers mean that THF is preferred)2.3OOMe0.6Comparing Dimer and MonomerWhat about the dimer/monomer balance? free energy of aggregation:OIt has an associatedby definition (one THF is the same as another)0DG0A2S2 + 2 S2 AS2As expected, THF is a better ligand than ether.Interestingly, amines and ether

16、s are about the same! More precisely, dimeric LiHMDS binds isostructural amines and ethers equally well:aggIt is commonly thought thatstronger donor ligands (more negative DG0solv) give more monomer (more negative DG0agg) (?)In fact, there is no correlation at all between the two!Lecture 17: Organol

17、ithium AggregatesE. KwanChem 106Solvent Donating Ability and Deaggregation: No CorrelationTo reiterate, the graph means that solvents which bind more strongly to lithium than THF may or may not deaggregate LiHMDS.A Steric ModelBoth LiHMDS and many of these solvents have bulky groups on them, so it i

18、s reasonable to consider the solvent-amide and solvent-solvent steric interactions in the dimer and monomer.more dimerSMe3Si Me3SiSSMe3SiLiSiMe3SiMe3N LiNNMe3SiLi Sdimermonomerstronger donors(1) Small Solvents: solvent-amide interactions in the dimer dominate. As the solvent gets bulkier, monomer is

19、 favored.(2) Large Solvents: solvent-solvent interactions in the monomer dominate. As the solvent gets bulkier, dimer is favored.- solvating power and aggregation state are not correlated(3) Note that there is not necessarily a correlation between steric bulk and donor ability.Enthalpic vs. Entropic

20、 Effects(1) Solvation and aggregation are dominated by steric effects.-more positive solvation = reference ligand (THF) is increasingly preferred over test ligand-more positive aggregation energy = more and more dimer is present(2) Steric effects are dominated by entropy.Lecture 17: Organolithium Ag

21、gregatesE. KwanChem 106Enthalpic vs. Entropic EffectsEnthalpyThe enthalpy of aggregation is basically zero:S(1) Translational Entropy: As mentioned in lecture 16, there are a lot more ways to arrange three things than two things. This favors the dimer.(2) Solvation Entropy: Solvation requires coordi

22、nation of a ligand in a relatively hindered environment. That means that the solvent cant move around very much, and is therefore relatively ordered. Thus, the dimer is favored.Me3SiLiSiMe3has the same enthalpy asMe3SiMe3SiSSNNN Li2Me3SiLiSiMe3 S+ 2 S(3) Solvent-Dependent Entropy:Q: Why does the dim

23、er/monomer ratio change from solvent to solvent? For example, there is more of a preference for dimer with diethyl ether than THF.There are two factors at work:(1) Solvation Enthalpy: The monomer is more heavily solvated than the dimer (2 vs. 1 solvent/lithium), so there is an enthalpic benefit to d

24、eaggregation.A: With diethyl ether, the free solvent is relatively disordered, while solvent in the monomer is relatively ordered. With THF, both the free and bound solvents are relatively ordered. Thus, there is not as much of a preference for dimer with THF.LDA vs. LiHMDSThere is a striking differ

25、ence between the aggregation behavior of LDA and LiHMDS (in monofunctional solvents):S(2) Dimerization Enthalpy: However, you can think of the dimer as simply exchanging a solvent ligand for an amide one. So there is a benefit to aggregation, too.Apparently, these enthalpic effects almost completely

26、 cancel (at least for LiHMDS)!Traditional Thinking: Monomer-dimer equilibrium is determined by how good of a donor the solvent is vs. another amide.Me3SiLiSiMe3Me3SiSSNN+ 2 S2N LiMe SiLi SdimerSiMeMe Si333New Thinking: One must also consider entropic effects!EntropymonomerHowever, the entropy of agg

27、regation is non-zero. direction depends on two factors:SIts overallSLiHMDS: dimer andmonomeriPriPrLiLi SiPriPrNNMe3SiMe3SiSSMe3SiMe3SiLi LiSSiMe3SiMe3entropically favored over2N Li+ 2 SNNLDA: just dimerdimer(for most solvents)Lecture 17: Organolithium AggregatesE. KwanChem 106LDA vs. LiHMDSQ: Why is

28、 there an increased preference for monomer with LiHMDS?LiHMDS monomer (2 THF ligands) total s(N-Li) to s*(Si-C): 21.1 kcal/molA: LiHMDS is more electronically stabilized than LDA: the vicinal delocalization of s(N-Li) is better when the acceptor is s*(Si-C) than when it is s*(C-C):Me3SiSSbetter than

29、iPrSSN LiN LiH3C SiH C CH3H3CCH3CH3This is related to the acidity of their conjugate acids:more acidic thanMe3SiMe3SiiPriPrN HN HpKa = 36 (THF)pKa = 26 (THF)So LiHMDS is a much milder base than LDA:LDA monomer (2 THF ligands)total s(N-Li) to s*(C-C): 5.6 kcal/molH3C H3CMe3SiMe3SiOH+OLiNLi+NHMe SiMe

30、Si33H3CH3CDH = -12.1 kcal/molH3C H3CiPriPriPriPr+OHN H+OLiNLiH3CH3CDH = -28.6 kcal/molThus, the aggregation of LiHMDS is not as beneficial as the aggregation of LDA.Here are some computed monomer structures taken from the literature (B3LYP/6-31+G*, Pratt J Mol Struct Theochem 2007 811 191). NBO anal

31、ysis shows LiHMDS is stabilized a lot more:Lecture 17: Organolithium AggregatesE. KwanChem 106Effect of TMEDAIt is often said that TMEDA is a good ligand for lithium because of the chelate effect. Indeed, with low concentrations of TMEDA in a hydrocarbon solvent, a monomer is formed.However, if TMED

32、A is forced to compete with THF, THF wins!THF(1) TMEDA is not a chelating ligand at any point along the reaction coordinate. In fact, dimethyl ethyl amine actsin a very similar way.(2) The reaction can go through a monomer or a dimer:RRNMeN LiMeiPriPrMe3SiLiSiMe3SiMeSLiNMe3SiMe3SiNNNLiNNMe SiLiTHFN3

33、3iPrLiiPrMeMeHiPrHNin THF/TMEDA/ pentanein TMEDA/ pentaneiPrmonomeric TSdimeric TSThe chelate effect might be overstated, too. For example, LDA and TMEDA form an h1-A2S2 structure:(3) The idea is that the dimeric pathway is faster, since relatively unstablized LDA doesnt have to give up the benefit

34、of aggregation. However, this requires boththe solvent ligands in the ground state to dissociate first. TMEDA is a weak ligand, and makes this possible, while THF is a strong ligand, and resists this.DeaggregationIt is often said that HMPA will deaggregate organolithiums, which in turn increases rea

35、ctivity. This is false.MeMeiPriPrNN LiNMeMeorNMe2Me2Nrather thaniPrLiiPrNNiPrLiiPrMe NNMe22NMe2Although LiHMDS and HMPA form a mixture of dimers and monomers in THF, the dimer/monomer ratio remains unchanged, even at high concentrations of HMPA:SAMe2NiPrLiiPrNNiPrLiiPrMe2NNMe2Me3SiMe3SiHMPAHMPAMe3Si

36、 Me3SiLiSiMe3N LiWhat about reactivity?MeConsider the lithiation of imines:MeNNLiSiMe3 SBAS2(monomer)HMPA =OLi105 faster than in THFNMeSA / SB = THFSA = THF, SB = HMPA SB / SB = HMPATMEDANMehexanePA S (dimer)Me NNMe2 222NMe2Collum JACS 1993 115 8008Lecture 17: Organolithium AggregatesE. KwanChem 106

37、It also forms lithium triple ions, which can be thought of as lithium-ate complexes. These are formed in many polar solutions of HMPA and may be responsible for much of the increase in reactivity.As drawn, the dimer dissociates to a monomer, which reacts. Now, lets suppose we add a donor ligand S, w

38、hich deaggregates the dimer to the monomer by selectively solvating the monomer:SiMe3Me3SiLi(HMPA)energyN Li N4Me SiSiMe33TSlithium triple ion (formal dimer)Analogous behavior is observed for LDA/HMPA; in both cases, HMPA fails to deaggregate lithium.Aggregates and ReactivitySo far, we have establis

39、hed that:energy barriermonomerdimermonomerSsolvent donor ability and lithium aggregation state are not correlated.As drawn, the monomer has to be desolvated to react. So deaggregation leads to ground state destabilization, which inherently slows down reactions.An equivalent view: the solvated monome

40、r is an unproductive side equilibrium, which ties up substrate, slowing down the reaction.However, it is possible that a new pathway might open up, in which the solvated monomer reacts faster:Now, we will establish thatlower-order aggregates are not necessarily more reactive.In fact, the idea that m

41、onomers are more reactive than aggregates may have more to do with the fact that people like to study reactions which are reasonably slow.One way to look at this is with an energy diagram. Suppose that in the absence of an aggregate disrupting ligand, S, dimer is prevalent:energyTSTSmonomerenergyene

42、rgy barrierTSenergy barrierdimermonomermonomerSdimerLecture 17: Organolithium AggregatesE. KwanChem 106So deaggregation can also (but might not) lead to transition state stabilization, and it is the relative importance of these two factors that determines whether aggregates are more reactive.Aggrega

43、te Solution StructuresLet us briefly consider two completely different ways of looking at aggregates in solution (without considering the details. (Colligative properties, like vapor phase osmometry, can work, but are sensitive to contaminants.)Job PlotsWhat do aggregates look like in solution? Lets

44、 forget about solvation for now.ROLiLiR OO RLiLiR OO RLiLiR OO RLiA2Li O RLiO RAABB2BAlthough the lithiums in the AB heterodimer are magnetically equivalent, meaning one signal per species, there are now up to five signals total.The amount of AB will depend on (1) statistics and (2) the relative sta

45、bilities of the various species, as judged by their chemical potential.Based on just statistics, AB will peak at when the mole fraction of A and B are equal:RLiR OO RLiLiOLi O RLi O ROLiRmonomertetramerdimerThe trouble is these all have very high symmetry, so all the lithiums look the same by NMR. I

46、n addition, Li and O do not have scalar couplings. Solution: desymmetrize!Monomers and DimersSuppose A forms monomers and dimers:LiR OO RLiLi O RAt most, there are two magnetically inequivalent lithiums: one for the monomer, and one for the dimer. There isone signal per species, making for two signa

47、ls total, but it is hard to a signal as belonging to a monomer or a dimer.If AB peaks at some other value, and there are no confounding factors like experimental error or byproduct formation, then that means there is some special stability to one of the aggregates.What if I mix in an organolithium w

48、ith a slightly different alkyl group R? Then a mixture of homo- and hetero- aggregates forms:Lecture 17: Organolithium AggregatesE. KwanChem 106Aggregate Solution StructuresIn real life, solvation is important, and if solvent exchange is occurring and visible, then many more resonances can be observ

49、ed. Thus, one hopes thatintraaggregate exchange is fast butinteraggregate exchange is slow.n-BuLi in d8-THF (187 K, mixture of dimers D and tetramers T)That means that the solvent exchanges in the aggregates will be averaged out, but the homo- and hetero-aggregates will still be distinguishable.In g

50、eneral, the method of continuous variation.Diffusion-Ordered Spectroscopy (DOSY)A completely different method called DOSY has been used by Williard and co-workers (Brown) to deconvolute NMR spectra.What: a way to obtain 2D NMR spectrum of a mixture, slices of which are hopefully clean spectra of the

51、 componentsChemical shift axis: usually proton, but can be lithium orother heteronucleiLi complex in d8-THF (chemical shift axis is 6Li)Diffusion coefficient axis: reliably linked to molecular weightHow it Works: pulsed field gradients (see Chem 117 next semester!)iPriPriPriPrNNLiLiLiLin-butyllithiu

52、m (dimer and tetramer)OOTIPSTIPSLi complexLecture 17: Organolithium AggregatesE. KwanChem 106Solution Kinetics: Order in ReagentsQ: What is the stoichiometry of a transition state?Consider the deprotonation of a ketone by LDA in THF.Such reactions have been proposed to proceed via monomeric transiti

53、on states (Nowak TL 1998 39 1661). Here is one plausible scenario:(Do not confuse the rate constant, which is a lowercase k, with the equilibrium constant, which is an uppercase K.)rate = kKA2S21/2SKThus:Under pseudo-first-order conditions, we use the ketone as the limiting reagent (a lot more base

54、than ketone).Thus: rate = kobsK; kobs a A2S21/2S(1) Because the ground state involves a dimer, while theTS involves a monomer, the reaction is half-order in LDA.OTHFdissociation of dimer, association with ketoneiPrLiiPrMe1/2NN+THFiPrLiiPrTHF(2) Because an additional solvent is incorporated into the transition state, there is a first-order dependence on THF.THFO LiTHFiPr N iPrHOLi(THF)2MeiPriPrMe +H N(3) The composition of the g