E.

Kwan

Lecture 5: Stereoelectronic Effects on Reactivity

Stereoelectronic Effects on Reactivity Eugene E. Kwan
B: H X

Chem 106

(1) Intermolecular or intramolecular?

O2 S O CH 3

base

SO 3 CH 3 SO 2Ar

SO 2Ar

Scope of Lecture directed reductions Felkin-Anh model geometric constraints in SN2 reactions Baldwin's Rules stereoelectronic effects on reactivity

(2) Which pathway dominates?

Me Me O

Me Me MO

Br

Me Me O

(3) Outcome of reaction? E1, E2, and E1cb reactions

Me TsO O O H O O H N H N

chelatecontrolled 1,2-additions Helpful References

the Burgi-Dunitz trajectory

220 C

1. Johnson, C.D. "Stereoelectronic Effects in the Formation of 5- and 6Membered Rings: The Role of Baldwin's Rules." Acc. Chem. Res. 1993 , 26, 476-482. 2. Menger, F.M. "Directionality of Organic Reactions in Solution." T etr ahedr on 1983, 39, 1013-1040. 3. "From Crystal Statics to Chemical Dynamics." Brgi, H.B.; Dunitz, J.D. Acc. Chem. Res . 1983, 16 , 153-161. 4. "...Aspects of Chelation-Controlled Carbonyl Addition Reactions." Reetz, M.T. Acc. Chem. Res. 1993, 26 , 462-468. 5. "...Merged Stereochemical Impact of - and -Stereocenters in ChelateControlled Carbonyl Addition..". Evans, D.A. et al. JACS. 2001 123 10840.

(4) What controls the product stereochemistry?

O Ph OMe Me OTMS Me + H Me O Me2 Mg THF, -70 C OPMB iPr Me OH Ph OMe Me BF3 OEt2 O Me Me OH OPMB iPr

99:1 dr

94:6 dr

I thank Professor David A. Evans (Harvard) for helpful discussions and the use of some material in the preparation of this lecture.

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

O2 S

Chem 106

The Endocyclic Restriction Test In SN2 reactions, the optimal approach angle predicted by stereoelectronic considerations is 180. But how stringent is this requirement? Nu X

For example, consider this base-promoted methyl transfer:

O2 S O CH3

base

O CH3

SO3 CH3 SO2Ar

SO2Ar

SO2Ar

One way to examine this is the endocyclic restriction test (see Beak Acc Chem Res 1992 25 215-222):

Crossover experiments show that the product is formed through a purely intermolecular process. This substrate cannot achieve the orbital overlap needed for reaction. In contrast, this one can:
O2 S O

X-Y

Y-Z

base

O2 S

SO3

Of course, such a reaction could take place either inter- or intra-molecularly. How can these be distinguished?

I SO2Ar

SO2Ar

SO2Ar

intramolecular product only Eschenmoser Helv Chim Acta 1970 53 2054 What is the effect of tether length? With a longer tether, the intramolecular process becomes somewhat more viable:

X*-Y* Z + X-Y Z

X* Y*-Z + X Y-Z

Y*-Z

X*

Y-Z

O2 S

O CH3

O2 S

intramolecular products

crossover products

NMe2

NMe3

16% intramolecular King TL 1982 23 4465

In a double-labelling experiment, both the molecule and the migrating group are labelled and mixed with unlabelled substrate. If the reaction is only intramolecular, then no singly-labeled crossover products will be formed.

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

The Endocyclic Restriction Test It has been estimated that a deviation of 17 away from linearity is allowed in this degenerate exchange, which is exocyclic in two five-membered rings, but endocyclic in one eight-membered ring:
Ar S SAr Ar SAr S

As it turns out, this reaction is at least partly intermolecular, as the reaction is supressed by dilution. Furthermore, subjection of terminally sulfenated product to the reaction conditions results in both secondary and doubly sulfenated material:
OH OSAr

base

OSAr + OH

OSAr OSHAr

Substituent effects show this to be a rapid, intramolecular SN2 reaction (Martin JACS 1973 95 2572). Interestingly, these restrictions appear to be relaxed for thirdrow atoms like silicon, which have longer bonds and more diffuse orbitals:
OTIPS S Ar Ph Li OTIPS Li OLi TIPS

Baldwin's Rules Baldwin has devised an empirical set of rules to allow one to determine if a certain ring closure will take place. All cyclizations are referred to as:

n - endo/exo - tet/trig/dig
n: ring size being formed exo/endo: whether the bond being broken is outside (exo) of or inside (endo) the ring tet/trig/dig: whether the atom being attacked is tetrahedral (sp3), trigonal (sp2), or digonal (sp)
X X

Rucker TL 1984 25 4349

How would you determine if this reaction is intra- or intermolecular?

O OSAr OH

base

OH OSAr

exo-trig

endo-trig

In this case, labelling is not required, since product with two sulfurs would be expected in an intermolecular manifold:
OSAr OSAr

Cyclizations are classified as favored or disfavored, rather than allowed or disallowed; the "rules" merely suggest whether a particular reaction would be facile or not.

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

O2 S O2 S

Chem 106

Baldwin's Rules According to Baldwin (Chem Comm 1976 734): EXO tet 3 4 5 6 7 yes yes yes yes yes trig yes yes yes yes yes dig no no yes yes yes tet no no no no no ENDO trig no no no yes yes dig no no yes yes yes

The methyl transfer from before is 6-endo-tet and disfavored:

O CH3

base

O CH3

SO3 CH3 SO2Ar

SO2Ar

intermolecular process With third-row atoms like silicon, endo-tet processes may become possible. Certainly, pericylic reactions do not obey Baldwin's Rules. 1,5sigmatropic hydrogen shifts, for example, could be considered formally 6-endo-tet, but clearly occur:
H

[1,5]H

Evidently, the endo mode is much more restrictive than the exo mode, and sp electrophiles are more flexible than sp3 ones. Here are some examples: tet cyclizations All exo-tet cyclizations are favored, but endo-tet cyclizations are generally disfavored unless the ring is very large (n>9). KOH, H2O
OH Cl O

trig cyclizations All exo-trig cyclizations are favored, but 5-endo-trig cyclizations and below are problematic. For example, this molecule has a choice between 5-exo-trig and 5-endo-trig pathways: 5-endo-trig
CO2Me MeO2C N H

65%
MeO2C NH2 CO2Me

disfavored 5-exo-trig
MeO2C N H O

3-exo-tet: favored; a good method for epoxide synthesis

discussion and refs: March, 5th ed., pg 282-284 Dorwald, F.Z. Side Reactions in Organic Synthesis 2005, Wiley-VCH, chapter 9.

favored What is the donor-acceptor rationale for this behavior?

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Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

trig cyclizations In the 5-endo-trig pathway, the amine lone pair must overlap with the * of the olefin. However, the five-membered ring prevents this:

In fact, the rate constants for the ring-chain tautomerism of some oxazines in CDCl3 have been determined by NMR (relative rates shown):
N HO O

1 1.4 6-exo-trig

N O OH

69 42 5-endo-trig

O O N H

Alcaide JOC 1992 57 2446 An alternative explanation is that addition occurs through an attack on a tetrahedral carbon, not a trigonal one:
O H2O OH O OH

5-exo-tet

5-endo-trig

SN2 reactions on relatively hindered carbons are unusual, but not unheard of, especially if they bear activated leaving groups:
Me Me N3 PF6 Me

B3LYP/6-31g(d)
Me

Bu4NN3 CHCl3

O Me Me

Attacks on oxocarbenium ions do not appear to follow the same rules. Ketalization reactions are clearly facile:
O HO OH O OH

evidence for an SN2 mechanism: (1) polar solvents and salt additives slow down the reaction
O

5-endo-trig

H+

(2) kinetics are second-order and first-order in azide

Me

Me

One might imagine that cationic electrophiles have more diffuse orbitals which relax the stereoelectronic requirements for cyclization, but that is speculation.

(3) DFT rules out this rapid equilibrium:

O Me Me Me

O Me

Mascal JACS ASAP doi: 10.1021/ja103880c

E. Kwan Enolate Cyclizations Consider this enolate cyclization:

Me Me O

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

5-exo-tet

Me Me MO

Br

5-exo-tet

Me Me O

Fragmentation Reactions Fragmentations can be very useful reactions in synthesis. For example, this sequence was performed en route to ent-shikimic acid (tamiflu) (DA Evans TL 1997 38 57):
O O + N O LiN(TMS)2; TBSOTf, 2,6-lutidine MeO OLi OTBS O O 1. AgSbF6, 5 mol% (R,R)-t-Bu-Cu(box) 2. LiSEt; MeOH CO2Me CO2Me O

5-enolexo-exo-tet (favored)

5-enolendo-exo-tet (disfavored)

Both products are formed through formal 5-exo-tet processes, but the process on the right has the same stereoelectronic requirements as a 5-endo-trig reaction. Thus, we need a different nomenclature for enolate reactions:
MO MO

X-Y

X-Y

Grob Fragmentations Reactions of the form

E X E + + X

enolendo-exo

enolexo-exo are known as Grob fragmentations (comprehensive review: Mulzer Chem Rev 2010 110 3741-4766). Actually, Cyril Grob (1917-2003, b. London, Ph.D. at ETH, research at Basel) was not the first to investigate such reactions (see review)! In concerted versions of this reaction, the stereoelectornics are rather strict and require antiperiplanarity. Fragmentation can also occur through stepwise processes, whether polar or radical in nature. Example: Please predict the product of this transformation:
OTs

This distinguishes between reactions where the enolate is within (endo) or outside (exo) the forming ring. In general: ENOL-ENDO exo-tet exo-trig 3 4 5 6 7 no no no yes yes no no no yes yes ENOL-EXO exo-tet exo-trig yes yes yes yes yes yes yes yes yes yes

KOtBu

OH

E. Kwan

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

Grob Fragmentations Example: Please predict the product of this transformation:

OTs

Unfortunately, things are not always clear cut. For example, please predict the outcomes of these reactions:
O H

KOtBu
O

KOtBu rt
OH

There are two donor-acceptor interactions at work here: n(p-type, oxygen) to *(C-C) and (C-C) to *(C-OTs). In both cases, the proper antiperiplanarity is present. What about the outcome of this reaction?
OTs HO H O OH

KOtBu rt

?
Holton TL 1984 25 4455

Interestingly, despite the apparently favorable alignment in the top structure and poor alignment in the bottom structure, these products are formed:
O H OH

KOtBu
O

KOtBu 89%

HO H O

KO O

This substrate also produces the same product. How about this reaction? elimination products observed

observed

not formed
O OH

KOtBu
O OTs H

H O OH

KOtBu 100%
OK O

observed Why didn't these substrates react as expected? It appears there are two factors at work: (1) in the top case, oxetane formation outcompetes Grob fragmentation; (2) in the bottom case, the enhanced overlap in the norbornyl system renders the syn geometry acceptable.

Here, the tosylate is not in an appropriate position to be displaced and elimination occurs instead.

E. Kwan

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

Grob Fragmentations Elimination Reactions In most cases, however, a simple stereoelectronic analysis Can you use donor-acceptor ideas to predict the ranking of the is sufficient. For example, what is the outcome of this reaction? rate of these solvolysis reactions? 80% EtOH/H2O

O Me TsO O H

O O

H N H N

220 C

OTs

OR'

R' = H, Et (1) R = H (3) NMe2 (4) Br Grob ACIEE 1976 15 569

Eschenmoser ACIEE 1979 18 634 If one thinks of these hydrogen bonds as donor-acceptor interactions between the carboxylate lone pairs and the H-N antibonds (a perspective to be discussed later in the course), then: (1) a hydrogen bond between an anion and a cation is much stronger than a hydrogen bond between neutral partners because an anion is a better donor and a cation is a better acceptor; (2) the hydrogen bonds labilize the C-CO2 bond, disposing it to decarboxylation; (3) the decarboxylation initiates a double-fragmentation:
O Me TsO O H H N O H N Me O O

(2) R=OMe

Electron-donating substituents tremendously accelerate the reaction (relative rates shown):

more electron donating

Evidently, OH is resonance-donating, but the acceleration is tempered by its inductive-withdrawl.

E. Kwan

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

Elimination Reactions Bimolecular eliminations (E2) are influenced by the same stereochemical factors as Grob fragmentations. The alignment of an acceptor antiperiplanar to a donor necessarily labilizes the acceptor bond while simultaneously stabilizing the molecule overall; in effect, a "free lunch":
B: D X B: D X weakend bonds, enhanced TS interactions

We can classify elimination reactions with a Jencks-More O'Ferall diagram:

BH X BH

anion

E1cb
2) (E

PDT

In effect, there are two donor-acceptor interactions at work: donation of a filled orbital on the base into *(C-D) and (C-D) into *(C-X). Which hexachlorohexane will eliminate faster?
Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl

extent of B-H bond formation

ED T ER C N CO

SM
B: H X

E1
extent of C-X bond cleavage
B: H X

B Cristol JACS 1947 69 338

B is approximately 1000 times faster, since it has a trans-1,2diaxial relationship between a hydrogen and a chlorine.

This shows whether B-H bond formation is synchronous with C-X cleavage (E2) or asynchronous (E1 or E1cb). This is important, because stereoelectronic considerations like these are only expected to apply in E2 reactions. Another way to think about it is that the intermediates along the stepwise pathways lie in deep energy minimums. Molecules in those states are long-lived enough to redistribute their energy (perhaps conformationally), so they do not "remember" which way they entered the well.

E. Kwan

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

Elimination Reactions However, other stereoelectronic considerations can apply to non-E2 eliminations. How can you explain the product distribution in this acid-catalyzed dehydration?

Ph HO

H3PO4

Ph

Ph

A: 21%

B: 9%

Schaeffer JACS 1956 78 124

Ph Ph Ph

C: 6%

D: 32%

E: 20% How do the other products arise? Ordinarly, the less stable 1,2-diaxial conformer would not be significant; however, in this conformation, the electron rich phenyl group is poised to stabilize the carbocation:
OH2 H * * H + * Ph

In its more stable 1,2-diequatorial conformer, the starting material gives rise to this carbocation:
Ph H Ph

* OH

Ph

H H

Ph Ph

Ph

Of course, an empty p-orbital on a cationic carbon is a very good acceptor, so this can be viewed as a (C-H) to p*(C) reaction. Below is a picture of the overlapping PNBOs in the carbocation intermediate (B3LYP/6-31g(d)). The phenyl ring is aligned to donate into the carbocation.

This is a highly stabilized phenonium ion. Although this can also lead to A, the adjacent (C-C) bond is a viable donor as well, especially since it gives a stable benzylic carbocation. [1,2]-shifts of carbocations are called Wagner-Meerwein shifts.

* Ph

E. Kwan Elimination Reactions

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

The benzylic carbocation is more localized, but benefits from greater donor-acceptor interactions between the carbocation and the phenyl ring:
* Ph

ca. -8 kcal/mol

phenonium carbocation

benzylic carbocation

Here are pictures of the phenonium and benzylic carbocations (also B3LYP/6-31g(d), with NBO charges shown).

-0.11 -0.47 -0.23 -0.11

H Ph Ph Ph

H+

-0.01
H Ph H Ph

H Ph

-0.48 -0.17
The charges are quite delocalized. Notice the illusion of formal charges (all the carbons are net negatively charged and all the hydrogens are positively charged) and the familiar ortho/para; meta separation of charges in the phenyl ring.
Ph Ph Ph

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

Case 2: Cyclic Aminoketones
Me N O

Chem 106

The Brgi-Dunitz Trajectory From Crystal Statics to Chemical Dynamics Brgi, H.B.; Dunitz, J.D. Acc. Chem. Res. 1983, 16, 153-161. Stereochemistry of Reaction Paths... Brgi, H.B. ACIE 1975 14 460-473. Q: What is the trajectory of attack of a nucleophile on a carbonyl group? Unfortunately, there is no way to observe reactions as they occur (yet). The idea is to instead infer reaction trajectories from perturbations seen from crystal structures. Case 1: 1,8-Disubstituted Naphthalenes
MeO O Me

Here, the N-C distance is 2.47 A, which is a bit more advanced. The N-C=O angle is 111.

This is a highly strained system where the oxygen nucleophile is forced to be close to the ketone. The O-C=O angle in the crystal structures is 103.

Brgi argues (JACS 1972 94 5805) that the relative rate of lactonization in various hydroxyacids is increased in substrates for which the O-C=O bond angle is close to 100.
OH OH O O OH OH O OH OH OH CO2H OH CO2H

1 Note that the O-C distance is 2.60 A, which is in the ballpark for a typical transition state.

79

315

6633

106

Of course, the structures shown above are not transition state energy maxima, but ground state energy minima because they are derived from crystals.

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Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

The Brgi-Dunitz Trajectory There are two approaches to this. In an ideal world, one could perform molecular dynamics simulations, where nucleophiles and electrophiles are initialized with random trajectories. The simulation would run, and one would examine the trajectories that lead to product and determine what their Nuc-C=O bond angles were. Unfortunately, with today's technology a picosecond's worth of simulation time correponds to about a week's worth of computer (wallclock) time, so this is entirely impractical. Another way to look at it is that most collisions do not actually result in a collisions; reactions are such rare events that one would have to run a huge number of trajectories to accurately sample anything. A less ideal approach is to simply constrain the Nuc...C=O distance and measure the electronic energy. This has been done at a relatively crude level (roughly Hartree-Fock):
O

Thus, one should not think of a specific Brgi-Dunitz angle, but rather a Brgit-Dunitz cone: (1) At large distances, the nucleophile and electrophile don't have a significant bonding interaction. The nucleophile approaches along the H-C(O)-H bisector, consistent with an electrostatic view. (2) At medium distances, bond formation begins to develop and we are in the neighborhood of a transition state. Given the numbers here for C, which has a realistic TS bond forming distance of 2.0 A, we guess that the H-C=O angle must be between 110 and 130. (3) At close distances, we are essentially wiggling a H-C bond in a methoxide, and the curvature of the well simply reflects the normal modes of the product. A: 3.0 A B: 2.5 A C: 2.0 A D: 1.5 A E: 1.12 A

+
H H

CH3O

The "tightness" of the angle of attack depends on how far the hydride is from formaldehyde:

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

chelate speeds up reaction ketone chelate slows down reaction chelate ketone product chelate product

Chem 106

Chelate-Controlled Carbonyl Additions ...Aspects of Chelation-Controlled Carbonyl Addition Reactions Reetz, M.T. Acc. Chem. Res. 1993, 26, 462-468. These are the easiest diasteroselective carbonyl additions to understand. Asymmetric induction is possible from both - and -stereocenters; in both cases, a metal chelate is formed, and the nucleophile comes in anti to the stereocenter: 1,2-induction
RO R M O Nuc R HO R OH Nuc R

(1) If the chelate is just an unproductive side equilibrium, then it will just stabilize the ground state and slow down the reaction. (2) Conversely, the chelate might just form in the transition state, lowering its energy and speeding up the reaction. It is found that chelation significantly accelerates addition: rate (102 M-1 s-1)

1,3-induction
RO R M O R Nuc RO HO Nuc R R

O Ph O Ph OR Me OR Me Me

Me2Mg THF, -70 C

Me OH Ph Me

0.51
attenuation is not steric

If this model is right, then changing the nature of the protecting group on oxygen should change the stereochemical outcome. Indeed, this is exatly what is found (Eliel, JACS 1992 114 1778):
O Ph OR Me Me2Mg THF, -70 C HO Me Ph OR Me + Me OH Ph

Me2Mg THF, -70 C

HO Me Ph OR Me

1000 (R=Me) 0.45 (R=TIPS)

chelate product

R=Me, 99:1 R=TBS, 89:11 R=TBDPS 68:32

(3) -Alkoxyketones and magnesium bromide do not visibly coordinate by NMR. This is expected, since THF is quite a good ligand for magnesium. However, in CD2Cl2, there is a substantial shift.
Br RO R O + MgBr2 R R R Mg RO O Br

Interestingly, TBS, which one might think of as quite a large group, evidently still chelates; the much bulkier TBDPS group is required. (Dimethylmagnesium is monomeric in THF.) What is the evidence for this model, other than the stereochemistry? Just because a chelate is possible does not mean that it will speed up the reaction:

The extent of chelation in CD2Cl2 depends on the protecting group. (4) The reaction is first order in ketone and Me2Mg.

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

ground state., slowing the reaction down.)

Chem 106

Chelate-Controlled Carbonyl Additions This means that the scenario is: product ketone chelate If we want to draw an energy diagram (and we do), we can can compare the competing chelated and unchelated transition states: energy TS
unselective selective

(5) This corresponds to inverted reactivity-selectivity: the more reactive chelate is also more selective. (6) Interestingly, -lkxoy ketones do not seem to experience any rate acceleration:
O OR R=Bn R=TIPS

TS

no rate acceleration (2.5x)

R2Mg

O OR

This is consistent with other organometallic precedents, which suggest that 5-membered chelates are far superior to 6membered chelates. However, they do give high selectivity (Evans JACS 2001 123 10840): ketone + Me2Mg
Me Me Mg RO O R R OTMS O OR

Nuc
O M O P O R H H R Me OH OBn

tBu CH2Cl2 Me2AlCl or TiCl4

alkoxide product

alkoxide product

H Me

97:3 dr

(1) There is no differentiation between forming major and minor products on this diagram. Thus, we have to think of each transition state as really representing two transition states, one for the major and one for the minor product. (2) Thus, we have to revise our picture from the last slide; rather than one magnesium reagent attacking a Mg-chelate, methyl delivery seems to be from the chelated reagent, seemingly contradicting the bimetallic SwainAshby mechanism. This could suggest rate-determining chelate formation, followed by selectivity-determining nucleophilic addition. (Unfortunately, the authors did not look at the dependence of rate on THF concentration.) (3) This gives the somewhat surprising conclusion that chelation can be accelerating and increase selectivity, even in highly donating solvents. (Going to a nonpolar solvent would increase chelation, but also stabilize the

Note that these reactions are done in dichloromethane, a non-coordinating solvent. Keck has shown that the association constant for this reaction is appreciable:
O H Me OBn +

MgBr2 or TiCl4

CD2Cl2

Me

O X OBn

Broad NMR lines indicate that both the chelated and unchelated forms are accessible (Keck JACS 1986 108 3847). Obviously, there is a contradiction here: if both forms are accessible, then there must be a rate acceleration, or else the reaction wouldn't be selective. However, the lack of rate acceleration with Me2Mg doesn't mean there's no rate acceleration here. So, the picture is probably that a nucleophile attacks a chelated electrophile, as drawn on the last slide.

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

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Intrinsic vs Chelate Selectivity Before analyzing the outcomes of these chelate-controlled additions in more detail, it is important to realize that there is an intrinsic selectivity that is being turned over when chelation occurs (Evans JACS 2001 123 10840): "intrinsic selectivity"
O H Me OTBS O TiCl4 CH2Cl2, -78 C TMS enolsilane Me3C OH

(2) the transition states are very early (exothermic reaction) (3) both the major and minor transition states place the largest substituent anti to to the incoming nucleophile (4) the major transition state minimized torsional interactions between the C-R bond in the front and the C-M group in the back (L=large, M=medium, S=small): major TS
O M L S

*
Me

OTBS

"Cram chelate selectivity"

O H Me OBn TiCl4 CH2Cl2, -78 C TMS enolsilane Me3C

93:7 dr
O OH

*
Me

OBn

Nuc

- L is opposite Nuc - the torsional interaction between C-R and C-S is small - also could imagine that S/Nuc interactions are small - L is still opposite Nuc - the C-R/C-M interaction is bad - so is the Nuc/M interaction

5:95 dr The idea here is that going from a bulky protecting group, TBS, to a less hindered, coordinating protecting group, Bn, gives chelate control. But where does the intrinsic selectivity come from? There are numerous models for how nucleophiles add to carbonyl groups. Without going into the very complicated details of what each model predicts, here is the canonical Felkin-Anh-Eisenstein model. Felkin-Anh-Eisenstein Model Felkin criticized (TL 1968 9 2199) the prior Cram and Karabastos models for having no physical basis for their conformations. In the Felkin model, one assumes: (1) all ground state rotamers are accessible (Curtin-Hammett)
O M L R S

minor TS
S O L M

Nuc

This model works for the vast majority of aldehydes and ketones and is generally accepted. However, it does seem to fail in some pathological cases, such as sterically unbiased ketones which are nonetheless slightly electronically biased. Effect of Electronegative Substituents In the above analysis, it was tacitly assumed that all three substituents were alkyl; i.e., not electronically biased. Anh and Eisenstein showed that polar substituents X can take the place of the large group: minor TS major TS
O M S O X R S M X

clockwise rotation all rotamers accessible

S O L M R

Nuc

Nuc

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Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

Effect of Electronegative Substituents The work of Anh and Eisenstein (Nouv J Chem 1977 1 61) was seminal because it showed that computational chemistry could be a powerful tool for analyzing real problems in organic chemistry. Even though their work was, in today's terms, at a very crude level of theory (HF/STO-3G), it is telling that it gives the right predictions most of the time.

(2) The minimum energy structures of the solid and dashed lines correspond to the rotamers depicted:
O Me Cl R H H O

Nuc

Nuc Me

X R

minor TS major TS In their study, they analyzed the reduction of 2-chloropropanal with hydride. The distance between the hydride and the (3) Notice that the nucleophile approaches at the Brgi-Dunitz carbonyl carbon was fixed at 1.5 A, and the Cl-C-C=O dihedral angle. Hydride is not a very realistic nucleophile, but the angle was varied. Bachrach (page 303 of his book) has Brgi-Dunitz constraint is still realized. recomputed their results at a more modern (B3LYP/6=31++g(d)) level of theory: (4) Why does the C-X bond take the place of the large group? O Me Me + H HO H Explanation 1. Donation from the forming (C-Nuc) into the Cl Cl *(C=O). However, this is a very early TS, so there is very little density in (C-Nuc); NBO analysis shows that this is not a very significant interaction. Explanation 2. The *(C=O) and *(C-Cl) combine to form a better acceptor: *(C=O) HOMO Nuc *(C-Cl) LUMO decreased HOMO-LUMO gap

(5) The possibilities of asymmetric * lobes (i.e., bigger on one diastereofacial surface) and electrostatic minimization (Cornforth model) have been examined (see Lecture 24). (6) In the Cieplak model (JACS 1981 103 4540), which has seen significant criticism, it is argued that donation from the (C-H) into the forming *(C-Nuc) antibond is responsible for selectivity. However, in these very early transition states, the *(C-Nuc) is probably very high in energy (bad acceptor).

(1) The solid line (circles) represents configurations that lead to the major product; dashed (squares) lead to minor product.

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

H H PO R H O Nuc H sterics avoided: carbonyl, R group OBn Me TiCl4 Ph O R OH OP

Chem 106

A Half-Chair Model for Chelate Control For 1,3-chelate induction, a half chair model has been proposed by Evans (JACS 2001 123 10840). In some cases, a 2:1 bidentate chelate is observable in the ground state; in others, a monodentate 1:1 complex. So given the lack of kinetic data, it is unclear whether one can view all of these reactions as adding a nucleophile to a chelated complex. However, if one assumes this, then the performance of the stereochemical model is very good. If one assumes a boat-like chelate, then the nucleophile comes in opposite the R group:
H R O H OP R P O M O H Nuc OH OP R

Here is an example:
OTMS Ph O

OH OBn Me

+
H

92:8 dr With BF3OEt2, which has only one open coordination site, there is 1,3-anti selectivity (but it's not as good):
OTMS Me Me O OPMB Me

+
H

BF3OEt2 Ph

OH OPMB Me

Nuc If it's a half-chair, the same prediction is obtained:

R H M O P O C H P O M O CH

81:19 dr

Steric effects seem to play a minimal role, since there is no induction from alkyl substituents, even when they are very different in size:
OTMS Me Me O Me Me H Me Me Me Me Me O OH Me

Nuc disfavored

Nuc favored

1:1 dr In summary:
O H L Me O H OP R

As usual the Furst-Plattener rule dictates chair-axial opening. Interestingly, even if a monodentate carbonyl-Lewis acid complex is formed, the same outcome is observed. A polar 1,3-stereoinduction model predicts this (Evans JACS 1996 118 4322). One positions the alkoxy group on the -substituent such that it is minimized with respect to the carbonyl dipole:

Felkin control
Nuc

OH

L Me

Felkin: 1,2-syn

1,3-polar
Nuc

OH OP

Me

1,3-polar: 1,3-anti

E. Kwan, D.A. Evans

Lecture 5: Stereoelectronic Effects on Reactivity

Chem 106

Merged 1,3-Dipolar and Polar Felkin Control What if we have both - and -stereocenters? Evans has proposed (JACS 1996 118 4322) a model which combines 1,3dipolar and Felkin pictures. Here is a reinforcing case:
OTMS Me + H Me O OPMB BF3OEt2 iPr Me Me O OH OPMB iPr

This product is 1,2-syn, but 1,3-syn (not 1,3-dipole minimized). With intermediate sized nucleophiles, it is not selective:
OTMS iPr + H Me O OPMB BF3OEt2 iPr iPr Me iPr O OH OPMB

68:32 dr Directed Reductions These are among the most useful of the chelate-controlled addition reactions. What happens in this reaction?
Me Ph MeO O Zn(BH4)2 MeO Me Ph OH

Felkin product; 97:3 dr This is explained by Felkin-controlled addition to the boroncoordinated aldehyde: Nuc
Me F3B O H R H H OP

97:3 dr

Felkin: favors 1,2-syn Polar/chelate: favors 1,3-anti Thus, both influences are mutually reinforcing or "matched."

This is matched Felkin/chelate control. This reaction is also chelate controlled. What is the stereochemical outcome?
Me Ph NH2 O Ph LiAlH4 Ph Me Ph NH2 OH

88:12 dr

In contrast, addition of an enolsilane to the other diastereomer is not matched. With a small nucleophile, 1,3-dipolar influences dominate. What product dominates?
OTMS Me + H Me O OPMB BF3OEt2 iPr Me Me O OH OPMB iPr

Evans has developed (JACS 1988 110 3560) reductions where chelation overrides Felkin selectivity:
OH O Me Me Me Me Me H R R2 R1 OAc O O B OAc H OH OH NaBH(OAc)3 HOAc Me Me Me 98:2 dr Me Me OAc

anti-Felkin product; 6:94 dr This product is 1,3-anti, but 1,2-anti (anti-Felkin). With a large group on the enolsilane, Felkin overrides. Which product is formed?
OTMS tBu + H Me O OPMB BF3OEt2 iPr tBu Me O OH OPMB iPr

R2 O B OAc H O R
1

Felkin product; 88:12 dr

disfavored TS favored TS Note that 1,3-diaxial interactions are much worse on the top than on the bottom, where R1 is the only axial substituent. In contrast, when R2 is axial in the disfavored TS, it interacts with the acetate and axial hydrogen on the top face.