The art of problem solving in organic chemistry

The Art of Problem Solving in Organic Chemistry Second Edition MIGUEL E... 1.3 Avoiding the Quagmire, 71.4 The Basic Steps of Problem Analysis, 8 1.4.1 Recognizing the Problem, 8 1.4.2 A

The Art of

Problem Solving in Organic Chemistry

Second Edition

MIGUEL E ALONSO-AMELOT

THE ART OF PROBLEM

SOLVING IN ORGANIC

CHEMISTRY

THE ART OF PROBLEM SOLVING IN ORGANIC CHEMISTRY

Copyright © 2014 by John Wiley & Sons, Inc All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Alonso-Amelot, Miguel E., author.

The art of problem solving in organic chemistry / Miguel E Alonso-Amelot, University of the Andes, Department of Chemistry, Merida, Venezuela – Second edition.

10 9 8 7 6 5 4 3 2 1

To Adela and Gabriel in this world Christiane and Ram´on, in the other

1.3 Avoiding the Quagmire, 7

1.4 The Basic Steps of Problem Analysis, 8

1.4.1 Recognizing the Problem, 8

1.4.2 Analyzing Problems by Asking the Right Questions,

Discarding the Irrelevant, 111.4.3 Drawing a First Outline for Guidance, 12

1.4.4 Asking the Right Questions and Proposing the Right

Answers is enough?, 131.5 Intuition and Problem Solving, 14

1.6 Summing Up, 17

References and Notes, 17

vii

2 Electron Flow in Organic Reactions 19

2.1 Overview, 19

2.2 Introduction, 19

2.3 Practical Rules Governing Electron Redeployment, 22

2.3.1 Issue 1: Electrons within Orbitals, 22

2.3.2 Issue 2: Electron Transfer and Stereochemistry, 23

2.3.3 Issue 3: Electron Energy Level and Accessibility, 24

2.3.4 Issue 4: Electron Flow and Molecular Active Sectors, 26

2.3.4.1 Case A: π–π Interactions, 262.3.4.2 Case B: π→ σ Interactions, 272.3.4.3 Case C: When Reactivity Patterns Seem to

Break Down, 272.3.5 Issue 5: Electron Traffic and Electronic Density Differences, 312.3.5.1 M0Metals as Electron Source, 31

2.3.5.2 Metal Hydrides and Organic Hydrides as

Electron Source, 322.3.6 Issue 6: Creating Zones of High Electron Density, 34

2.3.6.1 The Natural Polarization, 352.3.6.2 Reversing the Natural Polarization: Umpolung, 352.3.7 Issue 7: Electron Flow and Low Electron Density Zones, 362.3.7.1 Identifying LEDZs, 36

2.3.7.2 Creating a New LEDZ in the Substrate, 372.3.7.3 Finding Unsuspected LEDZs among the Other

Reagents in the Mixture, 412.3.7.4 When Compounds Show Double Personality, 422.4 Summing Up, 42

2.5 A Flowchart of Organized Problem Analysis, 44

References and Notes, 45

3 Additional Techniques to Postulate Organic Reaction Mechanisms 49

3.1 Overview, 49

3.2 Take Your Time, 50

3.3 Clear and Informative Molecular Renderings, 50

3.3.1 The Value of Molecular Sketches, 50

3.3.2 Two- Versus Three-Dimensional Renderings and the

“Flat” Organic Compounds, 523.4 Element and Bond Budgets, 53

3.5 Looking at Molecules from Various Perspectives, 55

3.6 Separate the Grain from the Chaff, 58

3.7 Dissecting Products in Terms of Reactants: Fragmentation Analysis, 593.7.1 The Fundamental Proposition, 59

3.7.2 Adding Potentially Nucleophilic or Electrophilic

Character to Fragments, 61

CONTENTS ix

3.7.3 When Fragmentation Analysis Fails, Getting Help from

Atom Labels, 633.8 Oxidation Levels and Mechanism, 65

3.8.1 Methods to Estimate Oxidation Status, 65

3.9 The Functionality Number, 66

Problem 1 to 60 See Graphical Problem Index, 79

The book you just opened is an entirely rewritten second edition of the homonymoustitle, published by Wiley Interscience years ago Growing on the success of thefirst edition, a set of three chapters describing time-proven techniques of problemsolving and organic chemistry concepts is compounded with a new collection of

60 solved advanced-level problems of organic reaction mechanism extracted fromgroundbreaking research

Proposing hypothetical solutions and contrasting them against chemical soundnessand experimental evidence constitute the fundamental line of reasoning Perhaps there

is no better way to get to the bottom of things organic and extract a most rewardinglearning experience This would not have been possible without first describing aset of concepts and strategies, old and new, of problem-solving analysis applied toorganic reactions Several examples and embedded problems dot these introductory

chapters in the belief that Seneca’s words were absolutely right: “Teaching by precept

is a long road, but short and beneficial is the way of the example” (Epistulae, 6, 5).

As there seems to be no end to what organic chemistry and reaction mechanismcan expand and achieve, a web page has been created to lodge a large and growingbody of supplementary material associated with chapter and problem discussions:http://tapsoc.yolasite.com

To better illustrate the purpose behind this brief introduction, let me take you to thefollowing setting Imagine, for a moment, that you are sitting at one of those multiple-choice tests wondering where to jot your tick mark The question might be thisone: Equimolar amounts of toluene and hydrogen bromide yield a C7H7Br productwith the aid of aluminum tribromide Which is the reaction involved? Your choicesare: A – Nucleophilic aromatic substitution; B – Addition; C – Rearrangement;

xi

O OR

infor-of memorized data to identify that tiny and highly specific string, match it with aparticular preselected choice in your test and finally tick that box hoping for the best

In this sort of test, thinking as far as reasoning proper is not there but at a veryrudimentary level You may have selected choice E as a topical answer However, ifyou stop and think rather than match memories, you will soon discover a high degree

of ambiguity in some of the choices: electrophilic aromatic substitution involvesanswers D and G, as well as bits of B and F, for example

Now, change the situation a bit as you are presented with an organic reactionlike that in Scheme P.1 and asked to provide a mechanistic explanation No multiplechoices or anything to tune your mind on any particular lecture; just you and a barebones chemical transformation: a real-life situation in which researchers expected a

standard O-acylation (product 2) but were surprised to find compound 3 coming out

of the silica gel column as the only isolable material [1]

Your brain’s attitude will undergo a virtual commotion as it deliberates in terms of

intellectual logic, beginning by detecting and selecting the important issues,

organiz-ing the available data; then move on to heat up educated imagination to new highs,throw in the inevitable intuitive kink, and, oh yes, explore memory banks deep in

that heavy gray mass up there in search for spectral interpretation and other reaction

courses sufficiently resembling this one, if at all Gradually a feasible mechanismemerges from the top of your head to be debated with yourself (who else during

an exam?) until you feel satisfied enough to draw the set of sequential molecularrenderings any other organic chemist can understand anywhere in the world, not justyour teacher (Is this not awesome?)

Before you read on, let me invite you to provide an answer to this problem (donot be discouraged if you cannot at this point) and then explore a full discussion inSuppl # 1 on http://tapsoc.yolasite.com

PREFACE xiii

In actual fact, everyday professional life is very much like this, unexpected dailysituations with options in a scale of grays rather than black or white Pondering,reasoning, and, why not, a bit of intuition, rather than memory alone, are the best andmost efficient tools to reach a correct (or more appropriate, under the circumstances)answer If so, why not do whatever it takes to improve these skills, so exceedinglyvaluable for the proficient organic chemist?

Albert Einstein was probably right when he said “Imagination is more important

than knowledge.” Coming from such a bright mind this unsettling sentence should

not be taken as a cold shoulder on mnemonic learning as an outmoded teachingphilosophy, a current trend by the way After all, culture, an exclusively human trait,

is almost entirely based on accumulated knowledge created by our predecessors and

stored in society’s collective memory The individual brain takes up whatever it can

and needs from this ample menu and mixes it with the daily information input,filters off the chaff (the largest portion) and retains the rest to be organized within itsneuronal maze in various depth levels Then recall these as required, sometimes inquite different forms from the original

Memory by itself, however, cannot replace imagination but only help support it.For one reason: human knowledge is far too large for one individual to remember, and

it expands at an impossible logarithmic rate growing on itself like bacteria in a petridish without nutrient limitation Currently, it doubles every 5 years! There is no way

to stay abreast with such a deluge, regardless of electronic ultrafast databases Andyet, people who changed our way of thinking and perception of the universe, Gallileo,Keppler, Kant, Newton, Rousseau, Liebig, Kekul´e, Maxwell, Freud, or Pasteur hadaccess to few books and knew just a small fraction of what average sophomores ofscience careers of our day store in their mind

How could such an “unenlightened clique” achieve such a huge goal? Becauseall of them put to good use the little they knew with a large dose of imagination(in Einstein’s terms), reasoning, and sense of purpose to pose the right questions,tie knots between dispersed bits of knowledge of their time and persevere to get theanswer They were not only unsurpassed thinkers but great problem solvers as well.They could also live up to changing times with fresh answers As Uruguayan poet

Mario Benedetti once said: “When we thought we had all the answers, suddenly all

the questions were changed.”

The kind of test of Scheme P.1 gauges your capacity to face this new world ofever expanding knowledge in the sciences and societal needs; that is, your ability tonavigate through uncharted territory without sinking For such steering, reasoning,and the ability to correlate apparently unrelated issues while using organized thinkingand creativity are much more valuable than anything else Although some privilegedones are born with such gifts, most of us need to acquire and develop these skillsthrough the hardships of problem-solving training Problem solving is not only amost powerful tool but a requisite for the good practice of the organic chemistryprofession

This is why the opening sentence of my first edition of The Art of Problem

Solving in Organic Chemistry was: “Few persons, if any, will argue convincingly against the premise that problem solving is one of the best means currently available

to educate future professionals.” This assertion continues to be true, perhaps more

at an advanced level and describing solutions and related chemistry in detail As such,

it is a workbook rather than a text although it may still be used as such

All these introductory concepts are dotted with numerous examples in problemform, which you, as a curious reader, may feel lured to solve before carrying on to theanswer in the discussion of each issue Specific links to this book’s website are given

at appropriate places in the text In this manner, the subject unfolds step-by-step with

an increasing involvement on your part as you work through

The second part of the book comprises a large set of fully discussed problems inreaction mechanism These reactions have been carefully selected from the currentresearch literature, chiefly synthesis and organic reaction areas, and organized roughlyaccording to level of difficulty

The techniques described in the first chapters are applied as problems require Youare expected to cuddle up and draw your own answers and then compare the resultcritically with the solutions offered here Alternatively, you may study the discussionstep-by-step, stopping at suggested places to work out your own way to partial orfinal solutions This is also brain material for group discussions Gradually you willbuild up your proficiency as problem analyst and solver and be able to tackle evermore challenging reaction mechanisms as you progress through this collection

In this new edition lecturers of organic reactions and synthetic methods may findinspiration for bringing increasingly demanding problems to class for students totake home and split hairs on them Also, it should serve as a source of examples ofcertain sophistication from the current literature for their courses and reaction typeexamples Besides, the subject of mechanism elucidation and hypothesis proposal is

in itself a much-needed topic for the advanced chemistry syllabus

to improve yourself in this direction? Then, read on.

This book includes a body of chemistry of considerable substance and scope andsome mistakes may have escaped scrutiny All of them are my own and not of theauthors in references or the editors

Miguel E Alonso-Amelot, PhD

REFERENCE

1 Banerjee AK, Bedoya L, Vera WJ, Melean C, Mora H, Laya MS, Alonso-Amelot ME

Synth Commun 2004;34:3399–3408.

PREFACE TO THE FIRST EDITION

“Science does not prove anything at all; rather it disproves a great deal,” asserted K

Popper in The Logic of Scientific Discovery This remarkable thought has triggered

a considerable amount of philosophical discussion throughout the world, and its fullmeaning may be debated for several years Among other possibilities, this sentenceimplies that scientific discovery is more solidly developed on the basis of the exper-imental negation or disapproving of models or working hypotheses that attempt toexplain a given phenomenon than on the basis of affirmation by experiment of thesemodels or hypotheses

The attitude associated with approval is generally recognized as requiring muchless effort than that associated with dissent, because the latter implies a more complexthought mechanism that includes analysis, synthesis, selection, comparison, construc-tion of opposing standpoints, and clear verbal composition to express and defend thedisagreement Therefore, Popper’s sentence may also be interpreted in terms of adesirable profile for a professional scientist That is, a person endowed not only withhigh level cognitive memory or recall thinking, but also with considerable ability for

critical thinking, which enables him or her to design hypotheses and experiments

intended to negate existing models

The latter quality has been condensed by Howard Schneiderman, Monsanto’s vice

president for research, in a recent college commencement address (Chemical and

Engineering News, June 21, 1982), as three essential abilities: development of good

taste, ability to communicate in clear language, and a great deal of problem solving

capacity.

It is clear that the system of scientific education shows inadequacies in at leastthese three aspects and this lack is currently the cause of deep concern among edu-cators and theoreticians of education Of these three abilities, problem solving is

xvii

probably the most important since it should permit the development of analyticalskills, synthetic reasoning, discernment in separating the important from the unwor-thy, and the ability to recognize valid solutions from a variety of alternatives Thesequalities help considerably in attaining insight, cleverness, and even artfulness andgood taste in professional practice in academic and most industrial environments.The question then becomes, which mechanism should we adopt to educate studentsproperly in this area and thus overcome this deficiency? There is no unique answer ormagic formula However, a good beginning is the intense practice of problem solving

in specific areas of knowledge, although it would be desirable to have a more generalsyllabus of widespread applicability, at least in the hard core sciences

And, there is chemistry In the words of Robertus Alexander Todd, better known

as Lord Todd, “there is no question that chemistry is the center point of science.”

I may add that organic chemistry is perhaps the heart of this center point because itunderlies so many disciplines, from agricultural production at all levels, biochemistry,industrial chemistry, polymers, pharmaceuticals, to 99% of the chemistry involved

in all living systems Furthermore, the multitude of mechanisms by which organiccompounds undergo transformation offers an ideal platform on which those desirableskills mentioned previously can be developed It is the purpose of this book toconstruct from this basis the educational means of achieving the development ofproblem solving skills in the student of advanced organic chemistry It is also possiblethat practicing professionals might find this work useful if their exposure to problemsolving during their college and university studies has been inadequate

The use of a number of examples that constitute the series of 56 problems collectedand discussed in the third chapter was preferred over long theoretical descriptions.Some necessary fundamental concepts are concentrated in the introductory chapters.This book may be found useful not only as a study guide but also as a source ofinteresting and somewhat challenging problems and as illustrations of reactions andphenomena of general interest

I want to express my gratitude to all those who read all or parts of the rough drafts,offering helpful comments I am particularly thankful to Professor Bruce Ganemand Professor Jerrold Meinwald for their useful suggestions and to Paul Gassmanfor his advice during the early stages of this work I especially wish to thank Mrs.Shirley Thomas for her dedicated Production work, Ms Cheryl Bush for her advice

on language usage, and to all my students who, over the years, have provided usefulfeedback for many of the ideas expressed in this work Finally, my thanks to theTarnawiecki family of Lima, Peru This book benefited greatly from the stimulatingand highly caring environment they provided while the writing of the first draft was

in progress Two most unusual people contributed the most to this environment, DonRafael and my wife, Adela

Miguel E Alonso-Amelot

Caracas, Venezuela

March 1986

A book like this one might not have been created without the help from a number

of people My special thanks go first to my wife Adela for supporting my work soblindly and enduring the long absent-minded periods when solving organic reac-tion mechanisms takes precedence over other family responsibilities My students ofadvanced courses in organic reactions over the years have taken their heavy load aswell, providing their invaluable feedback As many solutions here are my own, a mostnecessary second opinion in particularly tricky reactions was indispensable Profes-sors Achim Stolle and Bernd Ondruska of the Friederich Schiller University in Jena,Barry B Snider from Brandeis University, Javier Gonz´alez Fern´andez of Universi-dad de Oviedo, Juan Francisco Sanz-Cervera of Universidad de Valencia, and JuliaStephanidou-Stephanatou and Constantinos Tsoleridis at the Aristotle University ofThessaloniki were kind enough to revise, discuss constructively and suggest correc-tions to parts of the manuscript Likewise, my gratitude to Servicio de Biblioteca

y Documentaci´on of Universidad de Valencia, Spain, along with the Asociaci´on deAlumnii y Amigos of this university, both absolutely essential to access the currentliterature and older sources of difficult retrieval, must be acknowledged

I had the good fortune to work with Jonathan Rose and Amanda Amanullah,editors of John Wiley & Sons, Prakash Naorem, project manager of Aptara, Inc.,and the assistance of a variety of unnamed reviewers as this project gained maturity.Without them, this book would have never seen light

M E A

xix

This is what problem analysis (PA) is all about This chapter focuses on the basicsteps that will extract the most of each mechanistic riddle with the aid of a number ofembedded mechanistic problems for you to try and then compare your solution withthe one provided here In so doing, you will begin your training as a problem solver

in organic reaction mechanism from the first pages

Perhaps the educated guess to postulate a reaction mechanism is the most

popu-lar procedure among dilettante problem solvers Starting materials and reagents are

The Art of Problem Solving in Organic Chemistry, Second Edition Miguel E Alonso-Amelot.

© 2014 John Wiley & Sons, Inc Published 2014 by John Wiley & Sons, Inc.

1

O

N O

iv

SCHEME I.1 Adapted from Reference 1 Copyright © 1978 American Chemical Society,

by permission

treated using familiar reactions to approach products This task usually turns into

a stop-and-go stepwise protocol toward the goal Frequently enough, however, ther starting materials nor reagents look familiar enough and progress comes to afrustrating standstill

nei-As this is a workbook, let us put to test the previous assertion with a workingexample Take the reaction of Scheme I.1, extracted from a now classical transfor-mation [1] and try to propose a reasonable mechanism Do not be discouraged if youcannot

This set of reagents does not involve fancy components, extravagant catalysts, orextreme reaction conditions A good strategy at the onset is to focus your attention onthe molecular hot spots: the highly active functions Then, work your way through,supported by the chemistry you presently know After producing an answer, compare

your reactions with the belabored (on purpose) solution described below It may look

a bit lengthy, but keep in mind the point we want to make here: the awkwardness ofthis honest, exhaustive, stop-and-go educated guess approach So please be patient ifyou want to learn and enjoy

1.2.1 “Pushing Forward” a Solution in Formal and Exhaustive Terms

We shall resort to educated guesses in strict abidance to the rules of organic nism and thoroughness to leave no loose ends This is not the best recommendation

mecha-to proceed but good enough for what we want mecha-to demonstrate: Paying mecha-too muchattention to detail is unproductive, pathway branching, and confusing

A fast look at Scheme I.1 reveals that compound 3 appears to have many more carbon atoms than 1 or 2 taken individually, whereas the morpholine segment has disappeared Also there are lots of new C–C connections in 3, suggesting that bonding

the starting materials is a good idea Additional C–C bonds may be built from there

as needed

H H Cl

H 3 O +

Et 3 NH,Cl

SCHEME I.2

To that end, one makes use of the electronically active carbons in the starting

materials: Cl–C=O in 1 and the enamine in 2, a familiar electrophile–nucleophile combination Expectedly, β-diketone 6 is spawn effortlessly via 5 after aqueous acid

workup (Scheme I.2) Triethylamine mops up the HCl produced (leaving it alonewould have blocked the enamine as the pH decreased)

Take note that there are as many carbon and oxygen atoms in 6 as in target compound 3, so no additional moles of 1 or 2 are required The rest of the sequence

seems accessible enough, requiring only a few connections and disconnections here

and there in 6.

Well, let us see if this is so simple: Please go back to Scheme I.1 and observe thereaction conditions of Step ii Clearly, this is a standard acetylation Or is it really?There is no OH in sight to acylate, but one can create this OH easily by enolization

of 6 There are two firsthand enols 7 and 8 that, after acylation, will furnish enol acetates 11 and 12 In fact, enol acetates 13 and 14 are also conceivable by C=C

isomerization to the thermodynamically more stable conjugated acetates Now wehave four reaction products to submit to the next step Our educated guess has led us

to an irritating ramification of the reaction scheme (Scheme I.3)

Worse comes to worst: At this point one cannot conjecture a priori which is themost likely enol acetate, except for the stability of the conjugated systems Hence,more educated suppositions are in order and all potential intermediates need to beconsidered in the next step

Step iii: Activation comes from UV light of a high pressure Hg lamp (254 nm).Usually, this entails [2 + 2] coupling of C=C bonds located at accessible distances to

the two π bonds would be allowed for a concerted reaction But none of dienes 11–

14 can attain this conformation (try your own Dreiding models or visit Suppl I #

1 in http://tapsoc.yolasite.com/), acquiring chiefly the supra-antarafacial tion This argument would have serious consequences for the stereochemistry of theresulting cyclobutanes, but not in our present case

configura-Two C–C bonds are formed in the [2 + 2] photocycloaddition, taking us closer (but

we do not yet know how) to target 3 We are driven to this blind conclusion by the increase in scaffold complexity Rewriting enol acetates 11–14 to better observe the

photoexcited π−π∗ interactions, one may postulate not one but two intramolecular [2 + 2] cycloaddition products for each diene (Scheme I.4) This means that our

brainchild has tragically branched out into eight different compounds (15–22), while

product 3 is still as elusive as ever (none of them resembles it).

Things are getting a bit out of hand, so some clean up is due One may discard apriori some of the photo adducts of Scheme I.4 on the basis of two criteria withoutresorting to Procrustean methods1:

(a) Resemblance to product 3 backbone, if any, and

(b) Structural incongruence

stretching savagely their bodies with ropes if too short or amputating their limbs if too tall So, to place

an argument on the bed of Procrustes is adapting it to circumstance through arm twisting or irrational means.

INTRODUCTION 5

13

OAc O

O AcO

OAc O AcO O

11

O AcO

O

AcO +

(a) Resemblance: By comparing the [2.2.1] bicyclic portion of 3 with photo

prod-ucts 15–20, (with some concession to additional rearrangements still to come), tures 19 and 20 may be put aside momentarily to be retaken only if exploitation of

struc-the rest does not furnish struc-the target

(b) Incongruence: While there are limits to scaffold construction of carbon

[0.0.x.y ](multi)cyclic structures, organic synthesis has been able to produceincredibly strained compounds [2] Therefore, it is not that simple to filter off appar-ently implausible structures Besides, reaction conditions are mild (0◦C) and strainedcompounds may survive

In terms of intuitive (eye-assessed) relative probability of occurrence based on the

anticipated relative ΔH of each compound, I would propose the following order: 18 >

15> 17 > 16 Do you have a different opinion? Table I.1 may help to dissipate any

TABLE I.1 Total Strain Energy (kcal/mol) Relative

to Cubane of Photo Adducts 15–18 of Scheme I.4

(Calculated by Molecular Mechanics Methods

(ChemBioDraw (CambridgeSoft) MM2 Interface)

handweaving controversy by revealing, after some molecular mechanics calculations,that my prediction was completely wrong Was yours too? Mind that the more negativestrain energy values imply a more stable compound The order of stability suggested

by molecular mechanics, hence the probability of the dominant photolysis, is now

15> 16 > 18 > 17 This order holds if we assume product-like transition states, as

cyclization to such strained scaffolds are endothermic

Although one should not take blindfolded the dictates of molecular mechanics

calculations, the strain energy difference of compound 15 relative to the rest is so

large that not considering it first for the next reaction would be an unpardonable gaffe.Regrettably though, basic hydrolysis and retro-aldol bond breakage followed by the

reverse reaction on odd cyclopropenone 22 leads to a carbon scaffold (24) unrelated

to target 3 (Scheme I.5).

Acetate 17 would be next in line for scrutiny In light of the previous discussion, it is

clear that the other enolate would also give a bicyclo-cyclopropane far removed from

OAc O

15

– OH

O O

O HO

AVOIDING THE QUAGMIRE 7

3 Neither would 16 (try to convince yourself of this) All our hopes are seemingly pinned on compound 18 Scheme I.5 describes the retro-aldol disconnection and

reconnection applied to it

At the end of the day we finally succeeded with this last minute basket, and yet

it is not possible to clearly justify the chain of events leading to 18 as the most

favorable conduit It is of reassuring interest that this reaction can be stopped at the

stage of diketone 27 by replacing acetate with benzyl ether, which is then removed by

hydrogenolysis after UV irradiation [1] While allowing the retro-aldol condensation,

the neutral medium prevents further enolate recoupling (27 → 29).

1.2.2 Lessons from this Example

Although we were able to come up with an acceptable solution after treading through

so many possibilities and letting our sketch reach almost unmanageable proportions,there is this residual sense of unwise application of our chemical knowledge Exhaus-tiveness is not necessarily a formula for success in mechanism design and many other

endeavors of professional life Albert Einstein was once quoted as saying: “Any

intel-ligent fool can make things bigger, more complex, and more violent It takes a touch

of genius and a lot of courage to move in the opposite direction.”

I dare say that you are among those who wish to move in this “opposite direction.”

But you will never walk this road by pushing forward starting materials towards

products without previous analysis of the problem and drawing a clever plan from it

to select sound options and discard others, no matter if you are well intentioned and

supported by sound chemistry As will be shown in Chapter 3, working the other wayaround (understanding the product rather than starting materials) may be much morecreative, practical, and productive

A much more constructive and effective approach to reaction mechanism ops if, before throwing ourselves to scribble structures and curly arrows to convert

devel-starting materials into products, we take time first to focus our attention on precise

issues regarding associations between all compounds, starting materials, products,

and reagents in an organized way This is so obvious, you might say, but not manypeople do this

This planning begins with PA An introductory review of PA as applied to organicchemistry reactions is the subject of the rest of this chapter Subsequent chapters willdeal with specific techniques in the search of valid solutions

PA may be focused in many ways as the abundance of references dealing with thistopic leads one to believe In essence:

Problem analysis is an exercise in asking the right questions to clear the way toward the right solutions (notice the plural here).

This assertion is probably too simplistic, but it is a good launching pad as we allowthis idea to grow from this uncomplicated start Problem solutions generally emerge

after pondering options stemming from meticulous questioning and analysis.

There are three steps that may be applied not only to organic chemistry problems but

to almost any situation requiring PA

1 Recognize whether the reaction (or issue) under scrutiny is a true problem

2 Analyze the problem by asking the right questions, discarding the irrelevant

3 Drawing a first sketch for guidance in developing the definite answer

These steps are now described in detail with more embedded problems for you towork out as you read

1.4.1 Recognizing the Problem

What is a problem is our first question This is not as dumb as it sounds because

many students, no matter how advanced, confuse exercises with genuine problems A

key question solves this doubt: After a first bird’s eye view, do I recognize a feasible

solution right away? If the answer is yes, then the problem does not exist; the reaction

is just an exercise A problem-example illustrates this point

Suppose you are faced with the reaction of Scheme I.6, which I extracted from arecent synthesis sequence of (+)−austrodoral, a natural sesquiterpene [3] We shalltreat this reaction along the elementary lines described above

Queries at the onset, once you have a superficial evaluation:

(a) Is this really a problem?

(b) Is it worth the effort solving it?

(c) Will I learn anything by devising and testing a mechanism?

Answers will vary depending on each one’s background and attitude Scheme I.6may constitute a challenging problem with lots to learn from for sophomore

O I

BF 3 Et 2 O

Ph 3 P, I 2

O OH

SCHEME I.6

THE BASIC STEPS OF PROBLEM ANALYSIS 9

undergraduates but quite accessible for a hardened veteran of the graduate school,who may recognize familiar signs for a likely solution

The implication is clear: The magnitude of the problem depends on the observer:his/her knowledge store, readiness to use it, and a shed of audacity Try your witsnow and then carry on with our PA below

reac-tion in the following argument string

(a) Which is the main reaction here? Ring contraction of a carbinol while a ketone

ends up in the side chain of product 31 This has the flavor of a pinacol-type

rearrangement

(b) If (a) is correct, a carbenium ion is in order as pinacol rearrangements aregenerally preceded by a C+or equivalent next to a sec- or tert-carbinol like

the C–OH in 30.

(c) Where to find this C+? Epoxide and tert-carbinol in 30 are perfectly positioned

for this once we bring powerful Lewis acid (BF3.Et2O) on the scene

(d) But what do we make of the triphenylphosphine–iodine mixture? Having noother source of iodine, it should be responsible somehow for the α-iodoketone

in 31.

(e) A literature search tells us that, among other applications, triphenylphosphine–

iodine is useful for the mild elimination of tert-alcohols to give the

thermo-dynamic alkene, but here it would stop any pinacol rearrangement on its

tracks if this ever occurred on tertiary alcohol in 30 Road blocked here.

(f) One needs to operate first with Ph3P and I2 on the epoxide in a differentmanner and then see where to go from there, pursuing to create the desired C+for the pinacol rearrangement From this first analysis a working sketch can

be devised at this stage (Scheme I.7, top)

Based on this first plan, a reasonable sequence may be put together beginning

with active iodide as nucleophile At 36 the sequence splits While path A follows the classical pinacol rearrangement through a full carbenium ion, route B entails

a concerted redeployment of valence electrons reminiscent of the Wittig reaction

The latter would be more akin with the observed cis- dimethyl arrangement in

product 31.

The mechanism is solved and ceases to be a problem for those of you who thought

it was indeed problematic For other more advanced individuals it may not have beenreally a problem, just a moderately demanding exercise

Now, compare this relatively accessible sequence with the 38 → 39

transmogrifica-tion (Scheme I.8, top) Because the answer is not immediately apparent, this reactransmogrifica-tionlooks as if we have a veritable problem here The overwhelming effect of complex

product 39 may discourage more than one reader although it is simpler to solve than

it seems (see Problem 28 for a feasible solution)

O OH

Attach iodide here

Epoxide opens

This O becomes electron donor

stabilization of negative charge

or activation is required

I

Ph 3

P O OH

O OH

34

Ph3P I O

BF3

37

Ph 3

P I

O I

31

Pinacol rearrangement.

Pseudo-pinacol rearrangement

Therefore it may be safe to contend that a problem is any situation requiring a

solution not in sight after a first appraisal.

Corollary: Any situation with a detectable, accessible, and correct solution is not

a problem, but an exercise in cognitive management.

Dull jobs have a lot to do with this corollary; creative ones deal with fresh andauthentic, lively problems all the time

THE BASIC STEPS OF PROBLEM ANALYSIS 11

H

OH O

O

O

O O

i: BF 3 Et 2 O; E-α-ocimene; 0ºC (1.5 h) to 50ºC (10 h), CH 2 Cl 2

i

39 38

O

O R

O N

41 40

i: MeLi, THF; ii: 6N HCl; iii: EtOH

i, ii, iii

SCHEME I.8

1.4.2 Analyzing Problems by Asking the Right Questions,

Discarding the Irrelevant

The number of irrelevant questions asked in group discussions is astonishing Onemust be clear about what is a right question that will open the way rather than drive

attention away with immaterial prattle Take, for example, 40 → 41 (Scheme I.8,

bottom), a simple one to analyze for someone reasonably familiar with alkylationand hydrolysis [4] Now, compare the two following sets of questions and pondertheir relevance to constructive solutions These were construed randomly on purposeand stem from a real-life group discussion

1 Is it run under argon?

2 Is it useful for my thesis?

3 Does the product retain functional groups of the starting material unchanged?

4 Which ones?

5 Does this reaction have a name? And the source journal Does itcome from a Max Plank Institute lab or a university in Thailand? (nooffense)

6 Does it produce toxic fumes?

7 Does stereochemistry matter?

8 Why didn’t they use dioxane instead of THF?

Let us cut it short momentarily to weigh their impact on our specific aim:proposing a reasonable mechanism.

Irrelevant questions: 1, 2, 5, and 8, as they do not lend support to clarifythe problem As far as question 5, many nonmainstream universities produceexcellent research Question 6 is also beside the point if you do not plan torun this reaction on your bench or recommend it to someone else However,

it may contain useful mechanistic information only if you knew which toxicsubstance was being evolved for element balance and so forth

Here is a second set of more focused issues

9 As the lactam backbone contains four carbon atoms in line, is it likely that

these atoms end up as the four carbon chain of α-aminosuccinate 41?

10 If so, the lactam ring must be fractured at some stage At which stage? Doesthis make a difference? Are there lactam ring-opening reagents in the mixture?

11 By chance is MeLi the source of the extra methyl on C3of my target or does

it operate just as a strong base?

12 In case MeLi contributes to the carbon backbone as a nucleophile, which

electrophilic carbons are available in 40 for docking this methyl?

13 Is this site C4of lactam 40 in view of the vicinity to the C–N bond, given that

a C(CH3)–C(NH2) occurs in 41? Any other site available?

14 On the other hand, what does one do with the trioxabicyclooctane group (the

bulky thing to the right of 40)? Why was this orthoester placed there in the first

place? Is it just protecting a group, possibly of the second carboxylate in cinate in view of its abundance of oxygen atoms, or perhaps a stereochemicalauxiliary to control the enantioselectivity?

suc-15 Is the absolute configuration of product 40 of any significance to mechanism?

16 Is it worth the trouble to draw a 3D rendering to understand the chemistry?

stereo-In this second analysis round, all questions seem relevant These thoughts are

chained sequentially: One question drives your ideas to other queries that were not

in your mind at the beginning

1.4.3 Drawing a First Outline for Guidance

Sketching ideas in one single drawing is always helpful to see them in perspective,organize hypotheses, and discuss them with yourself and fellow mates A well-supported mechanistic sequence can then be proposed with stereochemical featuresincluded (Scheme I.9) Hopefully, you have tried your own and will be delighted

to check that your solution was correct This reaction is much more modest thanScheme I.9 leads one to believe since all it took was (1) 1,4 Michael addition and(2) extensive hydrolysis Details in the latter became necessary to emphasize the

origin of the (s,s) configuration in target 41.

THE BASIC STEPS OF PROBLEM ANALYSIS 13

O R

C 4 chain retained in product

Same nitrogen here, thus R is removed

Stems from bulky group

in 40 ?

Bulky group might exert stereo control

boc O O

O N Li

O boc

O OH

O N

H +

H 2 O

OH O OH

O O

N

45 46

Enantio controlled alkylation

Boc removal

SCHEME I.9

1.4.4 Asking the Right Questions and Proposing the Right

Answers is enough?

In simple situations like the preceding example it may suffice But more complex

problems demand additional considerations because even the right questions will

not crop up easily Read again the previous sentence and then consider the reaction

N N N

Ph

Ph N

N N Ph

Ph

H

N N N Ph Ph

Ph N

POCl3Pyridine C10H16O

1H NMR: d 5.37 ppm, J = 6.2 Hz (1H)

51

52

SCHEME I.10

49 → 50 (Scheme I.10, top) for a few minutes [5] A few obvious questions would

quickly find large roadblocks

(a) Main reaction here? Well, not sure

(b) If unable to answer, at least give a clue of what is happening? Hmm, twocyclohexyl units seem to walk off, heterocycles get busted and rearrangecrazily; definitely messy (increasingly gross language of an ever more anxiousstudent) Who dared to report this oddball?

And then, what relevant question comes next? Options are cut short; thus theanswer remains in an obscure corner As the first few assumptions and questions

failed, this reaction becomes a problem that demands systematic analysis and perhaps

some outside help Because you may need more training as a problem solver (read onand you will get it) before tackling this reaction, let us postpone its discussion untilProblem 49 later on

According to modern psychology, people face and interpret reality through twoparallel channels: the intuitive (System I) and the rational (System II) System I is

of more animal nature, whereas System II is exclusively human, or so we are led

to believe As anybody else, scientists use both systems most of the time every day

of their lives with mixed emphasis and results System I gets the upper hand when

solving problems with insufficient data, a very common predicament.

INTUITION AND PROBLEM SOLVING 15

The subject of the intuitive versus the rational in scientific endeavor has beendiscussed extensively and continues to be a matter of debate The consensus is thatscience cannot rely on intuition alone to achieve anything really valid Intuitionentries, which are humanly unavoidable, should be given some room only in the firststages of analysis of a problem without fully processed evidence After its many suc-cess stories in science, intuition is welcome as a jump start but only to be substantiatedafter careful rational analyses and experiments, and then approved or discarded

For example, consider the 51 → 52 reaction (Scheme I.10, bottom) [6] In providing you with only scant evidence of product 52, I have perturbed deeply (and hopefully)

the basic way of reasoning chemical problems to force a change in your mind settingtowards System I, especially during the first stages of assessment Later on I will pour

in more evidence to substantiate the case and let your wits drift toward System II.What does your intuition tell you? This is what I would predict: After scanning

your eyes swiftly across structure 51 and the empirical formula of 52, you know that

one oxygen atom was lost (intuition fingers OH) Also the1HNMR fingerprint of

a vinyl proton in 52 calls for a trivial cis- elimination of water at the heart of the

mechanism Intuition will also articulate that, as the malicious educator you assume I

am, I should be asking for something more substantial than elementary elimination of

water to explain 52 In the absence of alternatives, your inklings are more inclined to fracture the carbon backbone in 51 to make of this reaction something of substance.

After all, your chemist “chi” feels that cyclobutanols fused to other carbocycles are

prone to shattering by POCl3to dispose of all that ring strain Not bad for intuitionalone, aided with a drop or two of educated guesses

Next, let me throw in a bit of hard information to shove your mind toward SystemII’s rational thinking:1H and13C NMR spectra of product 52 (Figure I.1).

Analysis: The1H NMR data shows three methyl groups in 52, R3C–CH3, =C–CH3,and OCH3.13C chemical shifts support this picture adding the C=C and C–O–CH3carbons Also, no terminal =CH2is there, which would have meant a simple water

elimination in 51 in the direction of the carbinol methyl If so, there is no alternative

pathway but this one: Cyclobutane must be unraveled to accommodate the vinylsystem To this end, a C+ should be established without the β-elimination, likelythrough loss of OH encouraged by POCl3

Solid spectral evidence and our previous knowledge of POCl3 actuation oncarbinols and likely outcomes supplemented intuition in drawing Scheme I.11 with-

out much hesitation Regardless of the two divergent routes A and B, both NMR

spectra discard 55a as an option Also, the high field dd signal at δ 0.6 ppm is

deci-sive evidence in favor of the cyclopropyl structure Compound 55b was indeed the

C10H16O product observed experimentally [6]

While the intervention of intuitive thinking is almost unavoidable and even ing, indulging in instinctive contemplations for too long becomes a high risk attitude

pleas-in science In the next chapters we will deal with the rational systematic approach to

PA in organic reaction mechanism, appealing chiefly to thinking System II And yet,forfeiting System I altogether would not be possible, as half-animals we still are.For more on intuition in science, visit Suppl I # 2 in http://tapsoc.yolasite.com/

51

OCH3H H

B

55b 56

β-elimination

Ring contraction

POCl 3

HCl

SCHEME I.11

REFERENCES AND NOTES 17

1 Solving problems of organic reaction mechanism puts all your capacities atwork: accumulated knowledge, mind responsiveness, imagination, logic rea-soning, and a shed of courage to dare think out of the box occasionally

2 All this high power cerebral commotion is aimed at a single highly focusedobjective: elucidating the reaction mechanism reasonably well, so it demandswell organized and constructive thinking aided by the toolkit of strategiesoffered in this book

3 Pushing forward starting materials with assistance from reagents to get closer

to products as your only line of attack is not such a good idea Planning ahead

is much more productive

4 Mind boggling, distraction, and stumbling into dead ends, common and trating by-products of problem solving, can be avoided effectively by following

frus-an orderly plfrus-an based on the application of those basic concepts most advfrus-ancedstudents and practitioners have dropped behind long ago as too elementary,

in addition to a healthy dosage of advanced concepts and a hefty measure ofpractice and focused perseverance

5 Problems need to be identified as such and analyzed carefully by asking relevantquestions Proposed solutions need to be explored and assessed against goodchemistry grounds A single sketch encompassing preliminary ideas brings

an integrated view for fresh options to show up The amount of informationuptaken by eye-scanning over a plot, figure, or sketch is enormous Exploit it!

6 Although intuition is a valuable tool in interpreting our world and facing manydaily situations, it is of limited use in problem analysis in the hard sciences butuseful when evidence is scant Solutions to mechanistic problems should never

be left entirely to intuition, as bad chemistry will show its ugly head

7 Ultimately, problem solving as part of a profession is a game, no matter howchallenging, for which, in time, one develops an irresistible taste

It is all about orderly thinking up there in the brain This organ, weighing nomore than 2% of your body weight, swallows up 20% of the total oxygen you inhalewhile burning 25% of your daily glucose storage There has got to be a jolly goodevolutionary reason for this and the brain’s PA capacity stands as a most likely andpowerful driving force It is never a bad idea to put it to work for the good reasons

REFERENCES AND NOTES

1 Oppolzer W, Godel T J Am Chem Soc 1978;100:2583–2584 DOI:10.1021/ja00476a071

2 Dodziuk H (Ed.): Strained Hydrocarbons: Beyond the Van’t Hoff and Le Bel Hypothesis.

Weinheim, Germany: Wiley-VCH Verlag GmbH & Co., 2009 pp 49–52 Over 10,000scientific papers deal with strained hydrocarbons at this edition closing

3 Alvarez-Manzaneda E, Chahboun R, Barranco I, Cabrera E, Alvarez E, Lara A,

Alvarez-Manzaneda R, Hmamouchi M, Es-Samti H Tetrahedron 2007;63:11943–11951.

DOI:10.1016/j.tet.2007.09.016

4 Oba M, Saegusa T, Nishiyama N, Nishiyama K Tetrahedron 2009;65:128–133.

DOI:10.1016/j.tet.2008.10.092

5 Moderhack D Liebigs Ann Chem 1996;777–779 DOI:10.1002/jlac.199619960522

6 Ihara M, Taniguchi T, Tokunaga Y, Fukumoto K J Org Chem 1994;59:8092–8100.

DOI:10.1021/jo00105a028