stereochemistry of the reduction of an alicyclic unhindered ketone with some borohydrides and diborane.

Material Information

stereochemistry of the reduction of an alicyclic unhindered ketone with some borohydrides and diborane.
Series Title:
stereochemistry of the reduction of an alicyclic unhindered ketone with some borohydrides and diborane.
Wise, Hugh Edward,
Place of Publication:
Gainesville FL
University of Florida
Publication Date:


Subjects / Keywords:
Alcohols ( jstor )
Aluminum ( jstor )
Amines ( jstor )
Borohydrides ( jstor )
Hydrides ( jstor )
Ions ( jstor )
Ketones ( jstor )
Sodium ( jstor )
Stereochemistry ( jstor )
Stopcocks ( jstor )

Record Information

Source Institution:
University of Florida
Holding Location:
University of Florida
Rights Management:
Copyright Hugh Edward Wise. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Resource Identifier:
030112826 ( alephbibnum )
11069292 ( oclc )


This item has the following downloads:

Full Text







June, 1961


To merely acknowledge the technical assistance provided by

Dr. W. .. Jones in the course of this investigation would not only

understate the case, but also hardly express the author's sincere

appreciation for a relationship which has made Graduate study possible

in an atmosphere of friendly informality. For the patience with which

Dr. Jones has extended many hours of personal time, the author will

almwys be gratefully indebted.

The author vould also like to acknowledge the invaluable support

of his parents in helping him to rise to his present educational

level. without their constant encouragement, faith and financial

assistance made available in crucial periods, it would have undoubtedly

been a much rougher road.













Figure Page

1 Apparatus for Diborane Reduction3 45

2 Apparatus for the Production and Handling of
Aluminum Borohydride 51

3 Typical Gas Chromatograph of a Reduction Mixture 59


A study of the literature indicates the need for additional

stereochemicnl data to aid in further elucidation of the mechanism of

borohydride reductions, particularly in regard to the individual aspects

of each hydride transfer, This need becomes obvious when one attempts

to e::plain some of the stereoisomeric ratios obtained by previous inves-

tigators with reference to their generalizations concerning the nature

of the factors controlling these ratios. Other considerations, such as

the role played by the cation and the solvent, loom as distinct possi-

bilities in accounting for inconsistencies encountered in the appli-

cation of these generalizations, Insofar as the stereochemistry of

diborane reductions is concerned, there appears to be a decided lack of

information published to date.

With this situation in mind, it was decided to establish the

following objectives for this study.

(1) To evaluate the effect of the cation on the average stereochemis-

try of all four hydride transfers from the borohydride ion, as well as

the initial transfer separate from the remaining three.

(2) To obtain stereochemical data on sodium borohydride reductions in

diglyme (previously unavailable) and to use this information to support

or modify the currently suggested mechanism, particularly with respect

to the individual hydride transfers involved.


(3) To obtain stereochemical data on diborane reductions for purposes

of not only testing its consistency with the proposed mechanism in the

light of current stereochemical theories, but also to help clarify the

nature of the last three hydride transfers of the borohydrides.



The name "borohydride" has been adopted for compounds containing

the BH4I ion or its substituted derivatives,' even though they may

actually contain no hydrogen available as a hydride ion. The hydride

of boron, B2 6, has been assigned the name "diborane" and the B33

fragment "borine." Because the borne fragment, not diborane, appears

to be the species involved in the acid-base type complexes formed when

diborane acts as a Lewis acid, diborane is sometimes considered as a

dimerized version of borine.

History of the borohydrides and diborane

The real beginning of borohydride chemistry occurred in 1931, when

Schlesinger and Burg developed an improved method for preparing di-

borane.2 It wasn't until 1940 that this material was used in the synthe-

sis of the borohydrides of lithium, aluminum and beryllium by reaction

of the metal alkyl with diborane.3 Because the borohydrides of aluminum

and beryllium are volatile and because of their experience in working

with these materials, Schlesinger and Brown early in 1941 were requested

by the government to undertake an investigation of new volatile com-n

pounds of uranium.1 In the course of these investigations, improved

methods were developed for preparing starting materials and intermedi-

ates required for the preparation of the uranium borohydrides. As a

result of these efforts '"many new types of reactions were observed and


at least partially investigated, hitherto unknown compounds were dis-

covered, and the field of the chemistry of the hydrogen compounds of

boron was greatly enlarged." This study gave birth to the borohydrides

of sodium and potassium.4

Although the borohydrides were actually discovered before the

aluminohydrides,5 publication of their preparation and use as reducing

agents was stalled because the work was done under government contract

and had to be declassified following World War Il. Consequently,

lithium aluminum hydride became popular as a selective reducing agent

sooner than the borohydrides.6

Meanwhile, the behavior of diborane toward organic compounds conu

training a carbonyl group was noted in 1939.7 However, the development

of the metal borohydrides and aluminohydrides held off further investi-

gation of diborane as a reducing agent for organic compounds until the

late fifties.8

In 1949, Chaikin and W. G. Brown reported the reduction of alde-

hydes, ketones and acid chlorides with sodium borohydride.9 The

specificity of the borohydrides for reduction of carbonyl groups in

compounds containing other reducible groups, their solubility in water,

or alcohol-rater mixtures, and the fact that reductions could be carried

out in simple stirred vessels at atmospheric pressure quickly es-

tablished uses in the pharmaceutical industry. The first of these uses

was in the synthesis of cortical hormones.

During the next few years, the price of the borohydrides dropped

as process improvements were made and markets developed.10 Research

was devoted to seeking methods of increasing the mild reducing power of
sodium borohydride. It was found that the addition of certain metal

halides end alloxy groups would effect this increase.11,12,13 The

elcectivity of the alkaline-earth and aluminum borohydrides was also

noted.14 As a result of these efforts, the reducing power of the

borohydrides was increased to include the reduction of esters, nitriles,

amides and carboxylic acids. These changes, together with diborane,

gave a series of reducing agents which vary from mild to acLivc, from

basic to acidic, to selectively reduce certain functional groups and

leave others unaffected.

The stereochemistry of reductions by complex meta. hydrides

Initial consideration of the factors governing the stereochemistry

of reductions by complex metal hydrides began as early as 1937415.

While studying the relative stabilities of-the epimeric cis-5-hydrindan-
ols, Huckel found that a mixture of alcohols of the came composition a$

that obtained by direct equilibration could be obtained by treating the

alcohol with sodium in refluxing xylene. One isomer was found to pre-

dominate over the other in such equilibria, so that this technique

could be used to study the relative stabilities of the two diastereomeric

alcohols. Several years later, Hughes and Ingoldl6 concluded that the

reduction of a carbonyl group is a bimolecular addition reaction and

should, therefore, be one in which steric factors are operative. The

numerous investigators which followed all used these two factors, often

competitive, to explain the stereochemical consequences of reduction by

complex metal hydrides of a variety of alicyclic and acyclic hetones, as

well as numerous ketosteroids.

In 1949, Trevoy and Brown1 showed that lithium aluminum hydride

(LAR) opens epoxide rings by a bimolecular inversion mechanism,

indicating the possible importance of steric effects They saw a

common storic element in the attack of a complex hydride and a catalyst-

hydrogen complex. In the same year, Jackmann, .t S,, 1 studying the

results of the reduction of a series of substituted cyclohexanones with

aluminum isopropoxide, noted that increasing the steric hindrance of

the carbonyl group by bulky groups on adjacent carbons tended to increase

the yield of axial opimer. They also reduced menthone with the aluminum

derivatives of four secondary alcohols and found that increasing steric

hindrance in the alkoxide group increased the proportion of axial

ihomer. From these results, they concluded that the chief factor de-

termininng the relative amounts of ciL- and tranc-epimere was steric

hindrance about the carbonyl group, but that the relative stabilities of

the two epimers might also be important in some cases.

Noyce and Denney19 in 1950, studied the reduction of a series of

substituted cyclohexanones with LAH and noted the predominance of the

equatorial epimesr Since LAR had already been shown to open epoxides by

an SN2 mechanism, it seems likely that similar addition of hydrogen to a

carbonyl group should also occur opposite to a hindering group to give

a cia_ hydroxyl group. They pointed out that random reduction might be

expected in an unhindered carbonyl group if it were not for the fact

that the activated intermediate complex partakes of the character of the

product, so that marked steric hindrance would be required to prevent

the predominance of the more stable isomer. Applications of these

ideas to ketooteroids was made in the same year by Shoppee and Summoers.20

They made a poor case in attempting to account for a preponderance of

bg~ea-epimer in the reduction of a hetosteroid with LAU by attributing

it to steric hindrance by an angular methyl group in the 4-position,

relative to the carbonyl group, which favored rearward attack by A1H4".

Several studies since then have shown that 4-substituted alkyl groups

make no steric contribution to the reduction of cyclohexanones, so that

this explanation leaves something to be desired.

A year later Nace and O'Conner21 offered additional refinements

to these ideas as a result of their study of the reduction of cholesta-

none with LAH and aluminum alkoxides. They attributed more hindrance on

the 'lpha side to the 5-hydrogen (also on the alpha side) and noted that

increasing the sise of the alkoxy group resulted in an increase in the

yield of alpha-cholestanol. Even though hindrance favored the alpha*

epineride, the beta-epimeride was usually produced in greater quantity

because it is more stable. They concluded from this that the alpha"

producing transition states may rearrange to form the thermodynamically

favored beta-producing transition states,

Meanwhile, the acyclic systems were not being neglected. Cram and

Elhafez22 in 1952, studied reductions of substituted butanones with com-

plex metal hydrides and formulated a rule of "steric control of

asymmetric induction" to predict stereochemical direction in reactions

of acyclic systems in which a new asymmetric center is created adjacent

to an old, "That diastereoisomer will predominate which would be formed

by approach of the entering group from the least hindered side of the

carbonyl group when the rotational conformation of the C-C bond is such

that the carbonyl group is flanked by the two least bulky groups

attached to the adjacent asymmetric center."
In 1953, Barton23 pointed out the greater stability of equatorial

over axial substituents in cyclohexane derivatives and repeated the

generalization of earlier investigators that, in unhindered hetones, the

thermodynamically more stable isomer will predominate in LAH reductions.

He also defined a keto group as being subject to steric hindrance when

it does not react readily with reagents like semicarbazide and the


Several publications on the stereochemistry of hydride reductions

appeared in 1956.24,25 Among these was one by Dauben, Fonken and

Noyce,2 which showed that, in the reduction of alkylcyclohexanones,

changing the reducing agent from LAH to Al(O-i-Pr)3 leads to an in-

creasing proportion of axial (unstable) isomer, They then introduced

new nomenclature by discussing the mechanism of the reduction step with

reference to the ease of formation of the initial metallo-organic comr

plex (steric approach control) and to the relative energetic of the

formation of products aoce the complex is formed (product development


In 1958, Hardy and Wicker27 became concerned about the results

reported by these early investigators and undertook a study involving

the reduction of substituted cyclohexanones with four different re*

agents (KBHI4, aBB4, sodium in ethyl alcohol and aluminum isopropoxide).

They found no support from these results for some of the generalizations

made by previous workers as to the probable mechanism of these re-


An excellent summary of the steric and stability factors and how

they influence the stereoisomeric content of reduction products was

published in 1959 in a study by Beckett, j ~ I.,28 on the reduction of

tropinone using a variety of complex metal hydrides in different solvents.


A recent study by Eliel and Rerick9 provides an example of almost

complete thermodynamic control. In the reduction of 4-t-butylcyclo-

he:anone with LAH-A1C13 (1:4), if additional ketone is added at the end

of the reaction, equilibration of the bulky aluminum-oxygen complexes

results in over 99 per cent of the equatorial isomer.

In surmarizing the stereochemical generalizations proposed by

previous workers it may be said that, in the reduction by complex metal

hydrides of ketones capable of forming diastereoisomeric alcohols, two

factors appear to be operating to determine the ratio of epimers ob-

tained. One involves the competitive attack of the reducing species

upon a hindered versus a less-hindered side of the carbonyl group in

which steric factors are operative. The other involves the relative

thermodynamic stabilities of the two possible orientations of an initial

complex formed by the metal hydride and the carbonyl group. This latter

factor appears to be the more important of the two, especially in

alicyclic systems, and apparently begins to influence the nature of the

product as early as the transition state when orbital hybridization is

changing from sp2 to sp3*

Mechanism of borohydride and dlborane reductions

Brown, Schlesinger and Burg7 first proposed the mechanism for the

reduction of organic compounds containing a carbonyl group with diborane,

This mechanism involves "(1) the intermediate formation of a complex

compound of borine, BH,, with the carbonyl oxygen, followed by (2) the

migration of a proton with a pair of electrons from the boron atom to

the carbon atom of the carbonyl group."

In 1949, two years after he introduced it as a convenient reducing

agent for carbonyl-containing organic compounds,6 W. G. Brown17 proposed

a mechanism for reductions involving ULA with the following comments.

"With few exceptions the known reactions of IAH with organic compounds

consists essentially of the displacement of a strongly electronegative

element (oxygen, nitrogen or halogen) on carbon b hydrogen. Ion-polar

groups, eg., isolated double bonds, are not affected. It is therefore
reasonable to suppose that the reaction proceeds by a polar mechanism.

Moreover, the hydride reactions thus far reported have certain features

in common with the more familiar nucleophilic displacement reactions on

carbon and a common basis in mechanism is indicated. It appears likely

that the reactant is actually a series of complex aluminohydride ions,

AlXnH4-n~ there n progresses from zero to four during the course of a

reaction, which act as carriers for hydride ions." Thus, the initial

hydride transfer is by an incipient A1H4 ion and subsequent stages of

the reaction involve hydride migration in a ketone-A1H3 complex. He

goes on to say that, "in comparison with LAH, the borohydrides of

lithium and sodium differ principally in their lesser aggressiveness. It
is highly probable that the mechanism of their action is essentially

similar, and that their lower reactivity 4 ts a consequence of the greater

stability of the borohydride ion and of the reluctance with which it

transmits a hydride fragment to an electron-deficient center."

Further support for this picture was provided in a kinetic study

by H. C. Brown in 1957.30 It had previously been demonstrated by Garrett

and Lyttle39 that the reduction of 3-alpha-hydroxy-llalpha-acetoxy-

pregnan-20-one by sodium borohydride was second order. to simplify his

study, Brown used isopropyl alcohol as a solvent because it exhibited no

measurable reaction with sodium borohydride over extended periods of time,

and acetone as the reducible carbonyl compound. Second order kinetics
were observed, first order in acetone and first order in sodium boro-

hydride. To account for these kinetics, four successive stages were

proposed. A four-step reaction with second order kinetics was then
R2CO + BH4" k-- H3BOCHR2

PICO + Hg3EOC" -- k2'O- B(OCHR2)2

R2CO + H2B(OCHR2)2" k2.. IB(OCHR2)3

R2CO + BB(00CHR)3" -kz B(OCRIR)4
explained to be "consistent with a slow rate-determining reaction for the

first stage, with successive stages being considerably faster.31 This

explanation was shown to be reasonable by the preparation of the inter-

mediate NaBH(OCHR2)3, and the demonstration that its reaction with

acetone is much faster than the reaction of the ketone with sodium boro-

hydride itself.13 The observed rate constants may either represent the

rate of the direct reaction of borohydride ion with the carbonyl group,

C=0 + BH4 C2-

or it may represent the product of an equilibrium constant K for the
association of borohydride ion and the aldehyde or ketone, and the rate

constant k for the subsequent transfer of a hydride ion to the carbonyl
0 OBH3*

C=-0 + BH4" ... ..*B~I -- -> -P-H
A choice between these possibilities does not appear possible at this


in summary, previous investigators have suggested a different

mechanism for reductions involving diborane than for the borohydrides.

These would appear to require different modes of hydride transfer in

each case. Diborane is a Lewis acid which functions best as a reducing

agent in attacking groups at positions of high electron density. In its

reaction with a carbonyl group, the initial stage is believed to be an

acid-base interaction of BHI3 with the oxygen atom. This results in an

electron deficiency at the carbonyl carbon and is followed by the

transfer of a hydride intramolecularly. The borohydride ion, on the

other hand, functions as a Lewis base which prefers to attack a group

at positions of low electron density. For the first hydride at least,

this would necessarily involve a direct intermolecular hydride transfer

as the borohydride ion (perhaps solvated) approaches the carbonyl carbon

atom, rendered electron deficient by the polarization of he carbonyl

group. The subsequent hydride transfers could then occur intra- or

intermolecularly, depending on whether the remaining hydrides are pro-

vided by the BH3 fragment or, as Brown suggests, by all:oxyborohydride



Selection of the carbonvy compound

It was desirable to have a model compound which would remain

conformationally homogeneous during the course of the reaction in order

that the dinstereoisomeric composition of the products reflect the true

stereochemistry of the reduction step. Uinstein and Holnesc32 have

shown 4-t-butylcylohexyl derivatives to exist preferentially in the

chair conformation and that "the energy quantity by which a _-butyl

group favors the equatorial position is sufficiently large to guarantee

conformational homogeneity," In addition, "the t-butyl group is so

distant from the reaction zone that polar effects due to the _t-butyl

group tend to be small or negligible." For these reasons, 4-t-butyl-

cyclohexanone seemed ideal as the ketone with which to study the stereo-

chemistry of reductions with the borohydrides and diborane.

Selection of the solvent

It was desirable to have a solvent in which the borohydrides would

be sufficiently soluble and with which they would undergo no significant

reaction for the duration of the reduction period. Brown, head and

Rao33 have shown icopropanol and the dimethyl ethers of di* and triethylene

glycol (diglyme and triglyme, respectively) to be solvents which would

satisfy these requirements. To eliminate the possibility of solvent

effects causing differences in the stereochemical consequences of the

various reductions to be undertaken with different reducing agents, it


was decided to use only one solvent throughout the study, Accordingly,

diglyme was selected as the solvent.

Temperature of the reductions

Nace and O'Conner21 found that the isomeric composition upon

reduction of cholestanone by LAN and aluminum alkoxides was greatly

affected by temperature, Trevoy and Brown17 suggested that lower

temperatures increased the "directive effect" on LAH reductions of

l:2-diketones. However, Beckett, aZl .,28 found that changes in the

temperature of reduction had negligible effect on the stereochemical

course of the reduction using sodium borohydride. It was decided,

nevertheless, to minimize any effects caused by temperature differences

by running all reductions at about the same temperature. Most of them

were carried out at 20 degrees in a constant-temperature water bath,

with some undergoing reaction at room temperatures ranging from 24-28


Method of analyzing the products

Wicker34 gives a rather substantial review of some of the methods

that have been used by various investigators for analysis of the

isomeric composition of the products of reduction. Some of the early

work involved the use of refractive indices and densities. Later

workers based their analyses on viscosities and optical rotation.

Considerable work was reported which involved the conversion of the

alcohols into solid esters, fractionally recrystallizing them and running

a thermal analysis (heat of combustion) on the ester fractions. This

latter method proved to be unreliable because of poor material balances.

Still other work was based on incorrect refractive indices given by

earlier investigators and so cannot be considered valid.

Wicker defines "the most reliable method of analysis as one

based on physical properties of the total product in which the values

of the two stereoisomers concerned show a reasonably measurable

difference." In analyzing the methyl cyclohexanols, he favored density

over refractive index because of larger differences between isomers for

the former property. Another method he considers fairly reliable is

based on melting-point composition diagrams, but even this is of

questionable value because it depends on all impurities, e.g., unre-

acted ketone, being absent.

Two methods used with success by more recent investigators28'35

are infrared and gas chromatographic analysis. Results by these methods

compare very favorably with each other and show reasonably good pre-

cision. Also they avoid the serious disadvantage of the other methods,

insofar as the presence of impurities or unreacted ketone does not

drastically interfere with the analysis, which can be carried out on the

total product. For this reason, and the fact that specific information

was available on column packing which had proven effective in the sepa.

ration of 4-t-butylcyclohexanols, it was decided to use gas chroma-

tography as the method of analysis.

Review of the stereochemical considerations involved in the reduction of

4-k.-butylcyc lohexanone

Before turning to a discussion of the results of this study, it

was felt that a review of the considerations involved in the reduction

of cyclohexanone-type compounds might be helpful to the reader unfamiliar

with the steric situation prevailing in such systems. The following

description refers to the figure below.

Axial Plane of sp2
Position /Hybrid Orbitals
S Carbonyl Oxygen

L .-- ---Equatorial


The view is through the plane of the cyclohexane ringS chair

conformation, with the carbon skeleton shaded. For purposes of illus-

tration, hydrogen atoms other than those in the 3,5- and 2,6-axial

positions have been omitted.

According to the mechanism of carbonyl reactions, any species

attacking a carbonyl group must do so from a direction perpendicular to

the plane of the sp2 hybrid orbital, one of which constitutes the siga

portion of the carbon-oxygen bonding, This being the case, the illus-

tration clearly shows that the 3,5-hydrogens are in a position to inter-

act more effectively with any group approaching from direction A than

the 2,6-hydrogens could with any group approaching from directionE B The

basis of this difference lies in the fact that the plane of the carbonyl

group forms an acute angle with the plane of the 3,5-carbon-hydrogen

bonds, while the analogous angle for the 2,6-carbon-hydrogen bonds is

obtuse. Side A is, therefore, said to be more sterically hindered than

side E, a situation which favors approach of an attacking species from

side E with the eventual result of an axially positioned hydroxyl group.

Similar reasoning prevails in accounting for the greater thermo-

dynamic stability of the equatorial position. The greater interaction

of the 3,5-hydrogens with the oxygen atom of the incipient alkoxy group

favors the equatorial position in any equilibrium existing between an

axial-producing and an equatorial-producing transition state. This inter-

action with the 3,5-hydrogens would, of course, be even greater if the

oxygen atom were part of a complex which would increase its bulk.

By way of additional nomenclature, the names cEi and trans are

often used for the axial and equatorial isomers, respectively. These

terms, borrowed from geometric isomerism, have reference to the re-

lationship which the hydroxyl and t-butyl groups would enjoy with respect

to each other if the cyclohexane ring were planar.


Reductions with the borohydrides

A series of reductions was carried out involving the borohydrides

of three different cations with 4-t-butylcyclohexanone in a ratio of

1:4. The objective of this series was two-fold. One was to evaluate

the effect of the cation on the stereochemistry of the reduction. The

other was to provide data on the overall stereochemistry of all four

hydride transfers by exhausting the hydride content of the borohydride

ion* These results had not been previously available for such reductions

carried out in diglyme. The results are summarized in Table 1.

Table 1 ,

Borohydride Average peak height ratio % r.cis-isomer

Sodium 0.295 21.0

Magnesium 0.275 20.4'

Lithium 0.210 15.3

*This value represents an average, as explained in the experimental

The reduction of the ketone with sodium borohydride in a 1:1 ratio

was also investigated. The result was the same as that for the 1:4

reduction above. This supports Bromn's mechanism,30 which maintains

that the last three hydride transfers are rapid and that the first is

the rate-determining step. If one of the hydride transfers subsequent

to the first was slow,- then in the presence of excess borohydride, all

of the hydride content of the borohydride ion presumably would not be

utilized. In this case one should observe stereochemical results

different from the 1:4 reductions. It may be objected that all four of

the reduction steps may have the same stereochemistry. This is hardly

likely, as will be shown to be the case later in the discussion, because

a reducing species of different stereochemical potential is involved in

each of the four hydride transfers.

If the cation is involved in the mechanism of borohydride re-

ductions, one might expect two possible consequences of this involvement.

These concern the reactivity and the stereochemistry respectively.

Previous investigators appear to have devoted their attention

exclusively to reactivity differences between borohydrides of different

cations. Brown,33 for example, ran a reaction involving ethyl benzoate

with lithium and sodium borohydride in diglyme. It was found that the

sodium borohydride reaction mixture lost less than 10 per cent of the

available hydrogen in 24 hours at 75 degrees, while lithium borohydride

reduced the ester easily under the same conditions. Both salts were

completely in solution. He concluded from these results that such

differences in reactivity do not have their origin in colubility differ-

ences of the two salts.

It has been shown that the addition of lithium and magnesium

salts to diglyme solutions of sodium borohydride results in a more

aggressive reduction than can be achieved with sodium borohydride alone..

One possible explanation for this difference in reactivity might be that

the lithium and magnesium ions, because of their larger charge per size

compared to that of sodium, interact with the carbonyl oxygen to increase

the polarization of the carbonyl group. Thi' would render the carbonyl

carbon more susceptible to nucleophilic attack and account for the

increased reactivity resulting from the presence of the lithium and

magnesium ions in the reduction mixture.

No reference appears to have been made to possible cation involve-

ment in the stereochemical aspects of the reduction step. It can be

seen from the results shown in Table I that the presence of sodium and

magnesium ions lead to essentially the same stereochemistry, whereas

the lithium ion resulted in less of the cjs-isomer. Now, if a cation

actually does interact with the carbonyl oxygen, as suggested earlier,

the complex formed by the metal ion and the oxygen would certainly be

more bulky than the oxygen alone. Thus, in the light of concepts

discussed in the introductory section, the transition state should be

subject, at least for the first hydride transfer, to more thermodynamic

control because the bulkier complex would favor the equatorial position

as shown below. This should result in less of the cis-isomer, as is the


Equatorial position

case for the lithium borohydride reduction. The question then arises as

to why the magnesium ion had no such consequences on the stereochemistry

of the reduction, since it has been shown to influence the reactivity.

The most reasonable answer to this would seem to be that although the

presence of the magnesium ion is enough to amplify the polarization of

the carbonyl group, its interaction with the carbonyl oxygen is

apparently not sufficient to appreciably alter the effective size of

the oxygen atom. Thus, its stereochemical effect is negligible.

Reduction with the borohydrides in the presence of amine

One of the problems that has plagued investigators studying the

stereochemical aspects of borohydride reductions is that the product

obtained represents an average of the stereochemistry of all four re-

duction steps, It was recognized from the outset of this problem that,

if some means could be devised to study the stereochemistry of one of

these steps separate from the others, the nature of the reducing species

involved in each of the various hydride transfers might enjoy consider-

able elucidation.

With this quest in mind, perusal of a publication by Brown33

revealed a possibility that, with suitable application, might afford a

method of stopping the reduction after the first step. Brown provided

evidence which suggested that the presence of triethylamine caused the

reduction to temporarily cease after the first hydride transfer. He

found that the reaction of sodium borohydride with acetone in diglyme

at 0 degrees was far from complete even after 96 hours. However, in the

presence of triethylamine under the same conditions, 25 per cent of the

available hydride was lost within five minutes with no further loss for

periods as long as rix hours. He concluded that the catalytic activity

of the triethylamine was due to the participation of the amine in the

first hydride transfer by a Lewis acid-base reaction with the boro-

hydride ion.

1 \ I 6-
Et3N + BH4 + (0C3)2C00 -. Et3N...B..H...C-0 EtSVBH3 + (CHg3)2CHo

Brown goes further and attributes the halting of reduction after

the first hydride transfer to the conflicting steric requirements of

the alkoxyborohydride and the triethylamine. This explanation appears

to be inconsistent with his data and with the mechanism for these re-

ductions which he suggested in a paper published during the following

year, The mechanism indicates that the last three hydride transfers,

involving alkoxyborohydride ions, are rapid. If this is the case, it

is difficult to imagine how the amine could prevent rapid utilization

of the total hydride content once the rate-determining first step had

been accomplished. His data, however, show that only 25 per cent of

the hydride content had been used at the end of six hours. Furthermore,

his data also indicated that only 17.2 per cent of the hydride content

had been used after twelve hours in the absence of the amine. Now,

0.75 of this hydride contents or about 13 per cent, must have been

due to the loss of the last three hydrides, since this occurs rapidly

once the first hydride is lost. In the came period of time, the re-

duction mixture with the amine lost 32 per cent of its hydride con-

tent, only 7 per cent more than the 25 per cent lost within the first

few minutes of reaction. From these results, one can hardly conclude

that the alkoxyborohydride ion is present in the amine reduction

mixture, much loss its steric interaction with the amine.

A more reasonable explanation for the lack of further reduction

following the first hydride transfer in the presence of the amine is

that the borine fragment is completed by the amine. This complex is

then sufficiently stable under the reaction conditions to avoid the loss

of any additional hydride ions for several hours (at least six hours,

according to Brown's data).

Certain observations made during the course of the present

investigation strongly suggest the presence of the amine-borane complex

in these reduction mixtures. If the reduction mixtures are simply

hydrolyzed in acid solution (not subjected to the KIO3 workup explained

in the experimental section), infrared indicates a B-H stretch at 4.2-

4.3 microns for the pentane extract of this hydrolysis mixture. If the

hydride had not been rendered stable to acid attack by being completed,

these conditions would normally be severe enough to cause any hydrogen

bonded to boron to be liberated rapidly as molecular hydrogen. Synthe-

sis of the triethylamine-borane and comparison of its infrared spectrum

with that of the reduction mixture confirmed its presence in the re-

duction mixture beyond any reasonable doubt,

Further evidence that the amine is involved in a complex was pro-

vided by gas chromatographic analysis of this same pentane extract and

the observation of a peak corresponding to triethylamine (evaluated by

a separate injection of the pure amine). The acquisition of this infor-

mation was accidental and proved to be costly, because it resulted in

the gas chromatographic column being made useless for further analyses

of the alcohols.

The danger of ruining the gas chromatographic column by injecting

a reduction mixture containing residual amounts of the amine-borane

complex requires some additional comment. It was noted on the gas

chromatograph which recorded this incident that, although the peaks for

the alcohols were absent, a large peak of short retention time appeared

which was not recorded for the 1:4 reduction mixtures. To ascertain the

cause of this peak, some triethylamine-borane was synthesized and in-

jected into the vapor fractometer. An identical peal resulted. This

was followed by an injection of triethylamine, again with similar

results. It was concluded from this that the peak was due to tri-

ethylamine. Therefore, the amine-borane complex must thermally decom-

pose on contact with the hot injection block to produce the amine and

diborane. The diborane must then react with the column pacing causing

it to absorb the alcohols, because their peaks were never observed

thereafter using that particular column,

A series of reductions was carried out involving the borohydrides

of the same three cations used previously with 4-t-butylcyclohexanone

in the presence of a tertiary amine in a 1:1:1 ratio. The intent of

this innovation, to reiterate the considerations discussed above, was to

use one hydride only from each borohydride ion, the remaining BL,

fragment completing with the amine to form a so-called amine-borane

complex. Thus, the stereochemistry of the first hydride transfer could
R2CO + BHF R2CHO + B113

BH3 + (C2115) 3N-- (C25)3 311: B3
be observed independently of the remaining three. The results of this

series of reductions are summarized in Table 2.
S Table 2
Calc'd avg. % cis-isomer
Avg. pk. ht. for the last three
Borohydride ratio % ci-isomer hydride transfers
Sodium 0.242 16.4 22.5
Magnesium 0.209 15.2 22.1
Lithium 0.166 12.8 16.1

The results for sodium and magnesium are essentially the same,

at least within the experimental error inherent in the analytical

method. The lithium gave slightly less of the cis*isomero which is

consistent with the results of the lithium borohydride in the 1:4

reduction, In that reaction the average per cent cis-isomer for all

four hydride transfers was less than that of the other cations, so it is

reasonable to expect a proportionately smaller yield of cis-isomer for

the first hydride transfer of the lithium borohydride in this series for

.the same reason previously described.

It is reasonable to suspect that reduction may not cease entirely

with the formation of Et3N:BH3 in the presence of excess ketone, since

Brown's data indicates a decrease in hydride content of more than 25 per

cent after twelve hours. However, even though the reductions in this

series were run for as long as two days, insurance against further re-

duction after the first step was obtained by adding only sufficient

ketone to utilize one hydride from each borohydride ion, It has been

already pointed out that the amine may participate in the first hydride

transfer, If this possibility actually obtains, then a reducing species

which is bulkier than the borohydride ion may be anticipated. This should

lead to an increase in the cis-isomer content of the product because of

the increased steric requirements of a larger reducing species. Therefore,

the values in Table 2 represent a maximum value for the first hydride


These results allow calculation of the average stereochemistry of

the last three hydride transfers from the borohydride ion. This calcula-

tion is based on the following equation, where X is the average per cent

e-issomer for each of the last three reduction steps,

Per cent c.-isomer from first step + 3X/4 = per cent cis-isomer from

all four steps

These calculations have been made for all three of the borohydrides used

and are entered in the last column of Table 2.

An independent calculation of the stereochemistry of the first

hydride transfer was made using a calculated average of the last three

steps. The calculation of the average stereochemistry for the last three

hydride transfers was made by simulating the most probable situation

following the intermolecular transfer of the first hydride, 3 ketone

plus 0,9 alkoxide plus excess diborane. This reaction yielded 19,4 per

cent cis-isoner. Hydrolysis of a sample of the alkoxide showed it to

contain about 1-2 per cent c s-isomer, The calculation was as follows.

2.0 + 3X / 3.9 19.4 X = 24.5 per cent cislicomer

The 24.5 per cent doesn't correspond exactly to the other value of 22.5

per cent, but it is sufficiently close to provide support for a figure

somewhere in this range. This result and the result previously obtained

for all four hydride transfers (21.0 per cent) permit calculation of the

first reduction step as follows.

X + 3(24.5) / 4 = 21.0 X = 10.5 per cent SJ_-isomer

Now, because a 1 per cent error either way in the 24.5 or 21.0 per cent

figures can cause X to vary from 3.5-17.5 per cent, one cannot be certain

of the significance of this calculated value of 10.5 per cent. It is,

however, in the right direction to support the experimental results pre-

sented here which indicate that less ciS.isomer is produced in the first

reduction step than in the last three.

In conclusion, the borohydride ion was suggested as the reducing

species for the first reduction step. According to the principle of

steric control, it should give less of the cis-isomer than the more

bulky alkoxyborohydrido groups which follow in the last three reduction

steps, because it can approach the carbonyl group from an axial direction

with less steric interaction, Therefore, the stereochemical results of

this series are entirely consistent with both the previously suggested

mechanism for borohydride reductions and the partial control of

diastereomeric ratios by a steric factor.

Reduction of the ketone with NaBH4 in the presence of tertiary amines

In order to investigate the possibility that structural changes in

the tertiary amine used might change the stereochemical consequences of

its presence in the reduction mixture, amines other than triethylamine

were considered. The amine, ketone and sodium borohydride were combined

in the usual 1:1sl ratio to give the results in Table 3.

Table 3

Amine Kb Avg4 pk. ht. ratio % cis-isomer

Triethylamine 5.65 x 10*4 0.242 16.4

Pyridine 1.4 x 10*9 0.261 18.6

N,N-Dimethylaniline 2.4 x 10*10 0.308 21.0

Triisopropylamine was also originally included in the series, but

its amine-borane complex proved to be so stable that it resisted all

attempts at its decomposition. Consequently, the stereochemistry of

reduction in its presence was not determined.

Although it is obvious from these results that there is no relation

between the stereochemistry of the reduction and the stereostructural

aspects of the amine, it will be noted that there appears to be almost a

direct correlation between the basic strength of the amine and the pro-

portion of cia-isomer obtained, This can be explained in the following

manner. It is reasonable to assume that the stability of the amine-

borane complex, formed after the first hydride transfer from the boro-

hydride ion, will be determined by the ability of the amine to function

as a Lewis base. Thus, the pyridine and N,N-dimethylaniline are weaker

bases than the triethylamine and their complexes would be anticipated to

be less stable* It has already been demonstrated that negligible re*

duction occurs after the first hydride transfer in the presence of tri-

ethylamine, so that the stereochemistry of this reaction can be con*

sidered a limiting case for the series. The fact that a higher pro-

portion of the cis-isomer was obtained for the pyridine and N,IU-

dimethylaniline is consistent with the possibility that their complexes

were not stable enough to prevent further reduction. If this is the case,

the stereochemistry of the reduction involving pyridine and N,N-

dimethylaniline would be expected to approach that of the borohydride ion

alone. This, of course, was observed.

Reduction with diborane

To our knowledge, the stereochemistry of the diborane reduction of

a carbonyl group has never been examined Geperimentally. The proposed

mechanism for the reaction postulates an initial interaction of the BB3

with the carbonyl oxygen, followed by intramolecular hydride transfer.



It was, therefore, of interest to obtain stereochemical data for this

reduction and evaluate its consistency with the proposed mechanism.

According to Burg, Brown and Schlesinger, excess diborane reacts

readily %with acetone to produce the corresponding dialkoxy derivative

of borine, (RO)2BH. they attempted to isolate the monoalkosy deriva-

tive, but were unable to do so, This indicates that the first two re*

duction steps with diborane must be rapid and the third step is slow

With an excess of the ketone the trialkylborate ester was formed, in-

dicating that the BRE was forced to utilize all three of its hydride.

When these two.diborane reductions were carried out in the present

investigation using 4-.-butylcyclohexanone, a difference ia stereo-

chemistry was observed# The results are shown in Table 4.

_able 4

Type of reduction Avg. pk. ht. ratio % cig-isomer

Ketone + excess diborane 0.0813 7.6*

Diborane + excess ketone 0.180 12,6

*This is an approximate value, since the gas chromatographic standard
curve is not considered reliable in this range.

rhus, when only two of the hydrides are utilized, 7.6 per cent is ob-

tained, whereas use of all three hydrides yields 12.6 per cent of the


These results are consistent with a change in stereochesistry for

the last hydride transfer which may be calculated as follows.

2(7,6) + X / 3 12.6 X 22.6 per cent is*isomer

They also lead one to suspect an intermolecular hydride transfer for this

step. This is because an increase in the amount of cSO-isomer generally

means a larger reducing species being forced to approach the carbonyl
group more equatorially, transferring its hydride intermolecularly, to

give the axial hydroxyl group in the final product.

To determine if any equilibration of the isomers was taking place

under the reaction conditions, a mixture of the alcohols containing

more than 40 per cent of the cis-siomer was treated with diborane.

Analysis of the mixture following this treatment showed the isomeric

ratio to be unchanged, If equilibration had occurred, one would antici-

pate an increase in the amount of .trans-isomer.

At the same time, these results are somewhat puzzling in the light

of Bromw's suggested mechanism7 for diborane reductions, because one

would expect the dialkoxyborine to function as a Lewis acid, coordinating

initially with the electrons of the carbonyl oxygen and then transferring

its hydride intramolecularly. If this expectation actually obtains, it

becomes difficult to rationalize the increase in cis-isomer for the final

step of the diborane reduction because the dialkoxyborine-oxygen complex

should be forcing the transition state toward the equatorial position,

as shown below.

S+ .I ..---Equatorial position

The transfer of the hydride should then logically occur on the axial

side and should lead to an increase in the trans-isomer content of the

product. A way out of this dilemma presents itself in the postulation

of an intermolecular hydride transfer for the third step of the diborane

reduction and one is forced to seriously consider this possibility in

view of the stereochemical results. This transfer is structurally

represented as follows,
(RO) 2B + R2CO B (OR) 3
6+ C...H...B(OR)2
further elucdation of the mechanism of borohydride reductions from

the stereochemical results

Evidence has been presented thus far in this discussion to indi-

cate that the reducing 'species involved in the first hydride transfer

is the BH4" ion. Calculations made possible by experimental results

from the various reductions have established that the proportion of

c*ASisomer produced in each reduction step tends to increase with suc-
cecding steps. This has been the case for both borohydride and diborane

reductions and is consistent with the production of a progressively

bulkier reducing species following the transfer of each hydride.

the question then becomes, from what species are the last three
hydrides transferred? Two series of hydride donors become possibilities.

One is BH3 and its alkoxy derivatives, ROBH~ and (RO)2BH. The other is

the alkoxyborobydridee, ROBH3 (RO)2BHU and (RO)3BH suggested by

Brown. To distinguish between these, the stereochemistry of a reduction
in which the BH3 was forced to use all three hydrides was found to

average 12.6 per cent cis-isomer. It may be reasonably concluded from

this that the last three hydride transfers do not involve the alkoxy-

borine series because the results would be similar to those previously

calculated (22.5-24.5 per cent) for these steps. Therefore, in the last

three hydride .transfers* one and possibly all three involve an alkoxy-
boolhydride ion as the reducing species.

Brown't work7,30 indicates the relative reducing properties of the

hydride donors in the two series to be as follows.

(RO)3BH ) (RO)2BH- > ROBH3

The (RO)3BH ion has been demonstrated by Brown (for the case of tri-
isopropoxy-borohydride) to reduce more rapidly than the BI4" ion. The

(RO)2BH is unlikely as the hydride donor for the fourth step because it

is less reactive than its two predecessors. The (RO)3BE'" is therefore,
favored as the reducing species for the final step.

A further distinction in the nature of the reducing species involved

in the middle two steps should be possible if stereochemical results for

the last step could be obtained, These would be available from the re-
duction of 4-t-butylcyclohexanone by its trialkoxyborohydride ion. This

would allow the average stereochemistry of the second and third hydride
transfers to be calculated, since the stereochemical results of both the
first and all four reduction steps are known. There is good evidence

from the work of Brown, Burg and Schlesinger7 that the reaction of the
ketone with excess diborane involves the SBH and ROBB2. The average
stereochemistry of these two reduction steps has been experimentally
determined in this investigation. Therefore, by a comparison of the

stereochemistry of these two steps with that calculated for the second

and third steps of the borohydride reduction, one should be able to draw

some tentative conclusions as to whether steps two and/or three involve

an alkoxyborohydride ion.

Unfortunately, all attempts to prepare the sodium trialkoxy-
borohydride of 4-t-butylcyclohex-anol gave a product which on analysis

proved to be of uncertain identity. Most disappointing of all, perhaps,

was that this product had no apparent reducing properties. Even the

somewhat different tack of ni::ing a diglyme solution of the ketone with

NaH in the presence of the borate ester of the alcohol in 1:1:1 ratio

failed to achieve any obvious reduction. All this, of course, made

further elucidation of the mechanism of borohydride reduction by the

above approach virtually impossible.

Reduction with aluminum borohydride

It was originally intended to study the stereochemistry of aluminum

borohydride reduction as an example of the behavior of Group II1 boro-

hydrides, so that the results could be compared to those of Groups I and

II, in an effort to evaluate the effect of the cation on the stereo-

chemistry of these reductions in a homologous fashion. However, as the

acquisition of experimental results shown in Table 5 progressed, it be*

came increasingly apparent that they could be more profitably discussed

separately from the results obtained from the borohydrido reductions

involving the other cations.

The reductions of 4-t-butylcyclohexanone with aluminum borohydride

were of two types, those carried out in the presence of triethylamine

and those in which the amine was absent. The stereochemical results are

summarized in Table 5.

In the absence of amine, the reducing species may be the undis-

sociated Al(BH4)3, or it could conceivably be some dissociated form

which yields free borohydride ions. The results of these reductions

are so similar to comparable ones of the other borohydrides that, if

the latter case prevails, the stereoicomeric ratios could be explained

in the came manner.

Table 5

Molar ratios in reduction mixture
Al(BH4)3 Ketone Et3N Avg. pk. ht. ratio % cis-isomer

1 12 0.299 20.3
1.5 12 0.295 19,9
1 2.2 2.5 0.342 23.5
1 3 8 0.453 32.5*

*The gas chromatography standard curve used did not extend as far as the
peak height ratio obtained for this product. Therefore, the standard
curve for another similar column was used, .which did cover this range,
and indicated a value of 34.5 per cent for thick peak height ratio.,
Since the slopes of the two curves were about comparable, comparison of
values in the range where they covered the same ratios showed a -2 per
cent difference. Hence, subtraction of 2 per cent from the value
obtained from the other curve gave 32.5 per cent.
However, if the former possibility obtains, the similarity of the

results would be simply coincidental because in all likelihood a larger

reducing species is involved in the first step which is considerably

different in character from the borohydride ion itself. Schlesinger

and Burg3 interpret its structure as containing three BH4" groups, which

are so extensively distorted by the small highly charged aluminum ion,

that the ionic character of the molecule has largely, if not completely,

been lost. An examination of the physical properties of aluminum

borohydride also indicates the bonding involved to be much more covalent

in nature than that of the other borohydrides,1 i.e., lower m.p., b.p.,

higher volatility, etc.36

In those reductions involving the amine, it will be noted that

increasing the concentration of the amine causes.a sharp increase in

the cis-isomer content of the product. Theoretically, each mole of

A1(BH4)3 should require three moles of amine to stop reduction after

the first hydride transfer from each of the three borohydride.groups.

However, if it is assumed that the aluminum ion itself, because of its

electronic configuration, is capable of acting as a Lewis acid toward

the amine, then a fourth mole of amine could conceivably be utilized by

the reducing species, Inclusion of a two-fold (4 x 2 = 8) excess of the

amine in the reduction mixture resulted in 32.5 per cent aci-ioamer,

which is probably the maximum value obtainable for this type reduction.

These results argue strongly in favor of the aluminum borohydride

functioning in an undissociated form, at least for the first reduction

step, because free borohydride ions have been previously shown to givo

only 16.4 per cent cis-isomer in the presence of triethylaminie.

The remaining question is why the two reductions involving amine

differed in their stereochemistry with a change in the relative amine

concentration. It will be noted that, in the reduction in which the

amine was not in excess, there is less than the four moles which could

be theoretically utilized by the reducing species~s In fact, there is

not even enough for the three borohydride groups. Hence, the 23.5 per

cent cS~-isooer obtained is probably a result of the reduction being

allowed to proceed beyond the first step because of insufficient amines,

If this is the case, the diastereomeric ratio could be anticipated to

approach that of the reduction in which no amine was involved. This

would account for the observed results.

Summary of conclusions from the results

Lithium borohydride was found to give less cSgjalcohol than either

sodium or r-,Gnesium borohydride when all four of the hydrides were

utilized. Differences in the degree to which the cation interacts with

the carbonyl oxygen was advanced as an e:-=plnation for these results.

Stereochemical data for aluminum borohydride reductions was obtained in

the absence and presence of triethylamine. This information is con-

sistent with the aluminum borohydride functioning as an undissociated

molecule for the first hydride transfer.

A means of investigating the stereochemistry of the first hydride

transfer from the borohydride ion was made available by reduction in the

presence of triethylamine, because of the formation of an amine-borano

complex following the first hydride transfer. This was found to give

less of the SIg-alcohol than the average of all four reduction steps.

Therefore, more cls-alcohol must be produced in the last three re-

duction steps than in the first, which is consistent with a progressively

more bulky reducing species being forced to approach l-ho carbonyl group

from an equatorial direction.

The influence of structural changes in the tertiary amino used on

the stereochemistry of the reduction was investigated by considering

amines other than triethylamine, Ho relation was found between the

stereostructural aspects of the amine and the stereochemistry of the re-

duction. However, there appeared to be an almost direct correlation

between the basic strength of the amine and the proportion of c9s-isomer

produced. The stability of the amine-borane complex formed was ad-

vanced as an explanation for this relationship.

Previously unavailable stereochemical data for diborane reductions

was obtained which indicated a change in stereochemistry for the last

reduction step. The direction of change was consistent with an inter-

molecular transfer of the last hydride from diborane.


The reaucrig species ,involved : the first hydride transfer of
borohydride reductions is logically the -Sia toa* 'The average stereo-
chemistry of the last three steps has beea calculated. When these
calculated results were comparOr to those obtained when diborane was:
forced to exhaust its hydride content, it was concluded that one or all
of the reducing specie's i the last three reduction step are alkoxy-
borohydride ions, as opposed t tothe involvement of borne and its alkoxy





MgC12, anhydrous

Diglyme, Ether 141

isomericc mixture)


NaH, 53 per cent dis-
persionn mineral oil

B?3 etherate complex

Metal Hydrides, Inc.

Metal Hydrides, Inc.

Amend Drug and
Chemical Company

Ansul Chemical Company

K and K Laboratories

Dow Chemical Company

Metal Hydrides, Inc.

Allied Chemical




Procedure of Brown33
Mead and Rao. Reflux
and distill over CaH.
Redistill under
vacuum over WAII as


Recrystallize once
from pentane to bring
m.p. within 2 degrees





(free from mono)

Eastman Organic

Fischer Scientific

Hatheson, Coleman
and Bell

Distilled over acetic
anhydride. Redistilled
wver KOH pellets after
drying over anhydrous

None (reagent grade)


I er -*.ir *- k 'A-*1 I -1 -'l = Iw I .. -0^

M-t i l

Sourc a

Diglyme solutions of the borohydrides and hetone

Diglyme solutions of NaBH4, LBH4 and ketone were made up so as to

contain as close to one male per milliliter as possible.

Sodium ~broaydride solution. A 100 milliliter volumetric flask

was baked dry, flushed with dry nitrogen, corked and tared accurately.

It was then placed in a dry box under an atmosphere of nitrogen which

had been scrubbed with concentrated sulfuric acid and passed over

magnesium perchlorate. Because it is quite hygroscopic, the NaBH4 was

weighed approximately on a triple beam balance in the dry box. The

flask and its contents were then removed from the dry box and weighed

accurately. The flask was reintroduced into the dry box and freshly

distilled diglyme added until the solution was up to volume. Since the

solvation of NaBH4 is an exothermic process, the flask contained some-

what less than the correct volume when its contents cooled to room

temperature, so additional diglyme had to be added at that time. Even

after swirling for some time and allowing the solution to stand over-

night, a fine precipitate persisted on the bottom of the flask. The

supernatant liquid was withdrawn from the volumetric flask, still in the

dry box, with a long-needled hypodermic syringe and placed in a bottle

fitted with a rubber stopper suitable for multiple syringe withdrawals.

The solution was then removed from the dry box and one milliliter

aliquots titrated with standard KIO3 to determine the actual hydride

content. 'roma this the solubility of NaBH4 in diglyme was found to be

0.827 mole per milliliter,

Lithium borohydride solution. A 25 milliliter volumetric flask

was baked dry, flushed with dry nitrogen, corked and placed in the dry

box. Enough LBB4 was then weighed into the flask so that it exceeded

the solubility limits of the salt in 25 milliliters of diglyme (0.4493
grams),. It was made up to volume in diglyme and swirled, to promote

solution. This solvation process was also exothermic so that similar

precautions bad to be taken concerning the final makeup to the correct

volume, All of the UBIt4 did not dissolve because of the deliberate
excess of the solubility limits. One milliliter aliquota of the super*

natant liquid were withdrawn still in the dry box, and removed for

titration with standard KI03 for hydride content. From this the solu-

bility of LiUR4 in diglyme was found to be 0.5602 mvole per milliliter.
Ketone solution. Since the ketone is not hygroscopic, it was

weighed accurately outside the dry box into a 100 milliliter volumetric

flask which had been baked dry and flushed with dry nitrogen* The flask
was then introduced into the dry box and diglyme added up to about 5-

10 milliliters less than volume, The solvation of the ketone was an
endothermic process, so that on coming to room temperature, the volume
increased. The solution was then made up to volume, transferred to a

syringe bottle with the special rubber stopper and taken out of the dry

box. The ketone was extremely soluble in diglyma, so that no trouble
was encountered in getting 0.1 mole into the 100 milliliter of solvent.
Method of analyzing the borohydrides by titration

Determination of the tnoles of boron per gram of sample.7 The

sample was weighed (precautions taken against hydrolysis by moisture
in the air) and hydrolyzed by addition to water. Sodium ion was analyzed

as base by titrating to a methyl red end point with standard 0.1 N qHC

and boron as boric acid by titrating, after the addition of mannitol, to

a phenolphthalein end point with standard 0.1 N NaOH. hese two ti-
trations were run on the same sample. From this data, the mmoles.of

boron per gram of sample was calculated.

Determination of the moles of hydride tesr aram of sample.10 A

weighed sample was added to a known excess of standard KIO3 solution.

Water and an excess of IK were added after a few minutes of stirring.
The solution was then acidified with 10 per cent 0C1. If iodine pre-

cipitated, more EI was added until it all went into solution. After

neutralizing with NaBCO3 to prevent air oxidation of iodide to iodate,

the iodine solution was titrated with standard sodium thiosulfate
solution, using starch as an indicator, to a colorless end point. The

difference between the ieq. of K103 and Na2S203 indicated the number of

meq. of hydride reduced. Since there are two mteq, per mmole of hydride,

the number of meq, of hydride had to be divided by two to calculate the

number of roles of hydride per gram of the ample.

Calculation of the /lJ Since the mole of both hydride and boron

per gram of sample were now hInown, the ratio of moles hydride per mole
boron in the sample could be calculated.

General procedure for borohAdrde reductions of i the kot.on
A specially prepared 13 milliliter tube, sealed at one end, was

baked dry, flushed with dry nitrogen and capped with a rubber stopper

suitable for injections. The solutions were injected in appropriate

amounts using a hypodermic syringe of 2 ec. capacity, which had also

been baked dry. The tube was then placed in a water bath at 20 degrees
for two or three days, during which time it was removed periodically and

agitated. As far as specific quantities are concerned, the borohydrides

were usually used in 3 millimole quantities and the I:etone and amino
added in proportionate quantities depending on the ratio under con-


The general workup procedure for a 1:4 reduction mixture was to

pour it into 1004*150 milliliters of water, add several drops of con-

centrated IE1 and shalce thoroughly in a separatory funnel to hydrolyze

the alkoxyborohydride solid which formed in the reaction tube several

hours after injection of the reduction mixture. The alcohol usually

floated to the surface on standing after the shaking. Pentane was then

added to dissolve the alcohol and the entire mixture was shaken to

extract any remaining alcohol. The aqueous layer was then discarded and

the pentane layer washed twice with dilute HC1 and, finally, once with

water. The pentane solution was dried over anhydrous sodium sulfate and

concentrated on a steam bath to about 5 milliliters through a one foot

column packed with steel sponge.

The general procedure for working up a 1:1:1 amine reduction

mixture was to pour it into a mixture of 10 milliliters of isopropyl

alcohol and 10 milliliters of 10 per cent K103 solution which had been

mixed in such proportions with water (usually about 20 milliliters)

that a clear solution was obtained. The purpose of this was to dcccn-

pse the amine-borane complex which formed after the first hydride

transferred from the borobydride ion, After shaking this mixture in a

sepazatory funnel and allowing it to stand for about fifteen minutes,

pentane was added to extract the alcohol. After draining the aqueous

layer, the pentane layer was washed twice with dilute HC1 and once with

water. Sometimes iodine formed in the aqueous layer upon addition of

the acid. This was removed by washing with 10 per cent sodium thio-

sulfate solution followed by water. The pentane solution of the alcohol
was dried over aphydrous sodium sulfate and evaporated as in the case of

the 1:4 workup. Before this solution was injected into the column, it

was checked for B3H stretch (4.2*4.3 microns) by infrared to avoid

ruining the column, as explained in the discussion of results. If the

B-H stretch appeared in the spectrum, the workup procedure was repeated.

Magnecium borohydride reduction mixture

Kollonitsch, Fuchs and Gabor14 reported the preparation Of alkaline

earth borohydrides by the reaction of a3BH4 with the appropriate metal

chloride. These reactions were carried out in extremely dry alcoholic

solutions, giving about 80 per cent yield based on the amount of unre-

acted WaBH4. Application of this metathetical process for the production

of It(H4)2 to the problem at hand consisted of generating the magnesium

borohydride Z situ by mixing NaBI4 with anhydrous IgC12 in diglyme and

adding the ketone to this mixture. To ascertain whether the r~anesium

ion was actually involved in the reduction step, a series of four re-

ductions was set up in which the quantity of FMCl was varied from

stoichiometrically sufficient to 0.25 that amount. All of these re-

ductions gave essentially the same isomeric mixture. However, the

extent of reduction was directly dependent on the amount of 11C012 present

for equal reduction times. The proportions of the reactants were:

4 ketone + 1 NaBH4 + X KgCl2.
X 4 Avg. pk. ht. ratio % cis-isomer

0.500 0.275 19.6
0.375 0.297 21.2
0.250 0.290 20.7
0.125 0.297 21.2
i ~ ~ ~ ~ II-lJI IlI

Zaducti. with diborane
Diborane was generatedd external to the reaction flask by adding
diglyme saturated with NaBH4 to 1F3 etherate. The generator consisted

of a 50 milliliter flask fitted with a stopcock. joint and oblique side

arm capped with a rubber serum bottle cap through which injection of the

NaBUH solution took place. The generation procedure was to flush the

system with nitrogen admitted through the side arm yv a hypodermic

needle. The stopcock Was then closed and the joint removed with the

nitrogen continuing to flow. Apprcximat .ly 25 milliliter of BF3

etherate was added to the flask amid voluminous clouds of fumes and the

stopcock joint reinserted. After additional flushing of the system,

injection of the NaBH4 solution was initiated and continued in increments
sufficient to create a steady flow of gas as evidenced by the bubbles

in the reaction flask. Nitrogen flow was stopped when generation of the

diborane began. Diborane which escaped reacting in the reaction mixture

was exited through an acetone trap and vented to the hood.
Previous to this operation, solid ketone and, in one reaction,

sodium salt of the alcohol had been weighed and added to the reaction

flask while it was being flushed with nitrogen. Enough diglyrm was
added to bring the end of the addition tube* fitted with a scintered
glass plug, just below the surface. The reaction flask contained a

magnetic stirrer which was used to agitate the contents from time to

time. The connecting joints Were all secured to their respective flasks

by means of wire and rubber bands to prevent the positive pressures

developed from within from dislodging them. The reaction flask was later
modified to a tube with a side arm and the magnetic stirrer discarded,

To acetone trap


Reaction Tube

Apparatus for Diborane Reductions

Figure 1.

agitation being provided by the bubbling action. All apparatus, in-

cluding the hypodermic syringe, was dried in an oven prior to use. The

reaction tube and generator are illustrated in Figure 1.

The workup of these reduction mixtures was identical to that of

the 1:4 borohydride reduction mixtures described previously.

Preparation of the sodium salt of 4-Z-butylcyclohexanol

Several methods of preparing the alkoxide were attempted before a

usable product was obtained, These include tl.- -caction of the alcohol

with small cubes of sodium metal in dry hexane in a nitrogen atmosphere

and the reaction of the alcohol with sodium metal in a sealed tube

heated to about 110 degrees. Analysis of the product obtained by these

methods was carried out by hydrolyzing weighed samples and titrating

with standard acid. The results indicated contamination of the product
to be as much as 50 per cent, both high and low. Cunningham relates

a method of preparing an alcoholate of more than four carbons by re-

fluxing the alcohol with another alcoholate of lees than four carbons,

the two alkoxy groups mutually displacing one another and the more

volatile alcohol distilling off to shift the equilibrium in favor of

the alcoholate of more than four carbons. This method wan tried by

attempting to cause 4-g-butylcyclohexanol to react with sodium methylate

in diglyme. IHoever, no methanol was distilled over at temperatures up

to 100 degrees, so the procedure was abandoned. Synthesis of an alkoxide
product suitable for use was finally effected by stirring a mixture of

53 per cent NaH-mineral oil dispersion and alcohol in diglyme at a

temperature of about 130 degrees until evolution of hydrogen (volume

measured on a wet test meter) had ceased. The slurry was filtered under

nitrogen and the residue transferred in a dry box to a sublimation

apparatus where the remaining diglyme and alcohol were removed by

heating overnight under vacuum. Analysis of the product was as pre-

viously indicated and, in addition, the alcohol resulting from hydroly-

sis was recovered and weighed. The recovered alcohol was analyzed by

gas chromatography and found to be essentially pure trans-icomor (1*

2 per cent pis-isomer).

In analyzing the product, it was assumed that all of the alcohol

was removed from the reaction product by sublimation and that the

principle contamination is NaOH. Using two equations and the two un-

lmowns, the per cent alkoxide found in two samples was 78 and 77 per

cent. Calculating the per cent alkoxide from the recovered alcohol

of the same two samples gave 68 and 74 per cent respectively. A value

of about 70 per cent purity was used in calculations involving the

alkoxide. The analyses above would indicate this to be a valid esti-

mate of the minimum alkoxide content of the product.

Preparation of sodium trialkoxyborohydride and attempts to utilize it

in the reduction of the ketone

Into a 250 milliliter 4-necked flask fitted with a thermometer,

nitrogen inlet and wet-test meter was placed NaBiH and the commercial

mixture of the alcohols in a 1:3 ratio respectively. The system was

flushed with nitrogen and diglyme added to dissolve the contents of

the flask. The mixture was heated to 130 degrees with agitation by a

magnetic stirrer and maintained under these conditions for about five

days until no more hydrogen was evolved, as indicated by the wet-test

meter. Comparison of the volume of hydrogen obtained with the

calculated amount indicated the reaction to be 97 per cent completed.

A thick slurry gradually formed during the course of the reaction. The

solid was filtered under nitrogen i~ a special saintered glass filtering
apparatus and the residue dried by heating under vacuum.

Analysis of the product consisted of establishing its H/B by
titration and microanalysis for carbon end hydrogen. Two of the above

preparations were:undertaken. Titration analysis of the first gave a

H/B of 0.499, while that of the second wa. 0*209 Microanalysis:.;:
Calculated C 71.97; H, 11.68. Found C, 68,05; H# 10.81. tydrolyr-r

f, this product, gave the pure tran-alcohol as indicated by gas chroma-


S Two reductions were undertaken with this product. First, 1.1116
grams (2.224 millimnles,. assuming possession of NaBH(OR)3) of the product
was mixed tith 10 miltillters of diglyme and to this heterogeneous

mixture was added 2.224 millinoles of the ketone in solution. After..

24 hours, only slightreduction of the ketone was indicated. No esti-
mate of the isomeric ratio was possible from these quantities of the
alcohols produced in the reduction.

The second reaction attempted consisted of adding 0.7962 grams,

(1.593 millimolea) of the product to 10 milliliters of diglyme in a
tube fitted with a stirrer and sido-arm through which injections could

be made. To this was added 1.593 millimoles of ketone in solution.

After one week, only slight reduction of the ketone was indicated.

One last attempt to achieve the probable situation of the final
reduction step was made by preparing the borate ester Of the alcohol

and adding it to NaH and the ketone JAi a lt:i ratio. Preparation of

the borate ester42 was effected by the reaction of boric acid with

4-t-butylcyclohexanol in toluene solution and the use of a Dean-Stark

trap to allow removal of water from the toluene-water azeotrope. On

achieving approximately the theoretical quantity of water by refluxing

the reaction mixture overnight, the toluene was removed, first by

distillation at atmospheric pressure and finally under vacuum. Cold

acetone, which had been rendered reasonably dry by treatment with CaC12,

anhydrous sodium sulfate and distillation, was then added to the residue

and the mixture was triturated under an atmosphere of dry nitrogen,

washed on the filter with additional cold acetone and dried by low heat

under vacuum. The solid had a m.p. 113-115 degrees.

The 51 per cent NaH-mineral oil dispersion and the borate ester

were carefully weighed by the usual technique of transferring stoppered

tubes in and out of the dry box. The diglyme solution of the ketone

was then added by hypodermic syringe, additional freshly distilled

diglyme being added because the slurry in the tube was too thick for

effective mixing of the materials by shaking. After standing for three

days, with intermittent agitation, the mixtures were worked up for

analysis. A comparison of the peak height ratios of the hydrolysis

product of the borate ester and that of the reduction mixture indicated

no change.

Analysis of the precipitate from a 1:3 NaBH?-ketone reduction mixture

A reduction was carried out in the usual manner involving a 13

mixture of sodium borohydride and ketone respectively. After about two

days reduction time, the precipitate was filtered under nitrogen and the

residue dried by heating under vacuum.

Analysis by titration indicated the H/B was 0.0935. Microanaly-

sis: Calculated C, 71.97; HU 11.68. Found (duplicate analysis)

C, 71.91; Ho 11.76; end C, 72.12; H, 12.09.

P duction of aasnuM borohvdride and the procadre utilized to

introduce it into a reduction mixture

The procedure used for the production of aluminum borohydride is

that of Schlesinger, Brown and Hyde.43 Quantities of materials were

scaled down to 0,1 those used by these investigators in the preparation

described. The design of their vacuum system was modified slightly to

include a line connecting the manifold to the trap train, so that

manometric changes could occur independently of the traps. An outlet

to transfer the aluminum borohydride to a reaction tube and fo cali-

bration purposes was also added* These are illustrated in Figure 2.

Calibration of the system was effected with a bulb of known

volume (212.3 milliliters), fitted with a stopcock and 10/30 s.t.

male joint. The portion of the entire vacuum line defined as the

system was bounded by stopcocks As C, D, P and H (refer to Figure 2).

The procedure was to pump the system down with the bulb stopcockk

closed) connected to the outlet. The manometer reading at this point

was assigned a sero pressure value. After closing stopcock A, the air

in the bulb (at atmospheric pressure PI) was allowed to expand into

the system by opening the bulb stopcock. The manometer was again read

and the pressure differential between this reading and the former

constituted the final pressure P2 within the system. The volume of

the system was then calculated in the following way.


mercury reservoir

Apparatus for the Production and Handling of Aluminum Borohydride






Figure 2.

Atmospheric pressure, P1 758.3 millime cr-

Average pressure differential,. P 369.2 millimeter,

Volume of bulb 212,3 milliliters

Volume of system + bulb: 212.3 x Z8 =c 436.0 milliliters

Volume of system: 436.0 212.3 223.7 milliliters

From this volume, the pressure differential required to put one milli-

mole of-gas into the system was estimated.
P = aRT/V (1x103)(62,360)(299)/ 223.7 = 82.8 millmeters per

mititaoles of gas

The molecular weight of the product was also evaluated by means of

the Duass method. The system was evacuated with the bulb (stopcock

open) attached to the outlet. Stopcock A was closed and the product,

whtch had been previously transferred to U-3, allowed to warm to room

temperature. When a pressure differential of approximately 200 milli-

meters was reached, stopcock B was closed along with the bulb stopcock.

0-3 was recoiled in liquid nitrogen, stopcock B opened and condensation

of the aluminum borohydride back into U-3 allowed to continue until no

further pressure decrease was noted. Then with stopcock E closed, the

bulb (previously tared) was removed with its stopcock closed and weighed

to determine the weight of the material in the bulb by difference. The

molecular weight of the material was then calculated as follows.

Sample weight 0.1532 grams
Pressure differential 201.0 millimeters
Temperature 301 degrees K
)N.W. = (wt.)RT/PW (0.1532)(62.360) (301)/(201.0) (212.3) = 67.38
Value calculated from atomic weights 71~57

A duplicate determination was made and gave a result of 67.37,


Reductions with aluminum borohydride were carried out in 13 x 130
millimeter tubes, sealed at one end and fitted with a stopcoch and

10/30 s.t. male joint at the other. Before placing any materials in

a tube, it was first evacuated ad flushed twice with nitrogen in-

troduced into the system ia stopcock G. Filled with nitrogen under

positive pressure, the tube was removed from the outlet with its

stopcock closed. Diglyme solution, amine, etc., were introduced into

the tube by means of a long hypodermic needle which extended down'm

through the stopcock. This minimized the amount of air present in the

tube. In one run, solid ketone was weighed into the tube before

sealing on the stopeock and diglym added later to give a solution more
concentrated than the stock diglyms solution. The tube was then re-
attached to the outlet and cooled in a dry-ice-acetone bath before

evacuating, so that the materials within wouldn't distill. After
thoroughly evacuating the system and reaction tube, the reaction-tube
stopcock and stopcock A were closed. U*3 was allowed to warm up until

the pressure rose sufficiently to introduce the appropriate amount of
aluminum borohydride into the system (see previous calculation). Wh en

this pressure differential was reached, stopcock B was closed, the

reaction tube placed in liquid nitrogen and its stopcock opened. Con-

densation of aluminum borohydride out of the system into the reaction

tube was allowed to continue until the pressure had been reduced to

its original reading. It was found in practice that exactly the same

original manometer reading was never quite achieved in these condensa-

tibns. If the deficit was as mach as 10 millimeters, more aluinum

borohydride was introduced into the system and condensed into the re-

action tube until the deficiency was made up. The reaction tube

stopcock was then closed, stopcock A opened and the system evacuated

and flushed with nitrogen before closing stopcock E and removing the

reaction tube, which was allowed to come to room temperature. This

precaution was necessary to remove all aluminum borohydride residue

from the system prior to exposing the outlet connecting joint to the

air. The aluminum borohydride explodes spontaneously and burns

rapidly (green, orange flames) on contact with air containing traces

of moisture. Although Brown points this out in his experimnntal dis-

cussion, it wasn't fully appreciated by this author until a small

amount of supposed by-product from the preparation gave more than ample

demonstration of this hazardous property.

The reduction took place over a period of two to three days at

room temperature.

Comparison of the relative volatility of the two isomeric alcohols

Some of the commercially available mixed 4-t-butylcyclohexanols

was sublimed. Pentane solutions of the sublimate, residue and the

starting mixture were analyzed by gas chromatography.

material Avg. pkh ht. ratio % cis-isomar

starting mixture 0.2714 19.3
Sublimate 0.4001 29.9
Residue 0.2977 21.2

These results indicate the c.s-alcohol to be the more volatile of the

two. The fact that the residue appears to contain more cis than the

starting material becomes somewhat difficult to rationalize in the

light of these results. However, the difference is only about 2 per

cent which may be approaching the limits of accuracy for the method of

analysis. This information was of interest in connection with a

possible method of separating the alcohols from the unrencted ketone

in the product prior to analysis.

Preparation of triethylamine-borane

Into triethylamine was bubbled diborane generated by addition of

NaBH4 in diglyme to BF3 etherate, as described previously, Any

unrencted triethylamine was removed by evaporation under vacuum"

Pentane was added to the residue and a solid which formed was filtered

off. This left a clear filtrate which was dried over anhydrous sodium

sulfate. Removal of the pentane under vacuum left an oily residue.

The product was analyzed with KIO3 and Na2S203 solutions for hydride

content and 96 per' cent purity was indicated..

Preparation of Pure g- and Trans-4-t-butylcyclohexanolo

rXrai.4*-t butylcyclohexanol

(1) Preparation of tras-acid phthalate. This procedure was adapted

from that of Winsteein and Holness.32 Into a 250.milliliter flask fitted

uith a reflux condenser was placed 42 grams of the commercial mixture

of the alcohols, 42 grams of phthalic anhydride and 50 milliliters of

reagent grade pyridine. This was heated on the steam bath for five to

six hours. After cooling, the reaction mixture was poured into dilute

HC1 and extracted with ether. The ether extract was washed with dilute

acid and water, dried over anhydrous sodium sulfate and evaporated.

The residue was recrystallized three or four times from pentane to give

crystals melting 146-147 degrees.

'(2) Hydrolysis of _tran-acid phthalate. A 25 gram quantity of the

jtans-acid phthalate was dissolved in a solution of 20 grams of NaOH

in 100 milliliters of water and steam distilled, White clumps of solid

alcohol collected in the condenser which had to be allowed to warm up

periodically to avoid stoppage. The distillate was extracted several
times with pentane, the combined extracts dried over anhydrous sodium

sulfate and the solvent evaporated. The white solid residue had a m.p*

80-81 degrees and checked out satisfactorily as the trans-*alcohol using

gas chromatography.

(1) Preparation of &fn- butylcycloheyl-p*toluenesulfonate. This

procedure was also adapted from that of Winstein and Holness,. Since

that time, a more satisfactory method has been published utilizing the
formation of the 3,5-dinitrobenzoate.35 A solution of 9.60 grams of

the. trans-alcohol, 11I70 grams of p-toluene sulfonyl chloride and 60
milliliters of reagent grade pyridine was allowed to stand overnight

at room temperature. This solution was washed with dilute NatCO3

solution, dried and evaporated.- Recrystallization from pentane gave

98 grams of the tosylate m.p. 89-90 degrees (yield 51 per cent).

(2) Acetolyses 0of the tosylate. This procedure was adapted from that
of Stork and White.40 The entire 9.8 rrams of trans-tosylate was added

to 35 milliliters of glacial acetic acid containing 8 grams of anhydrouc
potassium acetate. This solution was kept on the steam bath for about

24 hours. It was cooled, poured into a liter of cold 10 per cent NaOH

and extracted with ether. The ether extract was dried over anhydrous
sodium sulfate and evaporated, The residue was hydrolyzed by refluxing
with 10 per cent NaOH for several hours and extracted with pentane. The

pentane extract was washed with water, dried and evaporated. The white

solid remaining melted at 81-82 degrees and was shown to be the qA*
alcohol by gas chromatography.

Gas chromatographic analyss ofthe. reduction product

A Perkin-Elmer Model 154*B vapor fractometer, operating at 140

degrees and 25-30 pounds per square inch and utilizing an 18-foot

coiled 1/4 inch copper tube packed with 30-60 mesh Tide detergent

(. and M Scientific Corporation) provided analysis of the reduction

Packing of the column was effected by allowing the correct length

of copper tubing to hang suspended down a stairwell, plugging up the

bottom end with glass wool and pouring in the detergent with sufficient

agitation of the entire tube by tapping until it accommodated no more.

After plugging up the other end, the tube was coiled about a pipe

approximately 2.25 inches o.d., with one end extending down through

the center of the helix whose coils were spread slightly after winding

so as to allow for a more complete heat equilibration during its

operation. Before the column was used for analysis, it was "baked"

in the heating chamber for about 18 hours at a temperature of 180-190

degrees and a helium pressure of 10 pounds per square inch to remove

excess liquid phase from the detergent packing, The liquid phase comes

off initially in a discontinuous fashion, finally leveling off to a

constant flow which continues throughout the operational life of the

column. If not removed prior to the column's use, this initial

effluent causes an erratic pattern of thermistor response which

interferes with the analysis.

The colta was standardized by making up samples of the two

isomeric alcohols of known composition and calculating the ratio of the

the cis peak (which occurs prior to the trang height to the sun of

the cis and trn peak heights for from three to five injections for

each sample, These ratios were averaged. A plot of per cent of cis

isomer versus average peak height ratio was then constructed from this

data, which is as follows.

Co.lumxn er 1 ..... Column twber 2..

% c~g-isomer Avg. pk. he. ratio % cis-isomer Avg. pk. ht. ratio

9.1 0.093 + 0.004

15.1 0.208+0.003

20.6 0.289 + 0.003

28.8 0.385 + 0.006

9.1 0.101 + 0.003

15.1 0.225 + 0.005

19.9 0.295 + 0.000
28.8 0.412 0.004
:! ~ "Z .r!I !H!

It can be seen that the average deviation from the average peak

height ratio ranges from 0.003*6, which is more than 1 per cent in

terms of the actual numbers involved. However, when this deviation is

evaluated in terms of per cent of cjl-isomer, the slope of the standard

curve is such that the error is less than 1 per cent. Therefore, the

analytical method appears to be easily within I per cent error. This

was interesting, for Eliel and Ro35 placed no greater confidence in

their results (measured the &ame way) than + 2 per cent. The gas chroma-

tograph for a typical reduction WAixurae is shown in Figure 3.

It was found that the value of this ratio would change for any

one sample as the absolute height of the peaks changed. Eowveer, when

the tallest peak (usually the .rans was approximately 12 centimeters

high, the ratio became reasonably constant. Therefore, the standard

curve and all analyses taken from it were derived fro ,trans peaks at

Ketone Pentane



ca. 20 minutes retention time

Figure 3. Typical Gas Chromatograph of a Reduction Mixture


least 12 centimetersin height, Tto standard curves are included

because two columns were used in the overall studyy and each gave

slightly different values for the same standard samples. Peak heights

were measured from the base line ineodiately preceeding the peak, even

though this line was seldom the same for the i~d and tRas peaks,

The volume of the injections generally was 0.03-.05 milliliters,

depending on the concentration of the pentane solution containing the

isomeric mixture. In any event, volume sufficient to yield the retired

peak height was always used, trial injections sometimes being necessary

to determine this volume,


1, H. 1. Schlcsinger, H. C. Brown, t al., J, Am. Chem. Soc. J5,
186 (1953).

.2. H. Schlesinger and A. B. Burg, iid. 4321 (1931).

3. H. I. Schlesinger, A. B. Burg, at_*, AidL l 3421 (1940).

4. H. I. Schlesinger, H, C. Brown, Hoekstra and Rapp,bkid. 75,
199 (1953).

SA. A. r. inholt, A. C. Bon ad ad H. 1. Schlesinger, ibid. 69,
1199 (1947).

6. R. F. Nystrom and W. G. Brown, ibid, 9., 1197 (1947).

7. H. C. Brown, H. I* Schlesinger and A. B. Burg, ib.. aj, 673 (1939).
8. H. C. Brown and B. C, Subba Rao, J. Org. Chem. ~., 1135 (1957),

9. D. E. Chaikin and W. G. Brown, J. Am. Chem. Soc. 7fl 122 (1949).

10. Metal Hydrides Inc., BIH4-NaBB4 Brochure.

11. H. C. Brown and B. C. Subba Rao, J. Am. Chem. Soc. 7., 2582 (1956).
12. Park and 0. Fuchs, J. Org. Chem. 21, 1513 (1956).

13. H. C. Brown, E, J. Mead and C,J. hosaf, J. Am. Chem. Soc. 7, 3616

14. J. Kollonitsch, 0. Fuchs and V. Gabor, Nnture 175f 346 (1955).

15. W. Huckel, Ann. 533, 1 (1937).

16. Dostrovsky, Hughes and Ingold, J. Chem. Soc., 173 (1946).

17. L. W. Trevoy and H. G. Brown, J. Am. Chem. Soc. ~j, 1675 (1949).

18. L. M. Jackann, A. K. lncbeth and J. A. Mills, J. Chem. Soc., 2641

19. D. S. Noyce and D.B. Denney, J. Am. Chem. Soc. 72, 5743 (1950).

20. C. W. Shoppee and G. H. R. Summers, J. Chem. Soc., 687 (1950).


21, R. NUce and 0. L, O'Conner, J. Am. Chem. Soc. IJ 5824 (1951).
22. D. J. Cram and F. A. A. Ehbafez, ,d. ,As 5828 (1952).
23. D. H. I. Barton, J. Chem. Soc., 1027 (1953).
24. J. B. Uoland and M. J. Jefraim, J. Am. Chem. Soc. l, 2798 (1956).
25. .Dauben, S ec., Ad. 18, 3752 (1956).
26. W* G. Dauben, 0, J. rFoken and D, S. oycea, ib. Z& 2579 (1956).
27. 4 D. Hardy and R. J. Wicker, bj d. ., 640 (1958).
28. A. H. Beckett, pj jo Tetrahedron 6, 319 (1959).
29. BE L. Eliel and M. H. Rcrick, J. Am. Chem. Soc. 1367 (1960).
30. H. C. Brown, Wheeler and Ichikawa, Tetrahedron 1, 214 (1957).
31. L, P. Hmoaett, Phys. Org. CheMin 331.
32. S. Winstein and N. J. tolness, J. Am. Chem. Soc. 2, 5562 (1955).
33. Hi C. Brown, BE J. Mand and B. C. Subba Bao, ,b. 77 6209 (1955).
34. R. J. Wicker, J. Cham. SoC., 2166 (1956).
35 E. L. Eliel and R. S. So, 3J Am. Chem. Soc. 79, 5992 (1957).
36. H, X. Schlesinger and H. C. Brown, ibid. 2, 3429 (1940).
37, H. C. Brown, H. I. Schlesinger#, S 4,. 75, 192 (1953).
38. H. C. Brown and W. Korytnyk, ibid. 2. 3866 (1960).
39. E. R. Garrett and D. A. Lyttle, ib.d. 6051 (1953).
40. G. Stork and W. N. White, id. 1., 4617 (1956).
41, G. L. Cuniagha3n, U. S. Patent 98,085 (1936),
42. H. Steinberg and D. L. Hunter, ind. Eng. Chem. .j, 174 (1957).
43. H. 1. Schlesinger, H. C. Brown and B. K. Hyde, J. Am. Chem, Soc.
^,i 209 (1953).


Hugh Edward Wise' Jr. was born October::12 1930, at Lafayette,
Indiana. In June, 1948, he was graduated from South Broward High

School, Dania, Florida, Ii Jrie, 1952, he received the degree of

Bachelor of Arts from Vanderbilt University. From 1953 until 1956,

M,. Wise played professional baseball during the sprii and sumer
and attended the Uaiversity of Florida in the fall semester. Since
that time, he has been on campus the year around. After being admitted

to the Graduate School in 1954, he was variously employed on contract

research, as a graduate assistant, teaching assistant, etc., in the
Department of Chemistry until 1960.0 e wtas self-employed during the
final year of his work toward the decree of Doctor of Philosophy.

He is a member of Kappa Sigma social krateinity, Qama Signm
Epsilon honorary chemical fraternity and The American Chemical Society.

This dissertation was prepared under the direction of the

chairman of the candidate's supervisory committee and has been approved

by all members of that committee. It was submitted to the Dean of the

College of Arts and Sciences and to the Graduate Council, and was

approved as partial fulfillment of the requirements for the degree

Doctor of Phiiosophy.

June $S 1961
Dean, College of Arts and Scfences

Dean, Graduate School


Internet Distribution Consent Agreement

1. In reference to the following dissertation:

AUTHOR: Hugh E.Wise, Jr.

TITLE: The stereochemistry of the reduction of an alicyclic unhindered ketone with
some borohydrides and diborane. (record number: 424019)


I, Hugh E. Wise, Jr., as copyright holder for the aforementioned dissertation, hereby grant
specific and limited archive and distribution rights to the Board of Trustees of the University of
Florida and its agents. I authorize the University of Florida to digitize and distribute the
dissertation described above for nonprofit, educational purposes via the Internet or successive

This is a non-exclusive grant of permissions for specific off-line and on-line uses for an
indefinite term. Off-line uses shall be limited to those specifically allowed by "Fair Use" as
prescribed by the terms of United States copyright legislation (cf, Title 17, U.S. Code) as well as
to the maintenance and preservation of a digital archive copy. Digitization allows the University
of Florida or its scanning vendor to generate image- and text-based versions as appropriate and to
provide and enhance access using search software.

This grant of permissions prohibits use of the digitized versions for commercial use or profit.

SignaturFof Copyright Holder

_Hugh E. Wise, Jr.
Printed or Typed Name of Copyright Holder/Licensee

Personal information blurred

Date of Signature

Full Text

xml record header identifier 2009-04-08setSpec [UFDC_OAI_SET]metadata oai_dc:dc xmlns:oai_dc http:www.openarchives.orgOAI2.0oai_dc xmlns:dc http:purl.orgdcelements1.1 xmlns:xsi http:www.w3.org2001XMLSchema-instance xsi:schemaLocation http:www.openarchives.orgOAI2.0oai_dc.xsd dc:title stereochemistry of the reduction of an alicyclic unhindered ketone with some borohydrides and diborane.dc:creator Wise, Hugh Edward,dc:type Bookdc:identifier (alephbibnum)11069292 (oclc)dc:source University of Florida