i

UNIVERSITY OF CALIFORNIA

SANTA CRUZ

THE REDUCING CAPABILITIES OF DIISOBUTYLALUMINUM BOROHYDRIDE

A Thesis submitted in partial satisfaction

of the requirements for the degree of

BACHELORS OF SCIENCE

in

CHEMISTRY

by

Madison Landi

April 2020

The Senior Thesis of Madison Landi is approved:

Professor Bakthan Singaram Date

ii

Acknowledgements

A special thanks to:

My family

Gabriella Amberchan

Kyle Lutz

Bakthan Singaram

iii

Table of Contents

Section Page Number

Abstract 1

Introduction 2

Results and Discussion 9

Conclusion 19

Experimental 20

References 24

Appendix 26

1

Abstract:

In synthetic organic chemistry there is an ongoing quest for modern reagents in the field of

reductions. The Singaram lab has synthesized a binary hydride reducing agent,

diisobutylaluminum borohydride [(iBu)2AlBH4], through a one to one equivalent reaction between

diisobutylaluminum hydride (DIBAL) and borane dimethyl sulfide (BMS). The capabilities of this

borohydride have been shown to reduce nitriles to amines with a 94% yield and esters to alcohols

with a 93% yield. These reactions occur at ambient conditions and are completed in 1 hour.

Products are obtained through simple acid-base extraction and the isolation of the amine and

alcohol are achieved without column chromatography.

2

Introduction:

Metal hydrides are classified as compounds containing a bond between the hydrogen and

the metal. The character of the hydrogen gives metal hydrides their distinctive properties that

place them at the forefront of advanced research and industrial technologies.1 In these

complexes, the hydrogen will act as a nucleophile and will donate its electron pair to an

electrophile, typically referred to as a reduction reaction.2 The reduction of functional groups is

an integral synthetic operation in many total synthesis reactions and there is an ongoing quest for

modern hydride reducing agents as many of them are pyrophoric.

The ability to reduce various functional groups depends on the relative strength of the

hydride. The strength of a hydride can be influenced by the hydride interaction with the solvent,

the polarity between the metal and hydrogen, steric and electronic influence, the development of

acidic reducing agents which could alter the relative reactivities towards functional groups, and

the effect of introducing substituent groups into such acidic reducing agents.3 The standard

reduction mechanism occurs when the hydride anion attacks an electron deficient center of the

functional group, thus transferring a hydrogen atom from the reagent to the compound.4 Herein,

we report the reductive scope of this binary hydride with nitriles, competitive reactions, and

esters.

3

Metal Hydrides

The most common reducing agent, lithium aluminum hydride (LiAlH4) was discovered in

1947 and has powerful reducing capabilities (Scheme 1).5 It can reduce ketones, esters,

carboxylic acids, and amides to generate the corresponding alcohols and amines in great yields.

However, the reagent will react with solvents that contain acidic protons and release flammable

H2 gas, therefore, aqueous and alcohol solvents must be avoided.6 This reagent has proven to be

soluble in many ethereal solutions therefore, tetrahydrofuran and diethyl ether are the preferred

solvents for LiAlH4.7,8 However, organic ethereal solvents are not considered Green solvents and

with increased pressure to move towards more sustainable practices, use of organic solvents

should be reduced. Due to the limitations of LiAlH4 only being soluble in ethereal solvents and

being highly pyrophoric, it is not an ideal reagent for commercial use.

Scheme 1. Reduction with LiAlH4

In the 1940’s NaBH4 found fame after being synthesized by Hermann Schlesinger

(Scheme 2).8 NaBH4 is a nucleophilic reagent and prefers to attack the centers of low electron

density.9 It can reduce ketones and aldehydes to alcohols but cannot reduce carboxylic acids,

esters, or amides; this offers a significant advantage in synthetic applications of

chemoselectivity.10 The weak reactivity is demonstrated in the solvents used in reactions. The

4

most common solvents used for this reagent are methanol or ethanol, while it is relatively

insoluble in ethereal solvents.10 Like LiAlH4, it lacks stability in air and hydrolyzes in water

releasing various borate compounds.10 Additionally, NaBH4 has shown to be unstable and

decomposes in acidic aqueous or neutral solutions.10

Scheme 2. Reduction with NaBH4

Diisobutylaluminum hydride (DIBAL) is an organoaluminum complex that exists as a

dimer that contains hydride ligands.11 Due to the relatively small size of the hydride, they prefer

to bridge to the alkyl groups.12 DIBAL is an electrophilic reducing agent and reacts rapidly with

electron rich compounds. This reagent has the capacity to reduce carboxylic acids, nitriles, and

aldehydes.

Boron Hydrides

Boranes are compounds composed of boron and hydrogen.13 Boron hydrides are

considered electron-deficient molecules because they have more valence orbitals than valence

electrons.14 Diborane (B2H6) is a gas and is highly reactive to air and moisture. It has

demonstrated to be sparingly soluble in ethyl ether, diglyme and hydrocarbon solvents; and

readily dissolves in tetrahydrofuran (THF).3 This molecule is sp3 hybridized with four hybrid

5

orbitals, one of which is empty, which made this structure a subject of considerable study and

speculation.14,3

The first application of hydrides for the reduction of functional groups was done by

Hermann Shclessinger at the University of Chicago in 1939.3 He discovered that when diborane

reacts with compounds containing a carbonyl group there is a rapid addition to the carbonyl

groups of simple aldehydes and ketones to form dialkoxyborines.15 This was the first reducing

method that was efficient for organic chemists around the globe. However, diborane was not

easily synthesized which hindered scientists’ ability to proceed with using this compound.3 The

first method for efficient diborane synthesis was developed in 1912 by Alfred Stock, which

involved the preparation and hydrolysis of magnesium boride. This discovery was followed by

William Lipscomb, Jr who employed the use of boranes to further understand chemical bonding

(Nobel Prize, 1976) and H.C Brown who discovered the famous hydroboration/oxidation

reaction (Nobel Prize, 1979).

Boranes have become increasingly popular in organic synthesis due to their ability to

provide hydride sources for a useful number of chemical transformations.16 One can see boranes,

such as borane:tetrahydrofuran (BH3:THF) used conventionally. This complex can be prepared

by reacting sodium borohydride in diglyme with boron trifluoride etherate and passing the gas as

generated into tetrahydrofuran (Equation 1).3,17 This reagent has shown to be capable of

reducing aldehydes, ketones, epoxides, esters, and carboxylic acids. However, BH3:THF has

adverse characteristics, including low concentration of borane, its high sensitivity to air and

moisture, and the occurrence of unwanted side-reaction to moieties that are vulnerable to attack

by borohydride due to the sodium borohydride that is in the reaction.18 Additionally,

6

this compound is temperature dependent and will decompose to form trialkyl borates if not

stored in cold conditions, making it hard for commercial production of BH3:THF.

3NaBH4, + 4BF3:OEt2 → 4BH3 + 3NaB4-

Equation 1. The synthesis of BH3:THF

An additional borane reagent that is widely used for reductions is borane dimethyl sulfide

(BMS). This reagent is very stable and is highly soluble in most aprotic solvents including

hexane, benzene, toluene, ethyl ether, and others.18 BMS has exhibited the ability to selectively

reduce carboxylic acids preferentially in the presence of nitriles, esters, nitros, and other

functional groups.18 In general, BMS is less reactive than BH3:THF, however, since BH3:THF

degrades easily BMS makes for a better reagent.19

The Singaram Lab has synthesized a binary hydride reducing agent, diisobutylaluminum

borohydride [(iBu)2AlBH4], that is safe, chemoselective, and economical. Diisobutylaluminum

borohydride is synthesized in a one to one reaction of DIBAL and BMS under ambient

conditions (Scheme 3).

Scheme 3. Synthesis of diisobutylaluminum borohydride

7

In a recent publication, the capabilities of this borohydride has been shown to reduce

nitriles to amines and demonstrated chemoselective capabilities with amides, selectively

reducing tertiary amides. The isolation of the reduced product can be completed in 1 hour and

requires no column chromatography to isolate the amine.

Application of the Reductions of Nitriles and Esters

The reduction of nitriles to yield primary amines is a fundamental process in synthetic

organic chemistry.20 The properties of amines are largely controlled by the electronic

characteristics of the electron pair on the central nitrogen atom, which allows it to act as Lewis

Base. The ability of the nitrogen atom to donate its lone pair of electrons in chemical reactions is

modified by the presence of the functional groups bonded to the nitrogen atom that can increase

or decrease this ability.21 Primary amines are ubiquitous in chemistry: as building blocks of

proteins, drug molecules, agrochemicals and dyes.22 Due to their high density of structural

information and inherent ability for hydrogen bonding, the synthesis of amines is heavily sought

out.23

8

Figure 1. Examples of amines that are being used in a clinical setting.

Reduction of esters to the corresponding alcohol is an important process in organic

chemistry. Despite the number of reagents available for efficient ester reduction, very few are

suitable for this transformation.24 A frequent synthetic route used is through the reduction of

esters in which the nucleophilic hydrogen from the hydride reagent will attack the electrophilic

carbon in the polar carbonyl group of the ester, creating a tetrahedral metal alkoxide

intermediate. The alcohol on the ester will act as a leaving group and form an aldehyde

intermediate. Finally, the complex will undergo nucleophilic addition to generate a primary

alcohol. Industrially, the most important alcohols are ethanol which is used in alcoholic

beverages, and the fatty alcohols which are used for detergents.25

9

Results and Discussion:

It is noteworthy to first look at the facile synthesis of our reducing agent,

diisobutylaluminum borohydride. On a quest for a binary hydride reagent we investigated the

reaction between BMS and DIBAL. In a 1:1 synthesis, BMS and DIBAL were combined and

analyzed via 11B NMR. Analysis of the 11B NMR’s chemical shifts allows us to determine what

type of boron species is present and use of the splitting pattern aids in calculating the number of

hydrogens present, 11B NMR follows the n+1 rule. Unfortunately, aluminum NMR is not a useful

tool except to show that aluminum is in fact present, so we only used 11B NMR to study the

binary hydride. We hypothesize that the hydrogen from DIBAL is donated into the empty p-

orbital of the boron in BMS to generate the reducing agent. When BMS and DIBAL are

combined, the 11B NMR spectra analysis shows a quintet at -36ppm ( J=87 Hz), which is in a

region typically occupied by borohydride species (Scheme 4). The splitting pattern of the

hydride is a quintet, indicative of a BH4-like structure. It is significant to note that the 11B NMR

spectra analysis of BMS shows a quintet at -20ppm ( J=103 Hz). The BMS peak is present when

the BMS and DIBAL are not combined in a one to one fashion. The combination of the

multiplicity and chemical shift led us to conclude that [(iBu)2AlBH4] is formed with the

hydrogen transferring from DIBAL to BMS to generate our novel borohydride compound. While

DIBAL and BMS are both Lewis acids, BMS is a stronger Lewis acid and accepts a hydride

from DIBAL, which is the weaker Lewis acid of the two reagents.26

10

Scheme 4. 11B NMR of [(iBu)2AlBH4]

Nitriles

A variety of methods are available for the synthesis of amines. Gabriel synthesis is the

typical mechanistic model that is employed to generate an amine. However, this method requires

extensive substrate preparation and is not atom economical. Boranes will reduce nitriles to

amines, however, this process is not efficient.27 Bulky and mild regents such as DIBAL will

reduce nitriles to an imine intermediate but upon an aqueous work up it will hydrolyze to give an

11

aldehyde (Table 1). Our reagent, [(iBu)2AlBH4], can reduce nitriles to primary amines in one

hour with a simple 1:1 equivalence of substrate to hydride at room temperature (Scheme 5).

Scheme 5. Reaction of nitrile and [(iBu)2AlBH4] to amine

To explore the reductive potential of our metal hydride compared to its parent hydrides,

we reacted it with benzonitrile for an hour with each hydride and compared the results (Table 1).

Benzonitrile when reacted with BMS for 0.25 hours produced benzylamine in 72% yield,

although the reaction needs to be refluxed in order to remove the methyl sulfide the reaction

would require longer reaction times as the methyl sulfide interferes with the reduction reaction.

When the same substrate reacted with DIBAL an aldehyde was formed as opposed to the desired

amine. [(iBu)2AlBH4] reduced benzonitrile at room temperature to generate the benzylamine in

good yields (68%, Table 1).

12

Table 1. Reduction of benzonitrile via BMS, DIBAL, and [(iBu)2AlBH4] Entry Hydride Time/Temp Yield (%)

1 BMS 0.25 hr/reflux

72%

2 DIBAL Time / 0 ℃ 5 hr/ -40 ℃

90% 50%

3 [(iBu)2AlBH4] 1 hr/ 25 ℃

68%

After examining how [(iBu)2AlBH4] performs with a nitrile, it was tested with more

nitriles to better understand its abilities. As shown in Table 2, [(iBu)2AlBH4] reacted with various

nitrile substrates and produced amines in high yields. In entry 1, 4-cyanotoluene was easily

reduced to the corresponding benzylamine with a high yield (94%). Regardless of

regiochemistry, halogens were tolerated by [(iBu)2AlBH4] and no de-halogenation occurred

(entries 2-5). Additionally, tri-substituted aryl nitriles were able to be reduced to the

corresponding benzyl amine (entry 3-5). However, for entries 4 and 5, we observed a low yield

likely due to steric interference by the halogens in the ortho positions. The steric hindrance of the

tri-substituted arenes overrides the increase in electrophilicity on the nitrile carbon, leading to a

decrease in reactivity. When in the presence of an electron withdrawing group such as a nitro

group, [(iBu)2AlBH4] proves to be a selective reagent reducing the nitrile to the amine with a very

13

high yield (98%, entry 7). The compound also demonstrated the ability to reduce more complex

nitriles such as 4-(4-methyl-5-thiazolyl)benzonitrile and isolated in high yields (90%, entry 8).

Table 2. Reduction of aromatic nitriles to amines using [(iBu)2AlBH4] Entry Substrate Yield Entry Substrate Yield

1

94% 5

16%

2

72% 6

47%

3

94% 7

98%

4

27% 8

90%

14

Esters

Scheme 6. [(iBu)2AlBH4] reduction of Esters (74% yield)

Historically, sodium borohydride and BMS have been too slow for the reduction of

carboxylic esters.2,28 Our reagent, [(iBu)2AlBH4] can efficiently reduce esters to the primary

alcohol, even in the presence of a variety of substituents on the aromatic ring (Scheme 6). As

expected, methyl 2-bromobenzoate and 4-(bromomethyl)benzoic acid methyl ester were reduced

to 2-bromobenzyl alcohol and 4-(bromomethyl)benzyl alcohol and isolated in 93% and 84%

yields respectively. These reductions were followed by NMR analysis and proven to be

complete.

Table 3. [(iBu)2AlBH4] reduction of representative esters.

Entry Substrate Yield

1

93%

2

84%

3

68%

15

Competitive Reactions

Chemoselectivity is highly desired amongst synthetic organic chemists. Efforts to

synthesize natural products often become case studies in the art and science of chemoselective

control.29 A reagent has a high chemoselectivity if the reactions occur with only a limited number

for different functional groups.30 To explore the chemoselective reducing capabilities of

[(iBu)2AlBH4], we ran a competitive reaction between 2,4-dichloro-benzonitrile and N,N-

diethyl-m-toluamide (Scheme 7). The reaction was monitored through infrared spectroscopy,

where after five minutes there was no presence of the corresponding nitrile peak. The ratio of the

products was calculated through NMR analysis.

Scheme 7. Competitive Reduction of 2,4-dichloro-benzonitrile and N,N-diethyl-m-toluamide with [(iBu)2AlBH4]

Temperature (°C) Yield (%) of C Yield % of D

0b 73 27

-5c 86 14

-15d 100 0

Yield based upon 1H NMR analysis. bIce bath. cNaCl and ice bath. dAcetone and dry ice bath.

16

To understand the chemoselectivity of our reagent we explored the kinetics by running

the reaction at different temperatures. At room temperature, the nitrile was preferred in a roughly

70:30 ratio and as the temperature was sequentially lowered it showed greater preference to

reducing the nitrile instead of the amide. The reaction was placed in an NaCl ice bath and cooled

to -5°C which yielded mixed products preferring the nitrile in a 86:14 ratio. When cooled to -

15°C using an acetone and dry ice bath, the nitrile was preferred in 100:0 ratio, demonstrating we

are able to thermodynamically control which functional group the hydride would interact with.

Furthermore, we wanted to study the reaction when both the amide and the nitrile shared

the same functional group. We ran a competitive reaction between 4-tolunitrile and N,N-diethyl-

m- toluamide. At room temperature, the amine to product ratio was 50:50. The reaction was

placed in an ice bath and the temperature was lowered to 0oC which yielded mixed products

preferring the amide in a 70:30 ratio.

17

Scheme 8. Competitive reaction of 4-tolunitrile and N,N-diethyl-m-toluamide

Temperature (°C) Yield (%) of E Yield % of F

25 45 55

0b 30 70

Yield based upon 1H NMR analysis. bIce bath.

To examine the characteristics of [(iBu)2AlBH4] with two weak electron withdrawing

substrates we ran a competitive reaction with 4-chloro benzonitrile and N,N-diethyl-m-

toluamide. At room temperature the amide was favored in 67:33 ratio. We then ran the reaction

in an ice bath and lowered the temperature to 0°C which also favored the amide in a 65:35 ratio.

18

Scheme 9. Competitive reaction of 4-chloro benzonitrile and N,N-diethyl-m-toluamide

Temperature (°C) Yield (%) of G Yield % of H

25 33 67

0 35 65

19

Conclusion

In summary, a new binary hydride reducing agent has been synthesized. The synthesis of

the reagent, diisobutylaluminum borohydride [(iBu)2AlBH4] is completed through a one to one

equivalent synthesis of diisobutylaluminum hydride (DIBAL) and borane dimethyl

sulfide(BMS). Overall, our findings illustrate that [(iBu)2AlBH4] is capable of reducing nitriles to

amines, esters to alcohols, and it can chemoselectively reduce nitriles when in the presence of

amides. These reactions are completed under ambient conditions, with short reaction times, and

no column chromatography was utilized to isolate the final product. Our final products were

confirmed via 1H NMR and 11B NMR. Future work will look into [(iBu)2AlBH4] reducing

capabilities when multiple functionalities are present on the compound in addition to continuing

to examine various functional groups.

20

Experimental

General Information. NMR spectra were recorded on Bruker 500 MHz at 297K. Chemical

shifts in ppm are referenced to the signal of the solvent (CDCl3, δH = 7.26). Coupling constants J

are given in Hz and signal multiplicities are abbreviated as s (singlet), d (doublet), t (triplet), m

(multiplet), and br (broad). All reagents were purchased from Sigma-Aldrich. THF was dried by

refluxing it with Na° and benzophenone.

Synthesis of Snelling Salt. In an argon-purged 100mL round bottom flask, BMS (0.474mL, 5

mmol, 1 equiv) and DIBAL (1M in toluene, 5 mL, 5 mmol, 1 equiv) were combined. The reaction

mixture was allowed to stir for 1 hour at room temperature. The Snelling Salt (1M) was used

without purification.

General Procedure for the Reduction of Esters using Snelling Salt.

1H NMR (500 MHz, Chloroform-d) δ 7.39 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 4.70 (s,

2H), 4.50 (s, 2H), 1.67 (s, 1H)

BrOH

21

1H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.34 (t, J

= 7.5 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 4.76 (s, 2H), 1.69 (bs, 1H)

General Procedure for the Reduction of Nitriles using Snelling Salt.

4-Methylbenzylamine

1H NMR (CDCl3, 500 MHz): δ 7.22 (d, J = 7.8Hz, 2H), 7.16 (d, J = 7.9Hz 2H), 3.83 (s, 2H), 2.35

(s, 3H), 1.36 (bs, 2H). 11B NMR (coupled, 500 MHz): δ -0.95, -18 (quartet), -36 (quintet). 13C

NMR (CDCl3, 500 MHz): δ 1405, 136.3, 129.2, 128.1, 46.2, 21.1. IR (film): = 3384, 2924, 1514,

1459, 802 cm-1.

3-Bromobenzyl amine

1H NMR (500 MHz, Chloroform-d) δ 7.46 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.6 Hz,

1H), 7.18 (d, J = 7.7 Hz, 1H), 3.83 (s, 2H), 1.42 (bs, 2H). 13C NMR (500 MHz, Chloroform-d) δ

162.59, 145.61, 130.15, 130.08, 129.81, 125.66, 122.61, 64.33, 52.50, 45.91, 22.35.

OH

Br

22

2,4-Dichlorobenzyl amine

1H NMR (500 MHz, Chloroform-d) δ 7.27 – 7.22 (m, 2H), 7.13 (dd, J = 8.3, 2.1 Hz, 1H), 3.80 (s,

2H), 1.40 (bs, 2H). 11B NMR (coupled, 500 MHz): δ -0.2.66, -18 (quartet), -36 (quintet). IR (neat):

= 3375, 3300, 3091, 2927, 2851, 1589, 1561, 1472, 1388, 1099, 1048, 867, 817, 735, 712, 696,

649 cm-1. 13C NMR (500 MHz, Chloroform-d) δ 158.82, 139.17, 133.93, 133.12, 129.70, 129.28,

127.28, 61.52, 49.96, 43.91.

2,6 Dichlorobenzyl amine

1H NMR (500 MHz, Chloroform-d) δ 7.21 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.9 Hz, 1H), 4.02 (s,

2H), 1.75 (bs, 2H). 11B NMR (coupled, 500 MHz): δ 40, -2, -5, -12, -18 (quartet), -36 (quintet).

13C NMR (500 MHz, Chloroform-d) δ 138.71, 135.11, 128.59, 128.41, 41.92.

2-Chloro-6-fluorobenzyl amine

1H NMR (500 MHz, Chloroform-d) δ 7.16 (hept, J = 2.8, 2.4 Hz, 2H), 7.00 – 6.96 (m, 1H), 3.99

(d, J = 1.9 Hz, 2H), 1.55 (bs, 2H). 13C NMR (500 MHz, Chloroform-d) δ 129.03, 128.89, 125.43,

114.39, 114.17, 113.98, 43.76 (d, J = 3.4 Hz), 37.29.

23

4-Methoxyphenethyl amine

1H NMR (500 MHz, Chloroform-d) δ 7.12 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 3.79 (s,

3H), 2.93 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 1.02 (bs, 2H). 13C NMR (500 MHz,

Chloroform-d) δ 158.05, 131.89, 129.72, 113.88, 55.23, 43.68, 39.18.

4-Nitrobenzyl amine

1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.01 (s,

2H), 1.53 (bs, 2H).11B NMR (coupled, 500 MHz)3: δ 2, -2, -12, -18 (quartet), -36 (quintet). 11B

NMR (decoupled, 500 MHz): δ -3, -12, -19, -22, -37. 13C NMR (500 MHz, Chloroform-d) δ

147.46, 128.63, 123.73, 115.06, 52.45.

24

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13. Schubert, D; Boron Hydrides, Heteroboranes, and their Metalla Derivatives; John Wiley

& Sons: New York, 2002.

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25

15. Brown, H.C; Schlesinger, H. I.; Burg, A; J. AM. Chem. Soc. 1939, 61, 673-680.

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26

Appendix

Compound Page

4-methylbenzylamine 26

3-Bromobenzyl amine 29

2,4-Dichlorobenzyl amine 31

2,6-Dichlorobenzyl amine 34

2-Chloro-6-fluorobenzyl amine 37

4-Methoxyphenethyl amine 39

4-Nitrobenzyl amine 42

4-Bromomethyl benzyl alcohol 45

2-Bromobenzyl alcohol 47

Competitive Reaction Products: Dichlorobenzyl amine and N,N-diethyl-3-

methylbenzamine

49

Competitive Reaction Products: 4-methylbenzyl amine and N,N-diethyl-3-

methylbenzamine

53

Competitive Reaction Products: 4-chlorobenzyl amine and N,N-diethyl-3-

methylbenzamine

55

27

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-5000

05000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

70000

75000

80000

1.90

3.01

2.00

2.032.00

1.36

2.35

3.83

7.157.167.207.22

28

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

-500

0500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

15.3021.0722.32

46.24

52.83

64.91

127.03127.97128.11129.06129.21136.32137.39140.46

161.48

29

-90

-80

-70

-60

-50

-40

-30

-20

-10

010

2030

40

5060

7080

90

f1(ppm)

-20

-10

0102030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

220

230

-36.87-36.32

-19.47

-2.84-1.19

30

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

-200

0200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

22.35

45.91

52.50

64.33

122.61125.66129.81130.08130.15

145.61

162.59

31

-90

-80

-70

-60

-50

-40

-30

-20

-10

010

2030

40

5060

7080

90

100

f1(ppm)

-200

0200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

3400

-37.39-36.86-36.34-35.81-35.69-35.28

-19.69-19.03-18.36-17.70-12.42-11.56

-2.01-0.312.20

37.73

48.3449.98

32

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

02000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

2.00

2.00

1.032.00

1.40

3.753.80

7.127.127.137.147.227.247.267.26

33

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

-100

0100

200

300

400

500

600

700

800

900

1000

1100

43.91

49.96

61.52

127.28129.28129.70133.12133.93139.17

158.82

34

-90

-80

-70

-60

-50

-40

-30

-20

-10

010

2030

40

5060

7080

90

100

f1(ppm)

-400

-200

0200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

3400

3600

-37.56-37.04-36.51-35.99-35.46

-20.09-19.43-18.77-18.10

-2.66

35

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-5000

05000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

2.00

2.00

1.021.99

1.75

4.02

7.027.047.057.077.217.22

36

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

-200

0200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

3400

3600

3800

4000

41.92

128.41128.59135.11138.71

37

-90

-80

-70

-60

-50

-40

-30

-20

-10

010

2030

40

5060

7080

90

100

f1(ppm)

-500

0500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

-37.65-37.12-36.60-36.07-35.87-35.54

-19.96-19.30-18.64-17.97-12.31

-5.12-2.38

40.32

38

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

05000

10000

15000

20000

25000

30000

35000

40000

45000

50000

2.01

1.97

1.002.01

1.55

3.983.99

6.966.966.986.986.997.007.137.147.157.167.167.177.187.18

39

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

-100

0100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

37.2943.7443.77

113.98114.17114.39

125.43128.89129.03

40

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

-1000

01000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

21000

22000

23000

2.00

2.031.98

2.99

2.002.00

1.02

2.682.692.702.922.932.943.79

6.846.867.117.13

41

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

0500

1000

1500

2000

2500

3000

3500

39.1843.68

55.23

113.88

129.72131.89

158.05

42

-90

-80

-70

-60

-50

-40

-30

-20

-10

010

2030

40

5060

7080

90

100

f1(ppm)

-1000

01000

2000

3000

4000

5000

6000

7000

8000

9000

10000

-37.34-36.81-36.29-35.76-35.24

-19.67-19.01-18.34-17.68-11.85

43

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-1000

01000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

2.00

2.00

2.00

2.01

1.53

3.934.01

7.497.517.537.558.188.20

44

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

-100

0100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

52.45

115.06

123.73

128.63

147.46

45

-90

-80

-70

-60

-50

-40

-30

-20

-10

010

2030

40

5060

7080

90

100

f1(ppm)

-200

0200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

-37.66-37.13-36.61-36.08-35.55

-19.97-19.30-18.64-17.97-11.65

-1.76

37.31

48.66

46

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

-1000

01000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

21000

22000

1.03

2.002.00

2.002.00

1.67

4.504.70

7.347.357.397.40

Br

OH

47

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

-20

02040

60

80

100

120

140

160

180

200

220

240

260

280

33.22

64.93

127.33129.27

137.20141.18

Br

OH

48

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

01000

2000

3000

4000

5000

6000

7000

8000

9000

10000

1.00

2.00

1.021.031.011.00

1.69

4.76

7.167.177.197.327.347.357.487.507.547.56

OH

Br

49

-10

010

2030

40

5060

7080

90

100

110

120

130

140

150

160

170

180

190

200

210

f1(ppm)

050100

150

200

250

300

350

400

65.13

122.60127.66128.94129.14132.61139.73

OH

Br

50

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

02000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000

2.08

2.00

1.021.38

0.662.00

0.340.360.350.381.031.001.00

1.031.041.051.47

2.342.502.512.532.543.523.90

7.037.057.117.127.157.177.187.207.227.247.327.347.367.37

51

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

02000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

0.99

0.490.66

0.331.95

0.170.250.190.171.031.001.01

1.021.041.051.191.201.221.672.332.342.492.512.522.543.523.907.037.057.067.087.107.127.137.157.177.187.207.227.227.237.247.327.337.367.37

52

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

02000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000

40000

0.69

0.340.46

0.202.00

1.031.001.00

1.021.041.051.442.042.052.332.492.502.522.533.523.89

4.587.037.047.107.117.147.177.187.217.227.227.237.237.317.337.367.367.857.867.877.87

0oC

53

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-1000

01000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

6.00

3.062.584.00

2.001.810.88

1.009.45

0.940.950.971.101.111.132.242.242.412.422.442.453.363.373.383.433.663.673.716.946.957.027.037.047.067.087.087.097.107.127.13

CNO

N

CH3

AlB

H4

N

CH3

1 eq

uiv

1 eq

uiv

THF

1 hr

2 eq

uiv

H3C

H3C

NH2

FE

54

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

02000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000

40000

6.00

0.85

2.573.004.01

2.000.860.62

1.007.01

0.940.960.971.562.242.252.412.432.442.463.443.673.72

6.946.967.027.047.057.057.077.087.107.117.127.137.14

CNO

N

CH3

AlB

H4

N

CH3

1 eq

uiv

1 eq

uiv

THF

1 hr

2 eq

uiv

H3C

H3C

NH2

FE

0oC

55

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

-2000

02000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

6.00

3.014.02

1.981.031.48

0.941.091.350.482.014.02

0.930.940.961.532.242.402.412.432.443.423.633.643.653.71

6.936.947.017.037.067.077.087.107.117.137.167.177.177.19

CNO

N

CH3

AlB

H4

N

CH3

1 eq

uiv

1 eq

uiv

THF

1 hr

2 eq

uiv

ClCl

NH2

HG

56

-3-2

-10

12

34

56

78

910

1112

1314

1516

f1(ppm)

05000

10000

15000

20000

25000

30000

35000

6.00

1.13

2.944.00

1.961.300.490.61

0.928.01

1.011.031.042.322.482.502.512.533.513.723.723.743.81

7.017.037.097.117.147.157.177.187.217.227.247.287.417.437.547.55

CNO

N

CH3

AlB

H4

N

CH3

1 eq

uiv

1 eq

uiv

THF

1 hr

2 eq

uiv

ClCl

NH2

HG